Clinical trial NCT01101438
Conditions: Breast Cancer
Keywords: stage I breast cancer stage II breast cancer stage IIIA breast cancer stage IIIC breast cancer male breast cancer HER2-negative breast cancer estrogen receptor-positive breast cancer HER2-positive breast cancer progesterone receptor-positive breast cancer
Sponsor: Canadian Cancer Trials Group
Start date: 2010-08-13; Completion date: 2023-08-18
Enrollment: 3649 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is looking at whether Metformin, an agent that is commonly used to treat diabetes, can decrease or affect the ability of breast cancer cells to grow and whether Metformin will work with other therapies to keep cancer from recurring. Health Canada has not approved the sale or use of Metformin to treat breast cancer, although they have approved its use in this clinical trial. Although Metformin is approved by the FDA for the treatment of diabetes, its use in breast cancer is considered investigational.

Detailed description:
This is a multicenter study. Patients are stratified according to hormone-receptor status (estrogen receptor- and/or progesterone receptor- positive vs both receptors negative), body mass index (≤ 30 vs \> 30 kg/m²), HER2 status (positive vs negative), and prior chemotherapy (any vs none). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral metformin hydrochloride twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive oral placebo twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

Blood and tumor samples are collected periodically for correlative studies.

Patients may complete quality-of-life, physical activity, and diet questionnaires at baseline and at 6, 12, 24, 36, 48, and 60 months. (Sub-set of patients).

After completion of study treatment, patients are followed annually.

Arms: arm 1: Patients receive oral metformin hydrochloride twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in receptor positive (ER and/or PgR positive) subjects in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive oral placebo twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in receptor positive (ER and/or PgR positive) subjects in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: metformin hydrochloride intervention 2: placebo
Intervention descriptions: intervention 1: Given orally intervention 2: Given orally

Protocol documents:
Prot_000.pdf: 
 
PROTOCOL AMENDMENT #5: 2021-APR-01 
 
NCIC CTG TRIAL: MA.32 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
NCI U.S. RE-SUBMISSION 
 
HEALTH CANADA SUBMISSION: 2010-APR-09 
 
AMENDMENT #1: 2011-AUG-15 
 
ADMINISTRATIVE UPDATE #1: 2011-DEC-19 
 
AMENDMENT #2: 2012-FEB-20 
 
AMENDMENT #3: 2015-JAN-15 
 
AMENDMENT #4: 2016-FEB-04 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE III RANDOMIZED TRIAL OF METFORMIN VERSUS PLACEBO  
ON RECURRENCE AND SURVIVAL IN EARLY STAGE BREAST CANCER 
 
NCIC CTG Protocol Number: MA.32 
Participating NCTN Groups: The Alliance, ECOG-ACRIN, NRG, SWOG  
Other Participating Groups: IBCSG, NCRI-BCSG - ICR- CTSU 
 
 
STUDY CHAIR: 
Pamela J. Goodwin 
 
 
TRIAL COMMITTEE: 
Karen Gelmon, Kathleen Pritchard, 
 
 
Timothy Whelan, Lois Shepherd, 
 
 
Jennifer Ligibel, Dawn Hershman, 
 
 
Ingrid Mayer, Timothy Hobday, 
 
 
Priya Rastogi, Dan Rea, Alastair Thompson, 
 
 
Judith Bliss, Manuela Rabaglio 
 
 
SENIOR INVESTIGATOR: 
Wendy Parulekar 
 
 
BIOSTATISTICIAN: 
Bingshu Chen 
 
 
QUALITY OF LIFE COORDINATOR: 
Julie Lemieux 
 
 
CORRELATIVE SCIENCE CHAIR: 
Vuk Stambolic 
 
 
STUDY COORDINATOR: 
Paul Stos 
 
 
SPONSOR: 
CCTG 
 
Metformin (NSC 91485) and Placebo provided by a generous donation from Apotex 
 
(For contact information of study personnel see Final Page.) 
 
 


 
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This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Institutions not aligned with CCTG will participate through the CTSU mechanism as outlined below and 
detailed in the CTSU logistical appendix. 
 
*The study protocol and all related forms and documents must be downloaded from the protocol-specific 
Web page of the CTSU Member Web site located at https://www.ctsu.org 
 
 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
Logistical Appendix for specific instructions and documents to be submitted. 
 
Patient enrollments will be done through the CCTG by means of a web-based Electronic Data 
Capture (EDC) System. Refer to the logistical appendix for specific instructions. 
 
Data management will be performed by the CCTG by means of a web-based Electronic Data Capture 
(EDC) System. Electronic case report forms must be submitted through the EDC system; clinical 
reports and supporting documentation may be submitted through the EDC system or sent by mail to 
CCTG unless otherwise directed by the protocol. Do not send study data or case report forms to the 
CTSU Data Operations.  
 
Data query and delinquency reports will be sent directly to the enrolling site by CCTG. Please send 
query response and delinquent data to CCTG and do not copy the CTSU Data Operations. Please 
note that data queries are both issued and should be responded to directly within the EDC system. 
 
Each site should have a designated CTSU Administrator and Data Administrator and must keep their 
CTEP IAM Account contact information current. This will ensure timely communication between 
the clinical site and the CCTG data center.  
 
 
Participating NCTN Groups 
 
Group Name 
Group Co-Chair 
 
The Alliance 
Dr. Jennifer Ligibel 
 
Dana Farber Cancer Institute 
 
44 Binney St. Dana 1210 
 
Boston, MA  02115 
 
Phone: (617) 632-3428 
 
jligibel@partners.org 
 
ECOG-ACRIN 
Dr. Ingrid Mayer 
 
Vanderbilt University Medical Center 
 
Hematology/Oncology 
 
777 Preston Research Building 
 
2220 Pierce Avenue 
 
Nashville TN  37232-6307 
 
Phone: (615) 936-3524 Fax: (615) 343-7602 
 
Ingrid.mayer@vanderbilt.edu 
 
 
 


 
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Participating NCT0N Groups continued: 
 
SWOG 
Dr. Dawn Hershman 
 
Herbert Irving Cancer Center 
 
Columbia University 
 
161 Fort Washington – 1068 
 
New York, NY, USA 10032 
 
Phone: 212-305-1945 
Fax: 212-305-1078 
 
dlh23@columbia.edu 
 
NRG 
Dr. Priya Rastogi 
 
NSABP Foundation , Inc. 
 
Four Alleghency Center – 5th Floor 
 
Pittsburgh, PA, USA 15212-5234 
 
Phone: 412-330-4600 
Fax: 412-330-4660 
 
rastogip@upmc.edu 
 
Other Participating Groups: 
NCRI-BCSG - ICR-CTSU 
Dr. Dan Rea / 
Partnership 
Professor Judith Bliss 
 
The Institute of Cancer Research – Clinical Trials and Statistics Unit 
 
Institute of Cancer Research, Division of Clinical Studies 
 
Sir Richard Doll Building 
 
Cotswold Road,  
 
Sutton, Surrey 
 
SM2 5NG 
 
Phone: +44 (0)208 722 4054 
 
 d.w.rea@bham.ac.uk 
 
Judith.bliss@icr.ac.uk 
 
IBCSG 
Dr. Manuela Rabaglio 
 
IBCSG Coordinating Center 
 
Effingerstrasse 40 
 
3008 Bern, Switzerland 
 
Tel: +41 44 387 2550 
 
Fax: +41 44 387 2551 
 
manuela.rabaglio@ibcsg.org 
 
Document History  
 
Modification 
Version Date 
Amendment #5 
2021-Apr-01 
Amendment #4 
2016-Feb-04 
Amendment #3 
2015-Jan-15 
Amendment #2 
2012-Feb-20 
Administrative Update #1 
2011-Dec-19 
Amendment #1 
2011-Aug-15 
Initial (Activation) 
2010-Apr-09 


 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE.................................................................................................... 1 
 
TREATMENT SCHEMA ............................................................................................................................................ 2 
 
1.0 
OBJECTIVES................................................................................................................................................. 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE .......................................................................... 4 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION.............................................................................. 17 
3.1 
Name and Chemical Information ................................................................................................................ 17 
3.2 
Chemical Structure ....................................................................................................................................... 17 
3.3 
Mechanism of Action ................................................................................................................................... 17 
3.4 
Toxicology .................................................................................................................................................... 18 
3.5 
Phase I & II Trials ........................................................................................................................................ 19 
3.6 
Adverse Effects ............................................................................................................................................ 19 
3.7 
Pharmaceutical Data..................................................................................................................................... 19 
 
4.0 
TRIAL DESIGN........................................................................................................................................... 21 
4.1 
Stratification ................................................................................................................................................. 21 
4.2 
Randomization .............................................................................................................................................. 21 
4.3 
Inclusion of Women and Minorities ........................................................................................................... 22 
 
5.0 
STUDY POPULATION .............................................................................................................................. 23 
5.1 
Eligibility Criteria ........................................................................................................................................ 23 
5.2 
Ineligibility Criteria...................................................................................................................................... 26 
 
6.0 
PRE-TREATMENT EVALUATION......................................................................................................... 28 
 
7.0 
ENTRY/RANDOMIZATION PROCEDURES ........................................................................................ 29 
7.1 
Randomization .............................................................................................................................................. 29 
7.2 
Stratification ................................................................................................................................................. 30 
 
8.0 
TREATMENT PLAN .................................................................................................................................. 31 
8.1 
Study Treatment Plan ................................................................................................................................... 31 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT................................................. 37 
9.1 
Evaluation During Protocol Treatment....................................................................................................... 37 
9.2 
Evaluation After Protocol Treatment .......................................................................................................... 38 
 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ............................................................ 40 
10.1 
Definitions of Evaluability .......................................................................................................................... 40 
10.2 
Criteria for Measurement of Study Endpoints ........................................................................................... 40 
10.3 
Evidence of Disease Recurrence/Progression ............................................................................................ 41 
10.4 
Dating of First Recurrence .......................................................................................................................... 42 
10.5 
Management Following Recurrence ........................................................................................................... 42 
10.6 
Contralateral Breast Carcinoma – Invasive and in situ ............................................................................. 42 
10.7 
Second Malignancy ...................................................................................................................................... 42 
 
 


 
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11.0 
SERIOUS ADVERSE EVENT REPORTING .......................................................................................... 43 
11.1 
Definition of a Reportable Serious Adverse Event.................................................................................... 43 
11.2 
Serious Adverse Event Reporting Instructions .......................................................................................... 43 
11.3 
Reporting Malignancies or Myeloid Dysplasia ......................................................................................... 44 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada (Office of Clinical 
Trials) ............................................................................................................................................................ 46 
11.5 
CCTG Reporting Responsibility to Apotex ............................................................................................... 46 
11.6 
Reporting Safety Reports to Local Research Ethics Boards ..................................................................... 46 
 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............. 47 
12.1 
Criteria for Discontinuing Protocol Treatment .......................................................................................... 47 
12.2 
Therapy After Protocol Treatment is Stopped ........................................................................................... 47 
12.3 
Follow-up Off Protocol Treatment ............................................................................................................. 47 
 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ................................................. 48 
13.1 
Central Pathology Review ........................................................................................................................... 48 
13.2 
Tissue Collection .......................................................................................................................................... 48 
13.3 
MA.32 Use of Tumour Blocks .................................................................................................................... 48 
13.4 
Blood Collection and Analysis .................................................................................................................... 49 
13.5 
MA.32 Use of Blood Samples..................................................................................................................... 50 
13.6 
Central Data Review .................................................................................................................................... 51 
 
14.0 
STATISTICAL CONSIDERATIONS ....................................................................................................... 52 
14.1 
Objectives and Design ................................................................................................................................. 52 
14.2 
Primary Endpoints and Analysis ................................................................................................................. 52 
14.3 
Sample Size and Duration of Study ............................................................................................................ 53 
14.4 
Safety Monitoring ........................................................................................................................................ 54 
14.5 
Interim Analysis ........................................................................................................................................... 54 
14.6 
Quality Of Life Analysis.............................................................................................................................. 55 
 
15.0 
PUBLICATION POLICY ........................................................................................................................... 56 
15.1 
Authorship of Papers, Meeting Abstracts, Etc ........................................................................................... 56 
15.2 
Responsibility for Publication ..................................................................................................................... 56 
15.3 
Submission of Material for Presentation or Publication ........................................................................... 56 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES......................................................... 57 
16.1 
Institution Eligibility for Participation........................................................................................................ 57 
16.2 
Investigator Qualifications .......................................................................................................................... 57 
16.3 
REB (Research Ethics Board) Approval for Protocols ............................................................................. 57 
16.4 
Informed Consent ......................................................................................................................................... 59 
16.5 
Retention of Patient Records and Study Files ............................................................................................ 60 
16.6 
Centre Performance Monitoring.................................................................................................................. 60 
16.7 
On-Site Monitoring/Auditing ...................................................................................................................... 61 
16.8 
Case Report Forms ....................................................................................................................................... 61 
 
17.0 
REFERENCES ............................................................................................................................................. 62 
 
 


 
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APPENDIX I -  
PATIENT EVALUATION FLOW SHEET ......................................................................... 71 
APPENDIX II -  
PERFORMANCE STATUS SCALES/SCORES ................................................................ 72 
APPENDIX III -  
DRUG DISTRIBUTION, SUPPLY AND CONTROL....................................................... 73 
APPENDIX IV -  
DOCUMENTATION FOR STUDY..................................................................................... 75 
APPENDIX V -  
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ................... 78 
APPENDIX VI -  
QUALITY OF LIFE ASSESSMENT ................................................................................... 79 
APPENDIX VII -  
PHYSICAL ACTIVITY AND DIETARY QUESTIONNAIRES...................................... 84 
APPENDIX VIII -  7TH EDITION OF THE TNM CLASSIFICATION OF MALIGNANT TUMOURS .... 91 
APPENDIX IX –  
EVALUATION METHODOLOGIES.................................................................................. 92 
APPENDIX X – 
CORRELATIVE SCIENCE PROCEDURES, BLOOD SAMPLING, PROCESSING 
AND SHIPPING ..................................................................................................................... 94 
APPENDIX XI –  
CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES ....... 96 
APPENDIX XII -  
A HEALTHY LIFESTYLE AFTER BREAST CANCER ............................................... 100 
APPENDIX XIII -  EQUIVALENT HEMATOLOGY UNITS ......................................................................... 108 
APPENDIX XIV -  EMERGENCY SITUATIONS AND COMPLIANCE ..................................................... 109 
 
LIST OF CONTACTS .................................................................................................................................. Final Page 
 


 
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STUDY ACKNOWLEDGMENT/DISCLOSURE 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. 
 
I will provide copies of the protocol and access to all information furnished by CCTG to study personnel 
under my supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study.  
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of CCTG. The foregoing shall not apply to disclosure required 
by governmental regulations or laws; however, I will give prompt notice to  CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ _________________________ 
Investigator 
Date 
(printed name and signature) 
 
 
Protocol Number: MA.32 
 
Centre: ___________________________________________ 
 
 


 
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Metformin 
850 mg po bid X 5 years 
(includes 4-week ramp-up of 850mg po daily) 
Identical Placebo 
One caplet po bid X 5 years 
(includes 4 week ramp-up of one caplet po daily) 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
TREATMENT SCHEMA 
 
The study population will include subjects with invasive breast cancer who, within the previous 12 months, 
have received the first histologic diagnosis of invasive breast carcinoma and have undergone definitive 
surgical treatment for invasive breast cancer. Subjects may have received, at the discretion of their treating 
physician, standard adjuvant loco-regional radiation, adjuvant endocrine treatment, trastuzumab or other 
biologics or bisphosphonates prior to or during study treatment. Chemotherapy (adjuvant or neo-adjuvant), 
if given, must be completed prior to randomization. 
 
Stratification: 
1. ER and/or PgR positive versus both receptors negative 
2. BMI < 30 versus > 30 (kg/m2) 
3. HER2 positive versus HER2 negative 
4. Chemotherapy – any versus none 
 
 
 
 
 
 
 
T1–3, N0-3,M0  
Invasive breast cancer 
Surgically removed +/- 
Radiotherapy, chemotherapy, 
Endocrine therapy, trastuzumab, 
Biologics, bisphosphonates 
 
 
 
 
 
 
Treatment is for 5 years or until primary endpoint is documented 
 
Planned Sample Size: 3582 (80% power to detect HR 0.785 with 2-tail alpha=0.05) 
 
 
Primary Endpoint: Invasive disease free survival 
 
Secondary Endpoints:  
 
Overall survival 
 
Distant relapse free survival 
 
Breast cancer free interval 
 
Breast cancer specific mortality 
 
Incidence of contralateral invasive breast cancer 
 
Long-term clinical and laboratory safety 
 
Relevant Medical Endpoints (new diabetes; new cardiovascular hospitalizations) 
 
Health-Related Quality of Life, Physical Activity, Diet 
 
Change in BMI 
 
Correlative Science Outcomes 
 
 


 
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1.0 
OBJECTIVES 
 
Primary objective: 
To compare invasive disease free survival (IDFS) between subjects treated with metformin (850 
mg  po bid for 5 years) versus placebo in addition to standard adjuvant therapy. 
 
Secondary objective(s): 
To compare the following endpoints between subjects treated with metformin (850 mg po bid for 
5 years) versus placebo: 
 
overall survival 
 
distant disease-free survival 
 
breast cancer free interval 
 
breast cancer specific mortality 
 
incidence of contralateral invasive breast cancer 
 
invasive disease free survival in hormone receptor (ER and PgR) negative and positive (ER 
and/or PgR) sub-groups 
 
changes in body mass index (BMI = weight (kg)/height(m)2) 
 
adverse events 
 
other medical endpoints –  including a new diagnosis of diabetes mellitus or cardiovascular 
hospitalization or death (stroke, myocardial infarction)* 
 
health related quality of life, measured using the EORTC QLQ-C30, supplemented by a trial 
specific checklist; the Block Alive Screener; physical activity items from the Nurses Health 
Study Questionnaire II on a sub-set of MA.32 subjects (sub-set enrollment completed 
2011NOV04) 
 
embedded correlative science outcomes including plasma insulin and molecular markers of 
metformin action 
 
metabolic parameters, including metabolic components of the insulin resistance syndrome as 
defined by the ATP III criteria, in a subset of subjects (and to be described in a separate 
protocol) 
 
* 
“hospitalization” includes an emergency room visit or overnight stay(and cardiovascular 
hospitalizations include all ischemic and non-ischemic events) 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Interest in metformin (an oral agent commonly used to treat diabetes) in the adjuvant setting in 
breast cancer reflects the recent convergence of several streams of research. In epidemiologic 
studies, metformin use in diabetics has been associated with reduced overall cancer risk and 
mortality [Evans, 2005; Bowker, 2006; Monami 2008; Libby, 2009]. Clinically, observational research has 
identified higher response rates to neoadjuvant systemic therapy in diabetic breast cancer patients 
receiving metformin for their diabetes compared to diabetic breast cancer patients who do not 
receive metformin or to non-diabetic breast cancer patients [Jiralerspong 2009]. Furthermore, obesity 
has been recognized as an adverse prognostic factor in breast cancer [Chlebowski 2006; Goodwin, 2006]. 
Variations in insulin levels within the normal range in breast cancer patients (reflecting varying 
degrees of underlying insulin resistance and strongly correlated with obesity) appear to be a likely 
mediator of this effect [Goodwin, 2002; Pasanisi, 2006; Pollak, 2006; Irwin, 2009]. Goodwin has shown that 
metformin reduces insulin levels in breast cancer patients, even in the absence of diabetes and when 
insulin levels are within the normal range [Goodwin, 2008]. The recent demonstration that metformin 
results in (1) initiation of an AMPK-dependent energy stress response which can adversely affect 
survival of BC cell lines and (2) inhibition of PI3K/Akt/mTOR signaling leading to reduced 
proliferation of breast cancer cell lines, has provided a molecular basis for additional, insulin 
independent, anti-tumour effects of metformin in breast cancer [Zakikhani, 2006]. Thus, metformin 
may exert anti-tumour effects through both insulin-dependent and insulin-independent mechanisms 
in women with a broad range of insulin levels commonly seen in newly diagnosed breast cancer. 
Because metformin is a generic, inexpensive, well known and generally well tolerated oral agent 
that is commonly used to treat diabetes (including breast cancer patients who have diabetes), its 
evaluation as a potential adjuvant treatment for breast cancer can take place in an accelerated 
fashion. 
 
Clinical Evidence - Obesity, Insulin and Breast Cancer 
Obesity is a recognized adverse prognostic factor in breast cancer - compared to normal weight 
women, overweight or obese women with breast cancer have a hazard ratio (HR) of distant 
recurrence of 1.7-1.9 and a HR of death of 1.6 [Goodwin, 1995]. Early postulated mechanisms for this 
effect, including underdosing of chemotherapy and elevated estradiol in obese women, do not 
explain obesity effects in women not receiving chemotherapy, in premenopausal women (in whom 
estrogen levels do not reflect obesity) or in estrogen receptor ER/PgR negative breast cancer. There 
is growing evidence that insulin is an important mediator of this adverse prognostic effect of 
obesity. We reported that insulin was strongly associated with obesity (r=0.58, p<0.001) and that 
it exerted an adverse prognostic effect in locoregional breast cancer that extended beyond the 
adverse prognostic effect of obesity [Goodwin, 2002], despite the fact that the vast majority of insulin 
levels (>98%) were in the normal range [Liu, 2006; Saxena, 2000]. Women with insulin levels in the 
highest (vs lowest) quartile had a doubled risk of recurrence and tripled risk of death, effects that 
persisted after adjustment for tumour and treatment related factors. These prognostic effects were 
somewhat greater in women with ER/PgR negative tumours but they were also present in ER/PgR 
positive breast cancer (the difference between these groups was not significant). A quantitatively 
similar effect of insulin was subsequently reported by Pasanisi et al [Pasanisi, 2006], who also found 
the insulin resistance syndrome, a clinical syndrome associated with high insulin levels, was 
associated with a tripled risk of recurrence [Pollak, 2006] and Irwin et al [Irwin, 2009] reported high C-
peptide levels (released when insulin is cleaved from proinsulin) were significantly correlated with 
reduced disease-free survival (DFS) in ER/PgR positive breast cancer. In a final study; a high waist-
hip ratio (a marker of insulin resistance) was associated with a tripled risk of breast cancer mortality 
[Borugian, 2003]. 


 
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Table 1 
Insulin and Related Factors and Breast Cancer Prognosis 
 
 
# 
Factor Measured 
Recurrence 
Death 
Goodwin 
2002 
512 
Fasting Insulin 
HR=2.0 
HR=3.1 
Pasanisi 
2006 
110 
Fasting Insulin 
Insulin Resistance Syndrome 
HR=2.42 
HR=3.0 
 
Pollak 
2006 
667 
Non-fasting C-peptide 
p<0.05* 
 
Irwin 
2007 
689 
Fasting C-peptide 
 
HR=3.0 
Borugian 
2004 
603 
Waist/hip ratio** 
 
HR=3.3 (post) 
* HR not provided 
** non-fasting insulin was not a significant prognostic factor 
Abbreviations: post=postmenopausal, HR = hazard ratio 
 
Recent analyses by our group have demonstrated that the increased risk of distant recurrence and 
death associated with higher versus lower insulin levels at breast cancer diagnosis persists for the 
first five years after diagnosis, but is no longer present after that time (see Figure 1, unpublished 
data). This pattern of recurrence is similar to that seen with ER/PgR negative breast cancer. This 
observation has contributed to our decision to administer metformin for 5 years in this trial. 
 
Figure 1 
HR Distant Recurrence and Death Over Time for Insulin at Diagnosis 
(midpoint of upper quartile vs. midpoint of lower quartile) 
 
HR for Distant Recurrence (df=3) 
Insulin Univariate 87.5th Percentile  
vs. 12.5th Percentile 
HR for Death (df=3) 
Insulin Univariate 87.5th Percentile  
vs. 12.5th Percentile 
 
 
 
Time (years) 
Hazard ratio 
0 
2
4 
6 
8
10
12 
0 
2 
4 
6 
8 
10 
Time (years) 
Hazard ratio 
0 
5
10
15
0 
2
4
6
8 
10


 
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Insulin levels in the upper portion of the normal range in women with breast cancer appear to reflect 
the presence of the underlying Insulin Resistance Syndrome, a condition that is improved by 
metformin. The Insulin Resistance Syndrome includes central obesity, hypertension, an abnormal 
lipid profile, coronary artery disease, type 2 diabetes and a group of laboratory markers of 
inflammation [Reaven, 2005; Bloomgarden, 2007]. We have shown a high prevalence of these conditions 
in women with breast cancer who have higher insulin levels (even when these levels are in the 
normal range); we have also shown that these high insulin levels reflect underlying insulin 
resistance [Goodwin, 2009] as assessed using the Homeostasis Model Assessment (HOMA), a 
validated model of insulin resistance [Vaccaro, 2004]. Furthermore, women with early breast cancer 
have somewhat higher insulin levels than healthy controls [odds ratio (OR) for breast cancer = 2.83, 
highest vs. lowest quintile], consistent with the presence of insulin resistance prior to breast cancer 
diagnosis (possibly reflecting lifestyle factors such as obesity, physical inactivity and high fat diets 
that have been linked to breast cancer risk) [Del Giudice, 1998]. Similar observations have been 
reported by Pasanisi [Pasanisi, 2006]. In a recent study, Genarri et al [Gennari, 2007] identified a 15-
gene set from 143 insulin resistance-related genes, that was predictive of DFS in both a training set 
(102 breast cancer patients) and a validation set (57 breast cancer patients) – they saw 91% 8 year 
DFS for expression scores above the median vs. 51% for scores below the median (p<0.001) in the 
training set [97% vs. 54% (p=0.009) in the validation set]. 
 
Insulin levels vary widely in relation to nutrient intake and health status (particularly the presence 
of diabetes). A normal reference range for fasting insulin has been defined variably from < 20 
microunits/ml (< 139 pmol/L) [Liu, 2006] to < 30 microunits/ml (< 209 pmol/L) [Saxena, 2000]. In our 
population based cohort study of non-diabetic breast cancer patients, [Goodwin, 2002] the mean 
fasting insulin was 44.6 pmol/L and the range was 8.1 to 339.8 pmol/L; < 2% of our subjects had 
fasting insulin levels 140 pmol/L or higher. We expect a similar range of insulin levels, mainly in 
the normal range, in MA.32 subjects. There is evidence that the use of metformin in individuals 
with “normal” insulin levels appears to be safe and it reduces insulin levels. For example, in our 
Phase II study of 6 months of metformin (1500 mg/day) in breast cancer patients, the mean baseline 
fasting insulin level was in the “normal” range (75.7 pmol/L) and only one woman had an insulin 
level above 140 pmol/L (the level was 150 pmol/L). Insulin levels were reduced by 22% without 
the occurrence of hypoglycemia [Goodwin, 2008], proportional reductions in insulin were constant 
across the range of baseline insulin studied. Similar safety and insulin-lowering effects of 
metformin have been reported in non-diabetic, non-breast cancer subjects with normal insulin 
levels. In a recent study of polycystic ovary syndrome (PCOS) [Goldenberg, 2005], metformin (2250 
mg/day) lowered fasting insulin levels by 18% from a mean baseline insulin of 64.5 pmol/L in 
women in the lowest quartile of baseline insulin (greater reductions were seen in women with 
insulin levels markedly above normal). Similar results in PCOS subjects were reported by 
Roumaldi [Romualdi, 2008] (mean baseline fasting insulin 47.0 pmol/L, 15% reduction after 
metformin at a low dose of 1000 mg/day for 6 months) and others [Baillargeon, 2004]. In another 
study, metformin use (2250 mg per day) in sedentary (non-diabetic) subjects having a mean 
baseline fasting insulin of 64.9 pmol/L led to a 17% reduction in insulin levels [Ou, 2006]. Finally, 
metformin (1700 to 2550 mg/day) safely reduced insulin levels by 18.5% (from 161.5 pmol/L to 
131.4 pmol/L) in obese subjects with normal glucose tolerance [Tankova, 2003]. No episodes of 
hypoglycemia were reported in these studies. Thus, at doses similar to those we plan to use, 
metformin safely reduces insulin levels in the normal range, by about 20%. Based on these 
observations, we anticipate that metformin will safely lower insulin levels to a similar degree in 
subjects enrolled onto MA.32. 


 
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The insulin receptor (IR) is commonly expressed in human breast cancer [Mulligan, 2007] (see Table 
below), thereby providing a biologic mechanism for a prognostic effect of insulin. IGF-1R is less 
commonly expressed. In our dataset involving 150 women with sporadic breast cancer treated at a 
single institution, IR expression on breast tumour tissue was not correlated with circulating insulin 
levels (r=-0.02), indicating absence of downregulation by insulin. Similar to ER, we found that 
high IR expression predicted good breast cancer outcome. If this parallel extends to treatment, 
reduction in insulin (for example by the administration of metformin) may improve breast cancer 
outcomes, similar to improvements seen with reduction in estrogen by aromatase inhibitors (AIs) 
in ER/PgR positive breast cancer [Baum, 2002]. 
 
Table 2 
Insulin, IGF Receptors in Sporadic Locoregional Breast Cancer n=150 
 
 
 
IR 
IGF-1R 
Immunohistochemical (IHC) (Allred Score) 
 
 
Negative 
Weak 
Strong 
(0-2) 
(3-5) 
(6-8) 
1.1% 
11.2% 
87.6% 
25.3% 
63.5% 
11.2% 
Spearman r 
 
 
 
Insulin 
IGF-1 
 
-0.02 
-0.11 
-0.10 
-0.02 
 
There have been no randomized trials targeting insulin reduction as a means of improving breast 
cancer outcomes. However, the Women’s Intervention Nutrition Study (WINS) [Chlebowski, 2006] 
randomized 2437 postmenopausal women to a low fat diet that was associated with a 2.3 kg weight 
loss (versus usual diet without weight loss). The diet improved 5 year DFS [HR 0.76, 95% 
Confidence Interval (CI) 0.60-0.98], with the largest effect in ER/PgR negative breast cancer (HR 
0.58, 95% CI 0.37-0.91 vs HR 0.85, 95% CI 0.63-1.14 in ER + breast cancer). In contrast, the 
Women’s Healthy Eating and Living Trial [Pierce, 2007], involving 3088 breast cancer patients, 
found no 5 year DFS or overall survival (OS) effects of a high fruit and vegetable, low fat diet that 
was not associated with weight loss. It is possible these divergent results occurred because weight 
loss (typically associated with reduced insulin levels) was critical in influencing DFS in WINS; if 
correct, the larger effect in ER/PgR negative breast cancer may reflect enhanced importance of 
insulin signaling in that breast cancer subset. Ligibel et al [Ligibel, 2008], have reported that exercise 
(a mixed strength and endurance intervention) promoted insulin reduction in women with breast 
cancer, providing evidence that lifestyle interventions targeting conditions such as physical 
inactivity that have been associated with poor breast cancer outcomes in observational studies can 
modify insulin in the breast cancer population. 
 
There is a large body of work examining insulin-like growth factors (IGFs) and related binding 
proteins (BPs) in breast cancer [Sachdev, 2007; Ibrahim, 2005]. Although circulating IGFs have been 
associated with BC risk in some studies [Hankinson, 1998; Schernhammer, 2005], evidence of a direct 
prognostic role is weak and inconsistent. Expression of these factors in tumour or stroma have been 
more consistently linked with prognosis and/or prognostic features of tumours, notably IGF1 
expression with favourable [Toropainen, 1995; Haffner, 2007] and insulin-like growth factor binding 
protein 3 (IGFBP3) expression with unfavourable [Rocha, 1996; Holdaway, 2003] features. The IGF 
pathway is being evaluated as a target for breast cancer therapy in separate research [Sachdev, 2006]. 


 
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An IGF-1 gene expression profile has recently been reported in breast cancer [Creighton, 2008] – this 
profile involved over 800 genes that were up or down regulated by IGF-1 – these genes (which 
were enriched for transcriptional targets of ER, Ras/extracellular signal-related kinase1/2 and PI3K, 
mTOR pathways) were involved in cell proliferation, metabolism and DNA repair. The expression 
profile was correlated with adverse clinical and pathologic markers (ER/PgR negativity, luminal B 
subtype) and it was independently associated with poor outcomes. As noted above, a similar profile 
exists for insulin [Gennari, 2007]. The key issue may be which ligand (IGF-1, insulin, or both) is 
binding to receptors – clinical and epidemiologic evidence (reviewed above) provides strong 
support for a clinically relevant role for insulin, the target of our proposed intervention. 
 
Clinical and Epidemiological Evidence – Metformin and Cancer 
A recent observational study [Jiralerspong, 2009] examined response rates to neoadjuvant systemic 
therapy in breast cancer patients, some of whom were diabetic receiving metformin (n=68), some 
diabetic not receiving metformin (n=87) and some non-diabetic (n=2374). Pathologic complete 
response (pCR) was 24%, 8% and 16% in these three groups, respectively (p=0.03). Corresponding 
39 month overall survival rates were 80.9%, 77.6% and 85.9%, respectively (p=0.02). That is, the 
use of metformin to treat diabetes was associated with higher pCR rates to neoadjuvant systemic 
therapy in early stage breast cancer patients (although the best survival was seen in non-diabetic 
patients). 
 
In observational epidemiologic work, Evans et al. [Evans, 2005] reported the risk of subsequent 
cancer diagnosis (all cancer types, including BC) was reduced in type 2 diabetics who received 
metformin (OR 0.85 for any vs. no metformin exposure). The protective effect increased with 
greater metformin exposure (measured as total dose prescribed or total duration of use). 
Additionally, Bowker et al. [Bowker, 2006] reported cancer mortality was lower in diabetics receiving 
metformin (vs. sulfonylureas or insulin, HR 0.50-0.77), but they did not study diabetics not 
receiving any drug therapy. Furthermore, while confirming lower cancer risk in diabetics receiving 
metformin (versus those not receiving metformin), Monami et al. [Monami, 2008] did not find similar 
beneficial effects in diabetics receiving thiazolidenediones; effects of sulfonylureas (another class 
or oral anti-diabetic agents) were drug specific rather than a class effect. Libby et al. [Libby, 2009] 
have reported a significantly reduced risk of incident cancers (HR 0.63, 95% CI 0.53-0.75) in 
diabetics receiving metformin (versus those not receiving metformin); they recommended a 
randomized trial be conducted to “assess whether metformin is protective in a population at high 
risk for cancer”. Finally, Currie et al [Currie, 2009] reported that diabetics receiving insulin or 
sulfonylureas had a significantly higher risk of subsequent cancer (HR 1.42 95% CI 1.27-1.60 and 
HR 1.36 (95% CI 1.27-1.60 respectively) compared to those receiving metformin alone. 


 
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Several reports recently published in Diabetologia (2009) have addressed a concern that an insulin 
analog (glargine) that is associated with increased mitogenic effects in vitro may be associated with 
increased risk of cancer in diabetic patients receiving this agent [Hemkens, Jonasson, Colhoun, Currie, 
Home, 2009]. The concern was first raised by Hemkens et al (Germany) who reported a dose 
dependent increased overall cancer risk in those receiving 50 IU/day og glargine (HR 1.31, 95% 
CI 1.20-1.42 compared to those receiving human insulin). Colhoun et al [Colhoun, 2009] identified a 
modest increased overall cancer risk in diabetics receiving glargine insulin (HR 1.55, 95% CI 1.01-
2.37), and they found a significantly increased breast cancer risk in this group (adjusted HR 3.65, 
95% CI 1.05-12.68). Jonasson et al [Jonasson, 2009] failed to identify an increase in overll cancer 
incidence in those receiving glargine insulin but they identified an increased risk of breast cancer 
(adjusted HR 1.97, 95% CI 1.29-3.00). Finally, Currie et al [Currie, 2009] failed to find an association 
of glargine insulin use with cancer incidence, but reported that diabetics receiving metformin had 
the lowest cancer risk (see preceding paragraph). In a meta-analysis of glargine insulin trials 
sponsored by Sanofi-Aventis, Home et al [Home, 2009] failed to identify an increased frequency of 
cancer reported as a serious event in diabetics receiving glargine (vs human) insulin. These results 
must for interpreted with caution for several reasons. First, it must be noted that these reports 
involved very short follow-up periods (less than 2.5 years in the observational studies and it was 
less than 1 year in all but one of the trials included in the meta-analysis). As a result, any effect of 
glargine insulin (or other insulins) on cancer risk see in these studies likely reflected an effect on 
progression of undiagnosed cancers rather than initiation of new cancers. Additionally, baseline 
imbalances between those receiving glargine and those not receiving galrgine (such as more obesity 
in the glargine group seen in some studies) may have accounted for effects on cancer incidence 
(representing confounding by indication. Furthermore, metformin (which may lower cancer 
incidence) was used concurrently with insulin in some studies, often to a differential extent in those 
receiving glargine versus other insulins. As a result, firm conclusions cannot be drawn regarding 
the effect of glargine insulin on cancer risk. Nonetheless, these observations are consistent with an 
adverse effect of insulin on cancer, possibly cancer progression and they strengthen the rationale 
for MA.32. 
 
Evidence from Animal Models and Cell Culture  
Insulin and Metformin in Laboratory Models of Breast Cancer 
Studies in rodent models and cell culture support the concept that insulin stimulates mammary tumour 
growth. Early experiments revealed that N-nitroso-N-methylurea- induced mammary carcinomas 
grew more slowly in insulin-deficient diabetic rats; this was reversed with insulin treatment [Cocca, 
2003]. Furthermore, chronic administration of a human insulin analogue, Asp B10, caused breast 
cancer in normal rats [Ish-Shalom, 1997; Milazzo, 1997]. Since this analogue has higher affinity than native 
insulin for IGF-1R, it was not clear whether one or both of IGF-1R and IR were responsible. Work 
by others has shown that IR is expressed in normal mammary epithelial cells and is upregulated in 
breast cancer cells [Frittitta, 1997]. In cell culture, insulin stimulates mitogenesis in breast cancer cells 
at concentrations which do not bind or stimulate IGF-1R and in the presence of IGF-IR specific 
blocking antibodies [Papa, 1996], consistent with a direct role of insulin. Additional data supporting a 
direct role for insulin in mammary tumour growth stems from experiments examining insulin receptor 
substrate 1 (IRS-1) and insulin receptor substrate 2 (IRS-2), major signaling proteins and substrates 
of the IR tyrosine kinase. Cells expressing a dominant-negative IRS-1 molecule with all 18 Tyr 
phosphorylation sites mutated to phenylalanine had reduced cancer cell growth [Chang, 2002]. Breast 
tumours induced in IRS-2−∕− mice expressing the polyanna middle T antigen in mammary gland grew 
as expected, but had a significantly reduced metastatic behaviour, even when the IRS-2 lacking 
tumours were transplanted into wild-type mice [Nagle, 2004]. These observations are consistent with a 
direct effect of insulin on tumour growth. 


 
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Recent studies have evaluated rodent models of insulin resistance (in which endogenous insulin 
levels are elevated) to provide in vivo data relevant to humans. In one diet induced model of obesity, 
two transplanted tumour cell lines (Lewis lung carcinoma and mouse colon 38-adenocarcinoma) 
showed increased tumour growth with increased obesity and insulin resistance [Yakar, 2006]. In 
another, more severely insulin resistant but non-obese “fatless” mouse model, breeding with a 
transgenic mouse mammary gland tumour model, C3(1)/T-Ag, showed a higher tumour incidence 
and multiplicity as well as decreased tumour latency in insulin resistant mice. Since these “fatless” 
mice lacked adipose tissue-derived hormones, including leptin, the role of insulin and/or IGF-1 (as 
opposed to adipocytokines such as leptin) was supported [Nunez, 2006]. Our own unpublished 
preliminary data show that a high fat diet in the HER2 overexpressing breast cancer mouse model 
leads to earlier and more frequent appearance of second and multiple tumours. Together, these 
observations strongly support a significant role of elevated insulin as an adverse effector of breast 
cancer growth. 
 
The effect of metformin in mouse mammary tumour models has also been explored. Anisimov et 
al [Anisimov, 2005] have reported that metformin significantly increases latency for mammary tumour 
development, significantly reduces mammary tumour size and significantly increases both mean 
and maximal life span in a HER2 overexpressing breast cancer mouse model. These effects were 
associated with a non-significant reduction in insulin levels. Similar results have recently been 
reported by Huang et al [Huang, 2008] in a PTEN deficient breast cancer mouse model – metformin 
suppressed tumourigenesis via the LKB1-AMPK pathway (described below). These two studies 
investigated metformin in doses that approximated the dose/plasma levels in humans (i.e: 
metformin 1500-2250 mg per day) – ranging from approximately 0.5 to 18 times the human dose. 
In contrast, another recent study [Phoenix, 2009] suggested metformin use in a mouse xenograft model 
was associated with an increase in VEGF production which led to augmented angiogenesis and 
mammary tumour growth. This study has been criticized because the cell line studied was actually 
derived from melanoma (not breast cancer) [Hadad, 2009] and the doses of metformin used in this 
study were 45 times (or more) that used in humans and plasma metformin levels were 300 times 
the recommended levels in humans [Stambolic, 2009]. Stimulation of angiogenesis occurs with other 
mTOR inhibitors and does not appear to be clinically relevant. In the case of metformin, VEGF 
effects appear to be dose and/or model related – large doses may provide excess metabolic stress 
leading to enhanced compensatory VEGF response. At present, there is no evidence to suggest that 
metformin in doses as high as 18 times the standard clinical dose exerts similar effects on VEGF 
or stimulates tumour growth in animal model systems.  
 
Molecular Mechanism of Metformin Action (see Figure 2 below) 
By inhibiting transcription of key gluconeogenesis genes in the liver and increasing glucose uptake 
in skeletal muscle, metformin reduces levels of circulating glucose, increases insulin sensitivity 
and reduces hyperinsulinemia [Cusi, 1998; Witters, 2001]. Activation of AMPK plays a prominent role 
in mediating the effects of this drug [Zhou, 2001; Vazquez-Martin, 2009; Santomauro Junior, 2009]. AMPK 
is a central cellular energy sensor whose activation leads to suppression of many of the processes 
highly dependent on ample cellular ATP supply, including gluconeogenesis, protein and fatty acid 
synthesis and cholesterol biosynthesis, while promoting catabolic processes such as fatty acid beta-
oxidation and glycolysis [reviewed in Hardie, 2007; Towler, 2007]. Metformin directly inhibits complex 
I of the respiratory chain leading to decreased ATP synthesis and a rise in the cellular AMP:ATP 
ratio, effectively mimicking conditions of cellular energy stress [El-Mir, 2000; Owen, 2000]. Increased 
association of AMPK with AMP under such conditions facilitates its phosphorylation and 
activation by the upstream kinase LKB1, the protein product of the tumour suppressor gene mutated 
in the Peutz Jeghers cancer predisposition syndrome [Lizcano, 2004; Shaw, 2004]. 


 
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While most research into metformin action has focused on insulin-responsive tissues, emerging 
evidence suggests that other cell types, including cancer cells, initiate an AMPK-dependent energy 
stress response to metformin. Metformin-induced AMPK activation directly impacts the adaptive 
response of certain cancer cells to nutrient limitation and affects their survival, in part via a p53-
dependent mechanism in colon cancer cell lines [Buzzai, 2005; Buzzai,2007]. This p53 dependence has 
not been seen in breast cancer cell lines [Zhuang, 2008]. In BC cell lines, metformin causes a strong 
growth suppressive response [Irwin, 2009]. This effect is independent of HER2 status and it has been 
found in a variety of cell lines having characteristics of the spectrum of molecular subtypes of 
breast cancer (e.g. luminal A and B, HER2, basal) [Zhuang, 2008; Alimova, 2009]. In human glioma and 
pancreatic cancer cell lines metformin exhibits an antiproliferative, antimigratory and proapoptotic 
effect [Wang, 2008; Beckner, 2005; Isakovik, 2007]. Recent data suggest there may be differential effects 
of metformin in hormone receptor and/or Her-2 positive versus triple negative breast cancer cell 
lines, with potential therapeutic activity being seen in all cell lines but a potential unique additional 
effect that includes enhanced apoptosis occurring in triple negative breast cancer cell lines and 
reduced expression of HER2 in HER2 positive cell lines [Alimova, 2009; Liu, 2006]. Because of these 
observations, and because a greater effect of dietary fat reduction (associated with weight loss) was 
reported in ER/PgR negative versus ER/PgR positive breast cancer in WINS (discussed above), we 
plan to conduct a formal subset analysis in the ER/PgR negative breast cancer subset enrolled onto 
MA.32. 
 
Figure 2 
Simplified schematic of the molecular mechanism of metformin action. See text for 
details. Phospho-specific antibody epitopes relevant to key molecular markers are 
highlighted within the black boxes. An additional marker, stathmin 1 (STMN 1), is a 
recently discovered surrogate marker for the signaling throughput via the PI3K/PTEN 
signaling pathway that can be monitored by immunohistochemistry [Saal, 2007] 
 
 


 
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In addition to the effects of metformin and AMPK on metabolic processes, activation of AMPK 
results in rapid inhibition of cellular protein synthesis and growth. Mechanistically, AMPK achieves 
this by phosphorylation and stabilization of the protein product of the tuberous sclerosis complex 2 
(TSC2) tumour suppressor gene [Corradetti, 2004; Inoki, 2003], which serves as an integrator of various 
regulatory inputs implicated in cell growth. TSC2 activity negatively regulates a small GTPase Rheb 
which serves as a binary switch for the master regulator of eukaryotic protein synthesis, the mTOR 
protein [reviewed in Manning, 2003; Sarbassov, 2005]. In addition to mediating the inhibitory effects of AMPK 
on protein synthesis, TSC2 integrates several activating inputs that impact cellular protein translation, 
notably signals emanating from the availability of amino acids and oxygen and growth factor-
dependent stimulation of PI3K/Akt signaling. Activation of mTOR-dependent protein translation, as 
judged by phosphorylation of its downstream targets, p70S6K and 4E binding protein 1 (4E-BP1), is 
often found in BC specimens and has been shown to correlate with malignant progression and an 
adverse prognosis [Armengol, 2007; Rojo, 2007]. 
 
Recent work indicates that increased mTOR-dependent protein translation and cell growth are 
hallmarks of tumourigenesis downstream of activated PI3K/Akt signaling. This cellular cascade is 
one of the most frequently deregulated oncogene/tumour suppressor gene networks in human breast 
cancer. Mutations in one of the genes encoding the PI3K catalytic subunit, PIK3CA, have been found 
in 20-35% primary breast cancer specimens and been associated with greater tumour size, lymph 
node metastasis and poor prognosis [Bachman, 2004; Lee, 2005; Li, 2006; Saal, 2005; Wu, 2005]. Mutations 
and loss of expression of the critical negative regulator of this pathway, the PTEN tumour suppressor, 
have been found in up to 40% of human breast cancers [Rojo, 2007; Bachman, 2004, Lee, 2005; Li, 2006, Saal, 
2005; Wu, 2005; Perez, 2007; Sansal, 2004; Vivanco, 2002], while up to 30% overexpress ErbB2, a potent 
activator of the PI3K cascade [Yu, 2000]. Notably, PI3K/Akt/mTOR signaling throughput correlates 
with hyperplastic changes in breast epithelium, increasing from normal epithelium to hyperplasia and 
atypia, to invasive lesions [Zhou, 2004] and contributes to resistance of breast cancer cells to 
chemotherapy, trastuzumab and tamoxifen [Morgensztern, 2005]. 
 
Clinical Experience with Metformin 
Metformin is a well known, readily available oral agent that is commonly used to treat Type 2 diabetes 
and, more recently, insulin resistance. It is inexpensive and, in general, it is well-tolerated. Its most 
potentially dangerous toxicity is lactic acidosis (estimated incidence: 3 cases per 100,000 patient years); 
when lactic acidosis occurs it is fatal in 50% of cases [Kirpichnikov, 2002]. There is considerable debate as 
to whether the lactic acidosis that occurs in diabetics receiving metformin is due to the use of metformin 
or to the presence of diabetes [Fantus, 2005; McCormack, 2005]. This controversy arises from results of a 
meta-analysis that showed comparable rates of lactic acidosis in diabetics who did, and who did not, 
receive metformin [Salpeter, 2003], by failure to demonstrate an association between lactic acidosis and 
metformin levels in diabetics [Lalau, 1995; Jones, 2003] and by the failure to observe increased lactic 
acidosis rates after the introduction of metformin in the United States [Brown, 1998]. Regardless, risk of 
lactic acidosis is increased in those over 80 years of age, in those with current or past congestive heart 
failure, renal insufficiency or hepatic insufficiency (including individuals with habitual excess alcohol 
intake), and in those with a prior history of metabolic acidosis. Risk of lactic acidosis is believed to be 
increased after surgery and use of radiologic contrast material – metformin should be temporarily 
discontinued for approximately 48 hours in these situations. Lactic acidosis is extremely rare if 
metformin use is restricted to individuals without any of these predisposing conditions. Additional 
toxicities include: gastrointestinal (> 1/10 - diarrhea, nausea, vomiting, abdominal bloating, flatulence, 
anorexia, metallic taste – usually transient when treatment is started and resolving spontaneously with 
continued treatment), rash (< 1/10,000), subnormal vitamin B12 (9% after 6 months – it is suggested 
that Vitamin B and/or hemoglobin levels be monitored at 6-12 months), hepatic dysfunction 
(<1/10,000), elevations in TSH (< 1/10,000). Modest weight loss (up to five pounds) is common. 


 
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Hypoglycemia does not normally occur when metformin is administered – extreme caloric 
restriction or excessive physical activity without adequate caloric intake may rarely lead to 
hypoglycemia. Metformin is commonly used for many years in diabetics without cumulative 
adverse effects. It also lowers risk of subsequent diabetes, and complications of the IRS (Insulin 
Resistance Syndrome) in individuals with IRS [Knowler, 2002; Orchard, 2005]. 
 
Quality of Life in Placebo Controlled Metformin Trials 
In this trial, metformin will be compared to a placebo. Clinical experience with metformin shows 
it is mainly associated with gastro-intestinal side effects. A literature review found six trials 
[DeFronzo, 1995; Grant, 1996; Hoffman, 1997; Horton, 2000; Chiasson, 2001; Mather, 2001] comparing 
metformin to a placebo that provided information about the frequency and magnitude of the main 
side effects and the contribution of GI symptoms to dropout rates. Although these trials reported 
toxicity, they did not formally evaluate QOL. Other trials that have not reported toxicity to date 
have not been included here. 
 
Clinical Trials Comparing Metformin to Placebo 
 
Study 
Intervention 
# of 
Pts 
Side-effects 
# of drop-outs due to GI 
symptoms/total drop outs 
DeFronzo RA et al.1995 Protocol 1: 
 
 
 
 
 
Metformin titrated up 
to 2250 mg/day 
n=143 Severe diarrhea  
Severe nausea 
8% 
4% 
11/31 pts 
 
Placebo 
n=146  
 
0/41 pts 
 
All for 29 weeks 
 
 
 
 
Grant PJ 1996 
Metformin 3g/day 
n=27 
GI symptoms, not defined 
 
13/13 pts 
 
Metformin 1.5g/day 
n=25 
 
 
8/12 pts 
 
Placebo 
n=23 
 
 
2/6 pts 
 
All for 6 months 
 
 
 
 
Hoffman U et al. 1997 
Acarbose 100 mg TID 
n=31 
Flatulence or bloating 
(mild to moderate; ↓ with time) 16 pts 
3 pts 
 
Metformin 850 mg BID 
n=31 
GI complaints: 
 
 
Nausea, emesis, diarrhea 
1 pt 
1 pt 
Flatulence 
1 pt 
1 pt 
 
Placebo 
n=32 
 
 
 
 
All for 24 weeks 
 
 
 
 
Horton ES et al. 2000 
Nateglinide 120 mg a.c. n=172 Diarrhea 
19.7% 1/5 pts 
 
Metformin 500 mg TID n=178 Diarrhea 
14.5% 6/12 pts 
 
Combination 
n=172  
 
6/16 pts 
 
Placebo 
 
 
 
3/9 pts 
 
All for 24 weeks 
 
Other side effects 
(comparable between groups): 
 
 
 
 
 
URTI  
Headache 
Abdominal Pain  
Nausea  
Fatigue 
Sinusitis 
14.3% 
7.1% 
6.3% 
5.7% 
5.1% 
5.0% 
 
Table continued on next page … 


 
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Study 
Intervention 
# of 
Pts 
Side-effects 
# of drop-outs due to GI 
symptoms/total drop outs 
Chiasson J-L 2001 
Miglitol 100 mg TID 
n=82 
Flatulence 
Diarrhea 
Constipation 
Nausea 
Dyspepsia 
Abdominal Cramps 
63.2% 
53.3% 
9.2% 
17.1% 
14.5% 
7.9% 
11/11 pts* 
 
 
 
 
 
 
 
Metformin 500 mg TID 
n=83 
Flatulence 
Diarrhea 
Constipation 
Nausea 
14.5% 
10.8% 
6.0% 
2.4% 
5/5 pts* 
 
 
 
Dyspepsia 
Abdominal Cramps 
2.4% 
2.4% 
19/19* 
 
Combination 
n=6 
 
 
2/2 pts 
 
Placebo 
n=83 
 
 
 
 
All for 36 weeks 
 
 
 
 
Mather KJ et al. 2001 
Metformin 500 mg BID 
n=29 
GI symptoms (mild GI 
discomfort) 
4 pts 
1/2 pts 
 
Placebo 
n=15 
GI symptoms (mild GI 
discomfort) 
2 pts 
1/2 pts 
 
All for 12 weeks 
 
 
 
 
* It is assumed all drop-outs were due to GI tocicity 
 
It can be seen that gastrointestinal toxicity occurred more frequently in patients receiving metformin 
but, at doses comparable to those we plan to use in this study (we plan to give 1700 mg/day), it 
infrequently led to dropout from the study (0 to 6% dropout rate at doses ≤ 2000mg/day). 
 
In other studies of metformin in diabetes patients, QOL has been measured. However, the 
questionnaires used are not relevant for our study. For example, the “Diabetes Specific Quality of 
Life Scale” [Bott, 1998] and the “Diabetes Treatment Satisfaction Questionnaire” [Bradley, 1994] deal 
with the impact of being diabetic on social functioning or glycemic control. Metformin has been used 
also in polycystic ovary syndrome. A Cochrane review found no study of metformin vs. placebo 
where QOL was an outcome [Costello, 2007].  
 
Even though it is unlikely that a decision to implement metformin as an adjuvant treatment in early 
stage breast cancer will depend on QOL results, we have elected to include HRQOL measurement in 
a subset of the population of MA.32 because metformin is associated with side-effects that may lead 
to discontinuation of the treatment and may impact QOL (e.g. diarrhea, flatulence). Furthermore, its 
effects on QOL in breast cancer patients receiving standard breast cancer therapy (.e.g. aromatase 
inhibitors, tamoxifen, herceptin) are not known. We will use the EORTC QLQ C-30 (Aaronson NK, 
1993) supplemented by additional items from the CCTG item bank/new items. QOL assessments will 
be conducted at baseline, 6 and 12 months and then annually until 5 years. There is little evidence to 
suggest there are major differences in overall HRQOL according to adjuvant hormone therapy use 
(tamoxifen, aromatase inhibitors, none), however, there may be small but important differences in 
endocrine symptoms and bone pain similar to those that have been reported in adjuvant randomized 
trials of aromatase inhibitors compared to tamoxifen or placebo. In the CCTG MA.17 randomized trial 
comparing an aromatase inhibitor (letrozole) to a placebo in the extended adjuvant setting, there were 
small differences in favor of the placebo for bodily pain, general health, vasomotor and physical 
symptoms using the SF-36 and the Menopause Specific Quality of Life Questionnaire [Whelan, 2005]. 


 
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In the ATAC trial which compared anastrozole to tamoxifen, there was no difference in QOL 
between the two arms, but there were small differences in endocrine symptoms assessed with the 
FACT-B (less cold sweats and vaginal discharge but more vaginal dryness, painful intercourse and 
loss of sexual interest with anastrozole) [Fallowfield, 2004]. In the International Exemestane Study 
(exemestane versus tamoxifen after 2-3 years of tamoxifen), there was more vaginal discharge in 
those receiving tamoxifen when symptoms were assessed using the FACT-B [Fallowfield, 2006]. 
 
Because endocrine symptoms and bodily pain may differ with different adjuvant endocrine 
therapies, we plan to enroll equal numbers of patients in the HRQOL sub-study in each of the 
following groups defined by adjuvant hormone therapy at randomization: no hormone therapy, 
tamoxifen or aromatase inhibitor. 
 
We will also assess patterns of diet and physical activity in women who participate in the Quality 
of Life sub-study in order to evaluate changes in these behaviours over time in the group as a whole 
and in the participants randomized to Metformin as compared to those randomized to placebo. 
Dietary intakes will be assessed using the Block Alive Screener. In validation testing, the 
questionnaire was demonstrated to have good reliability (Pearson Correlation Coefficients [PCC] 
0.65 – 0.8) construct validity (PCC 0.56 – 0.92) and predictive validity as compared to the full 
Block Food Frequency Questionnaire (PCC 0.44 – 0.56). The instrument was designed to focus on 
intake of saturated fat, trans- fats, total sugar, added sugars, fruit and fruit juices and vegetables 
along with estimates of Glycemic Load and Glycemic Index. Secondary estimates can be made for 
kcal, protein, total fat, carbohydrate and dietary fibre. Physical Activity patterns will be assessed 
through the Nurses Health Study II Questionnaire which asks participants to indicate the frequency 
with which they participate in a number of common recreational activities. This information will 
be utilized to generate a weekly Metabolic Task Equivalent (MET- hour score) which will provide 
a measure of both duration and intensity of physical activity. The Physical Activity Questionnaire 
has been validated on a number of populations and has been shown to correlate well with 7-day 
activity diaries and seasonal past 4-week questionnaires (Wolf, A. 1994). It has been widely used 
in observational studies to quantify physical activity patterns in breast cancer and other populations 
[Holmes, M 2005; Meyerhardt J, 2006: Meyerhardt J, 2006]. 
 
Correlative Studies 
Correlative studies will be an integrated component of the MA.32 clinical trial. Investigations of 
fasting glucose and insulin levels at baseline, 6 months post randomization and at the end of study 
treatment will be mandatory and will explore the indirect insulin-mediated effect of metformin on 
protocol defined outcomes. Tumour related factors at baseline, serum and plasma biomarkers will 
be evaluated and sample collection for this component will be strongly encouraged but remains 
optional. Proposed studies are outlined in section 13 of the protocol. 


 
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Summary 
There is strong clinical evidence that fasting insulin levels are associated with poor BC outcomes 
across the normal range of insulin levels that is typically seen in women with early stage breast 
cancer, without evidence of a floor or ceiling effect. At the dose we plan to use in MA.32, 
metformin safely lowers insulin levels by about 20% in non-diabetic BC and non-cancer subjects 
who have baseline fasting insulin levels in the normal range. Observational evidence suggests that 
metformin use in diabetics may reduce cancer risk and mortality and may be associated with 
enhanced responses to neoadjuvant systemic therapy in diabetic women with BC. We hypothesize 
that metformin will reduce BC growth through its effect on insulin levels and we believe there is 
no justification for selecting subjects by insulin levels based on an insulin dependent action of 
metformin. Growing molecular evidence that metformin may also exert an insulin independent 
effect on breast cancer via activation of an insulin independent, AMPK-dependent energy stress 
response and/or inhibition of PI3K/Akt/mTOR signaling strengthens the rationale for studying 
metformin in BC. The existence of this direct (non-insulin dependent) metformin effect on 
AMPK/mTOR provides additional justification for inclusion of women with a broad range of 
insulin levels in MA.32 rather than limiting enrolment to those with insulin levels above an 
arbitrarily chosen cutpoint. Because metformin is a readily available, inexpensive oral agent, with 
known (and easily manageable) toxicities, we believe evaluation of its therapeutic effects in early 
stage BC can proceed at an accelerated pace. 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
(For a complete summary, please consult your current Metformin Product Monograph.) 
 
3.1 
Name and Chemical Information 
 
N,N – dimethyl biguanide hydrochloride 
 
3.2 
Chemical Structure 
 
 
Molecular mass = 165.6 
 
Metformin HCl is a white crystalline powder soluble in water and 95% ethyl alcohol. It is 
practically insoluble in ether and in chloroform. 
 
Melting Point: 218-220o C 
 
3.3 
Mechanism of Action 
 
Metformin HCl is a biguanide derivative producing an antihyperglycemic effect which can only be 
observed in man or in the diabetic animal and only when there is insulin secretion. Metformin, at 
therapeutic doses, does not cause hypoglycemia when used alone in man or in the non-diabetic 
animal, except when using a near lethal dose. Metformin has no effects on the pancreatic beta cells. 
The mode of action of metformin is not fully understood. It has been postulated that metformin 
might potentiate the effect of insulin or reduce hepatic gluconeogenesis. 
 
 
Metformin absorption is relatively slow and may extend over about 6 hours. The drug is 
excreted in urine at high renal clearance rate of about 450 mL/min. The initial elimination of 
metformin is rapid with a half-life varying between 1.7 and 3 hours. The terminal elimination 
phase accounting for about 4 to 5 % of the absorbed dose is slow with a halflife between 9 
and 17 hours. Metformin is not metabolized. Its main sites of concentration are the intestinal 
mucosa and the salivary glands. The plasma concentration at steady-state ranges about 1 to 
2 mcg/mL. 
 
Certain drugs may potentiate the effect of metformin HCl, particularly sulfonylurea type of drugs 
in the treatment of diabetes. The simultaneous administration of these two types of drugs could 
produce a hypoglycemic reaction, especially if they are given in patients already receiving other 
drugs which, themselves, can potentiate the effect of sulfonylureas. These drugs can be: long-acting 
sulfonamides, tubercolostatics, phenylbutazone, clofibrate, monoamine oxidase inhibitors, 
salicylates, probenecid and propanolol. 
 
In healthy volunteers, the pharmacokinetics of propranolol and ibuprofen were not affected by 
metformin when co-administered in single-dose interaction studies. 


 
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Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with 
highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as 
compared to sulfonylureas, which are extensively bound to serum proteins. 
 
3.4 
Toxicology 
 
3.4.1 
Human Toxicity 
 
In man, no adverse effect has been reported on liver or kidney function, the hematopoietic system 
or on the blood vessels. 
 
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low 
(approximately 0.03 cases / 1000 patient/years with approximately 0.015 fatal cases / 1000 
patient/years). 
 
The consecutive administration of both phenformin and metformin to the same patient has allowed 
for the demonstration of a fundamental difference between these two biguanides in relation to 
lactacidemia. In some instances, patients developed hyperlactacidemia with phenformin when the 
same patients were presenting normal lactic acid levels while being treated with metformin. In other 
instances, hyperlactacidemia observed during a treatment with phenformin did regress when 
metformin was substituted for phenformin. Metformin may increase lactacidemia but to a degree 
that is clinically less significant than the elevation seen after phenformin. 
 
3.4.2 
Teratology 
 
Teratological studies were carried out in albino rats divided in three groups: 
 
No abnormalities were found, even when high doses were administered. The number of animals 
was the same in each group. 
 
Death rate in the three groups of treated animals and controls was approximately the same. 
However, the number of living animals in each group treated was slightly lower than in the control 
group. Also, the frequency of litters exceeding 10 live animals was slightly higher in the control 
group. A loss of weight at the time of weaning has been observed when compared to the control 
group. 
 
Nevertheless, on a statistical basis, differences were shown to be non-significant. There is no 
difference between the groups of treated animals and the control group regarding the number of 
stillborn. The number of deaths after birth was slightly higher in metformin treated groups than in 
the control group, but the comparison of average death rates is not significant (p > 0.05). 


 
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3.5 
Phase I & II Trials 
 
Goodwin studied physiologic and quality of life effects of metformin (500 mg po three times daily 
for 6 months) in a single arm Phase II study involving 32 women with early BC who had completed 
their primary therapy; > 95% had baseline insulin levels in the normal range (see table below) 
[Goodwin PJ, 2008]. Insulin levels fell by 22.4% and insulin sensitivity [evidenced by the Homeostasis 
Model Assessment (HOMA)] [Vaccaro, 2004] improved by 25% after 6 months of metformin. 
Because participants were disease-free, effects on tumour proliferation could not be assessed. In 
general, metformin was well tolerated. There were no significant changes in HRQOL as measured 
using the EORTC QLQ C-30 (overall physical condition, global health, overall QOL, physical 
functioning, social functioning) or specific symptoms (nausea, appetite, diarrhea, constipation, 
pain) during the study. Mild to moderate GI toxicity led to discontinuation of the drug in 4 (12%) 
of the women. This compares to an aromatase inhibitor discontinuation rate of 22% in a recent 
clinic-based study [Ohsako, 2006]. An additional 6 (19%) did not complete the study for other reasons 
– vacation (2), development of diabetes requiring withdrawal from the study (1), pneumonia (1), 
family physician preference (1), scheduling problems (one woman completed six months of 
metformin but did not attend for final study measurements). Non-completion of the study was 
significantly associated with lower baseline HRQOL (global health, overall physical condition, 
overall QOL, physical or social functioning, pain). We believe non-completion rates will be lower 
in the phase III trial proposed here because we will gradually ramp up the metformin dose (850 mg 
po daily for 4 weeks, then 850 mg bid for the remainder of the 5 year intervention) and because we 
will explain to participants that we are hypothesizing metformin may influence breast cancer 
outcomes (no such claims were made in the Phase II study), thereby enhancing motivation to 
continue though intercurrent illnesses and vacations. 
 
Phase II – Metformin in Locoregional Breast Cancer 
(post surgery, chemotherapy)   n=32 
 
Baseline 
6 months 
% Change 
p 
Insulin (pmol/L) 
70.7 
54.9 
-22.4 
0.02 
Glucose (mmol/L) 
5.0 
4.9 
-2.3 
0.29 
HOMA 
2.24 
1.67 
-25.6 
0.02 
Weight (kg) 
75.4 
73.5 
-2.5 
0.01 
BMI (kg/m2) 
28.1 
27.4 
-2.5 
0.007 
 
3.6 
Adverse Effects 
 
Please refer to protocol section 2, heading “Clinical Experience with Metformin” for a summary of 
adverse effects. 
 
3.7 
Pharmaceutical Data 
 
Metformin 
 
Supplied: 850 mg caplet, white to off-white, capsule-shaped, biconvex, film-coated. Engraved APO 
850 on one side, plain on the other side 
 
Stability: 2 year expiration 
 
Storage: Store at room temperature (15° to 30°C) in well-closed containers 
 
Route of Administration: Metformin is administered orally, with food 


 
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Placebo 
 
Supplied: caplet, white to off-white, capsule-shaped, biconvex, film coated. Engraved APO 850 on 
one side, plain on other side 
 
Stability: 3 year expiration 
 
Storage: Store at room temperature (15° to 30° C) in well-closed containers 
 
Route of Administration: Placebo is administered orally, with food 
 
 


 
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4.0 
TRIAL DESIGN 
 
The trial population will consist of subjects with invasive breast cancer who, within the previous 
12 months, have received the first histologic diagnosis of invasive breast carcinoma and have 
undergone definitive surgical treatment for invasive breast cancer. Subjects may have received, at 
the discretion of their treating physician, standard adjuvant loco-regional radiation, adjuvant 
endocrine treatment, trastuzumab or other biologics or bisphosphonates prior to or during study 
treatment. Chemotherapy (adjuvant or neoadjuvant), if given, must be completed at least 4 weeks 
prior to randomization. 
 
The first 888 eligible English/French -speaking MA.32 subjects will complete questionnaires 
dealing with Quality of Life. English-speaking subjects from the Quality of Life sub-study will also 
complete the Physical Activity and Diet Questionnaires. (Appendices VI and VII). 
 
All subjects (regardless of randomization) will be given basic information on healthy lifestyle (diet, 
physical activity) developed by the American Cancer Society (www.cancer.org). The information 
to be provided is included as Appendix XII. 
 
4.1 
Stratification 
 
Patients will be stratified by: 
• 
Receptor Status (ER and/or PgR positive versus both negative*) 
• 
BMI (< 30 versus >30 kg/m2) 
• 
HER2 Status (positive versus negative**)  
• 
Chemotherapy (any versus none) 
* 
 It is recommended that ER and PgR assays be considered positive if there are at least 1% 
positive tumour nuclei in the sample on testing in the presence of expected reactivity of 
internal [normal epithelial elements] and external control[Hammond 2010].  
** Positive = 3+ over-expression by IHC in > 30% of invasive tumour cells 
 
OR  
HER2 gene amplification by FISH/CISH > 6 HER2 gene copies per nucleus 
 
OR  
a FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of > 2.2 
All other results will be considered negative. 
 
4.2 
Randomization 
 
Subjects will be randomized (in a 1:1 ratio) to receive one of the following treatments: 
 
Metformin or placebo, to a planned sample size of 3582. 
 
Patients will be randomized to one of the following two arms: 
Arm 
Agent(s) 
Dose 
Route 
Duration 
1 
Metformin 
850 mg 
p.o (with food) 
b.i.d. X 5 years (includes 4 week ramp-up*) 
2 
Placebo 
One caplet 
p.o. (with food) 
b.i.d. X 5 years (includes 4 week ramp-up*) 
 
*The “ramp-up” to protocol dose and schedule will occur as follows: 
• 
1 caplet po daily for 4 weeks, then 
• 
1 caplet po bid for the balance of 5 years 
 
 


 
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4.3 
Inclusion of Women and Minorities 
 
There are no exclusions based on race or ethnicity in this trial. In the Canadian Cancer Trials Group 
as a whole, 60% of patients have been female and 40% have been male. The female preponderance 
reflects the number of studies performed in breast cancer. Insufficient data has been collected to 
test whether recruitment to breast cancer trials reflects race/ethnicity incidence in the Canadian 
population. This study, however, will be presented to patients through the major cancer-treatment 
institutions of the Canadian provinces, to which all racial/ethnic groups have equal access. The 
intention, therefore, is to recruit subjects from racial/ethnic groups in close approximation to the 
incidence of the disease in these groups. It will also be presented to patients of any race or ethnicity 
through participating centres of major American Cooperative Groups. Patients at participating 
American sites will have equal access to this study regardless of race or ethnicity; furthermore, 
Minority Outreach is a component of all CTEP-sponsored trials. 
 
Within the United States, lower breast cancer incidence rates have been reported for blacks, Asians, 
American Indians, and Hispanics in comparison to non-Hispanic whites. Yet, blacks tend to have 
lower breast cancer survival rates. Several factors are thought to explain this difference. Among 
them are age at diagnosis, delay between onset of symptoms and diagnosis/treatment, stage, 
hormone receptor levels and socio-economic levels. During 1996, the racial composition of the 
women enrolled on NCCTG breast cancer protocols was non-Hispanic white (95%), black (4%) 
and Hispanic (1%). 
 
Although there is some evidence that obesity and/or insulin resistance may occur more frequently 
in African Americans than in Caucasians, and that breast cancer outcomes may be poorer in African 
Americans [Rose, 2007], there is insufficient evidence to conclude that these are causally linked, nor 
is there evidence that metformin has different biologic effects or efficacy in different racial groups. 
As a result, we will recruit subjects of all ethnic and racial groups to approximate the racial 
distribution of breast cancer seen at participating centers. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
358 
+ 
1 
= 
359 
Not Hispanic or Latino 
3188 
+ 
35 
= 
3223 
Ethnic Category: Total of all subjects 
3546 (A1) 
+ 
36 (B1) 
= 
3582(C1) 
Racial Category 
 
American Indian or Alaskan Native 
36 
+ 
1 
= 
36.25 
Asian 
107 
+ 
= 
107.25 
Black or African American 
180 
+ 
= 
180.25 
Native Hawaiian or other Pacific Islander 
107 
+ 
= 
107.25 
White 
3116 
+ 
35 
= 
3151 
Racial Category: Total of all subjects 
3546 (A2) 
+ 
36 (B2) 
= 
3582(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
Accrual Rate: 
100 
pts/month 
Total Expected 
Accrual:  
358
2 
Min 
358
2 
Max 
Projected Start Date of Study: 
Q1    2010 
 
 
 
 
 
 
 


 
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5.0 
STUDY POPULATION 
 
The study population will consist of subjects with invasive breast cancer who, within the previous 
12 months, have received the first histologic diagnosis of invasive breast carcinoma and have 
undergone definitive surgical treatment for invasive breast cancer. Subjects may have received, at 
the discretion of their treating physician, standard adjuvant loco-regional radiation, adjuvant 
endocrine treatment, trastuzumab or other biologics or bisphosphonates prior to or during study 
treatment. Chemotherapy (adjuvant or neoadjuvant), if given, must be completed at least 4 weeks 
prior to randomization. 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed PRIOR to calling for randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that subjects who enter this study are medically appropriate candidates for 
this therapy. For the safety of the subjects, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
5.1.1 
Subjects must have histologically confirmed invasive breast cancer and be enrolled in the trial 
within 12 months after the first histologic diagnosis of invasive breast cancer. A core biopsy 
interpreted as invasive cancer meets this criterion; otherwise, the date of first histologic diagnosis 
will be the date of first surgical procedure that identifies invasive cancer (biopsy, lumpectomy or 
mastectomy). TNM Stage (AJCC Version7) must be one of the combinations presented in Section 
5.1.4. Neoadjuvant subjects should have no evidence of clinical T4 disease prior to chemotherapy 
and surgery. Please refer to 5.1.4 for eligible cTNM classifications. Bilateral breast carcinoma is 
allowed provided diagnoses are synchronous – that is, within 3 months of one another – and at least 
one of the two breast carcinomas meet the eligibility criteria and neither violates the eligibility 
criteria. 
 
5.1.2 
All subjects (both adjuvant and neo-adjuvant) must have sentinel lymph node biopsy and/or axillary 
lymph node dissection.  
 
Sentinel lymph node biopsy alone is allowed in the following instances: 
a)  sentinel lymph node biopsy is negative: pN0 
b)  sentinel lymph node biopsy is positive for isolated tumour cells only: pN0 (i+) 
c)*  clinically node negative, T1-2 tumours with sentinel lymph node biopsy positive in < 2 lymph 
nodes without extra-capsular extension or matted nodes and undergoing breast conserving 
surgery and tangential whole breast irradiation  
 
(* excludes subjects treated with neo-adjuvant systemic therapy) 
 
 


 
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5.1.3 
Definitive surgery and/or chemotherapy have been completed at least 4 weeks prior to 
randomization. Surgical margins must be clear of invasive carcinoma. If there is microscopic 
residual ductal in situ disease present at lumpectomy or total mastectomy margins, further excision 
is highly recommended. If further excision is not undertaken, the subject may still be entered on 
study, provided that in addition to breast or chest wall irradiation, a boost to the tumour bed is 
delivered. In situ lobular disease at the margin is acceptable. 
 
5.1.4 
Adjuvant subjects with the following pT pN combinations are eligible: 
• 
pT1c, pN0 AND negative estrogen and progesterone receptors AND HER2 negative  
OR 
• 
pT2N0 and at least one of the following tumour characteristics: histologic grade 3, 
lymphovascular invasion, negative estrogen and progesterone receptors, HER2 positive, 
Oncotype Dx recurrence score > 25 (or if Oncotype Dx recurrence score is not available, Ki67 
> 14%) 
OR 
• 
Subjects with pT3, pN0 
OR 
• 
Subjects with pT1-3, pN1-3 
 
The eligibility of neo-adjuvant subjects is assessed on the basis of cTNM. The same eligible TNM 
combinations apply. 
 
5.1.5 
Estrogen and progesterone receptor status must be known. (Receptor positive by 
immunohistochemistry: ERICA or PgRICA versus both receptors negative. It is recommended that 
ER and PgR assays be considered positive if there are at least 1% positive tumour nuclei in the 
sample on testing in the presence of expected reactivity of internal [normal epithelial elements] 
and external control. [Hammond 2010] 
 
5.1.6 
HER2 status must be known. (Positive = 3+ over-expression by IHC in > 30% of invasive tumour 
cells OR HER2 gene amplification by FISH/CISH > 6 HER2 gene copies per nucleus, OR a 
FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of > 2.2. All other results will be 
considered negative). 
 
5.1.7 
Patients must have had a bilateral mammogram within 12 months prior to randomization, unless 
the initial surgery was a total mastectomy, in which case only a mammogram of the remaining 
breast is required. (Subjects with bilateral total mastectomies and no mammogram within 12 
months prior to randomization must, instead, have a physical examination of the chest wall to 
ensure there is no residual or recurrent disease at the time of randomization. The date of this 
examination is used in place of the mammogram date on the eligibility checklist.) 
 
5.1.8 
Investigations, including chest X-ray or CT chest, bone scan (with radiographs of suspicious areas) 
and abdominal ultrasound or liver scan or CT abdomen have been performed between the first 
histologic diagnosis and the time of randomization. 
• 
Chest X-Ray, 2 view (or Chest CT) is mandatory 
• 
Bone scans (with x-rays of abnormal areas) are required only if there are signs or symptoms 
of metastatic disease 
• 
Abdominal imaging is required only if there are signs or symptoms of metastatic disease 
 
 


 
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5.1.9 
Hematology investigations (WBC, Granulocytes, Platelets, Hemoglobin) have been completed 
within 28 days prior to randomization and results are available. 
 
5.1.10 Biochemistry investigations have been completed within 28 days prior to randomization and values 
are within the parameters required by the protocol. 
 
AST < 1.8 X ULN 
ALT < 1.8 X ULN 
Alkaline Phosphatase < 2 X ULN 
Serum Creatinine < 115 μmol/L (1.3mg/dL) 
Serum Bilirubin < institution ULN (except for subjects with Gilbert’s Disease who are eligible 
despite elevated serum bilirubin level) 
 
5.1.11 ECOG Performance Status of 0,1 or 2 (at baseline evaluation visit within 28 days prior to 
randomization). 
 
5.1.12 Age > 18 and < 75 and life expectancy of at least 5 years (18 years of age was used as a cut-off due 
to the lack of data indicating that breast cancer is a health issue in the < 18 years age group and 
metformin safety in pediatric patients has not been confirmed. Age > 80 carries increased risk of 
lactic acidosis and study intervention is for 5 years). 
 
5.1.13 Subjects must be accessible for treatment and follow-up. Investigators must assure themselves the 
subjects randomized on this trial will be available for complete documentation of the treatment, 
adverse events, and follow-up. 
 
5.1.14 In accordance with CCTG policy, protocol treatment is to begin within 10 working days of patient 
randomization. 
 
5.1.15 Subject consent must be obtained according to local Institutional and/or University Human 
Experimentation Committee requirements. It will be the responsibility of the local participating 
investigators to obtain the necessary local clearance, and to indicate in writing to the CCTG Study 
Coordinator that such clearance has been obtained, before the trial can commence in that centre. 
Because of differing requirements, a standard consent form for the trial will not be provided but a 
sample form is given in Appendix XII. A copy of the initial full board REB approval and approved 
consent form must be sent to the central office. The patient must sign the consent form prior to 
randomization or registration. Please note that the consent form for this study must contain a 
statement which gives permission for the CCTG and monitoring agencies to review patient records 
(see Section 16 for further details). 
 
For the first 888 eligible English or French-speaking subjects only (sub-set enrollment completed 
2011NOV04): 
 
 


 
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5.1.16 Subject is able (i.e. sufficiently fluent) and willing to complete the Quality of Life (EORTC QLQ 
C-30 and Trial Specific Checklist) in English or French. The baseline assessment must already have 
been completed at the time of enrolment. Inability (illiteracy in English or French, loss of sight or 
other equivalent reason) to complete questionnaires will not make the patient ineligible for the 
study; however, ability but unwillingness to complete the questionnaires will make the patient 
ineligible. (Once the target number of 888 subjects is achieved, this criterion will no longer need 
to be fulfilled.) [See Appendix VI]. Sub-set enrollment completed 2011NOV04. 
 
5.1.17 English-speaking subjects who have completed the Quality of Life Questionnaire who are able (i.e. 
sufficiently fluent) and willing to complete Nurses Health Study II Physical Activity Questionnaire 
and Block Alive Screener in English. The baseline assessment must already have been completed 
at the time of enrolment. Inability (illiteracy in English, loss of sight or other equivalent reason) to 
complete questionnaires will not make the patient ineligible for the study; however, ability but 
unwillingness to complete the questionnaires will make the patient ineligible. (This component of 
the study will close at the same time as the Quality Of Life sub-study.) [See Appendix VII]. Sub-
set enrollment completed 2011NOV04. 
 
 
5.2 
Ineligibility Criteria 
 
Subjects who fulfill any of the following criteria are not eligible for admission to the study. 
 
5.2.1 
Subjects with a history of other malignancies, except: adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with 
no evidence of disease for > 5 years. 
 
5.2.2 
Subjects with locally recurrent or metastatic breast carcinoma. (Subjects with prior invasive breast 
cancer at any time are not eligible. Subjects with prior DCIS only in either breast are eligible 
provided the DCIS has been curatively treated including surgery, radiotherapy and/or Tamoxifen). 
 
5.2.3 
Subjects whose axillary node status is unknown. 
 
5.2.4 
Known diabetes (type 1 or 2) or baseline fasting glucose > 7.0 mmol/L (126 mg/dL). (Sampled and 
assayed according to local institution’s procedures.) 
 
5.2.5 
Known hypersensitivity or intolerance to metformin. 
 
5.2.6 
Any condition associated with increased risk of metformin-associated lactic acidosis (e.g. 
congestive heart failure defined as New York Heart Association {NYHA} Class III or IV functional 
status [see Appendix IX], history of acidosis of any type; habitual intake of 3 or more alcoholic 
beverages per day). 
 
5.2.7 
Currently taking metformin, sulfonylureas, thiazolidenediones or insulin for any reason. 
 
5.2.8 
Current or planned pregnancy or lactation in women of child-bearing potential. Men should not 
father a child. (An effective method of birth control should be used while on study treatment which 
could include abstinence, IUD, condoms or other barrier methods of birth control because the safety 
of metformin in pregnancy or in male fertility has not been established). 


 
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5.2.9 
Concurrent or planned participation in randomized trials of weight loss or exercise interventions or 
trials targeting insulin, IGF-1 or their receptors, or involving P13K inhibitors (at the time of 
randomization)*. 
 
* These interventions would interfere with the primary endpoint. (Also, in general, double 
randomizations in breast cancer trials for MA.32 patients are permitted only if the patient meets 
all the eligibility criteria for MA.32 and the sponsor of the previous trial has no objection to the 
patient also being enrolled in MA.32). 
 
 


 
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6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations 
Timing 
History and Physical Exam 
including: 
• 
Date of LMP, Menopausal status, Height, 
Weight , Waist and Hip Circumference, Blood 
Pressure, Performance Status (ECOG), BMI, 
smoking history, alcohol intake 
Within 28 days prior to 
randomization 
Pathology of Primary 
Tumour 
• 
Histology, ER/PgR, HER2, pTNM, Histologic 
Grade 
 
Hematology 
• 
WBC, Granulocytes, Platelets, Hemoglobin, 
MCV 
Within 28 days prior to 
randomization 
Biochemistry 
• 
AST, ALT, Alkaline Phosphatase, Serum 
Creatinine, Serum Bilirubin, Serum Vitamin 
B12 
• 
Fasting Glucose, Fasting Insulin (same draw; 
Fasting Glucose measured locally; Fasting 
insulin measured centrally) 
Within 28 days prior to 
randomization 
Radiology 
• 
Bilateral mammogram (please note that MRI 
may not be substituted for mammogram but 
may be done in addition to a mammogram) 
Within 12 months prior to 
randomization 
• 
Chest X-ray(2 view), chest CT (mandatory) 
• 
Bone scan (with x-rays of abnormal areas) if 
there are signs or symptoms of metastatic 
disease 
• 
Abdominal imaging if there are signs or 
symptoms of metastatic disease  
Between the date of first 
histologic diagnosis and the 
date of randomization.  
Other Investigations 
• 
Women of child-bearing potential not pregnant Within 7 days prior to 
randomization 
• 
Blood samples for correlative science 
(optional) 
Within 28 days prior to 
randomization* 
• 
Tumour block submission (for subjects who 
consent) 
When requested by Queen’s 
University Department of 
Pathology 
Concomitant Medications 
• 
Current medications/Indications 
Within 14 days prior to 
randomization 
Adverse Event 
• 
Baseline adverse event evaluation (to 
document residual adverse event from 
previous therapy and baseline symptoms) 
using CTC AE version 4 
Within 14 days prior to 
randomization 
Quality of Life  
(N = first eligible 888 
English/French speaking 
subjects) 
• 
EORTC QLQ-C30, Trial Specific Checklist,  
Within 28 days prior to 
randomization (sample size 
achieved by 2011NOV04) 
Physical Activity and Diet 
Questionnaires 
(English-speaking subjects 
of QoL sub-set) 
• 
Physical Activity items (Nurses’ Health Study 
II), Block Alive Screener  
Within 28 days prior to 
randomization (sample size 
achieved by 2011NOV04) 
* 
Optional correlative science samples going to the central lab and not required for eligibility may be drawn after 
randomization and prior to start of study treatment so that they can be labeled appropriately with patient ID#. 
 
 


 
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7.0 
ENTRY/RANDOMIZATION PROCEDURES 
(CTSU sites please refer to the CTSU Logistical Appendix)  
 
7.1 
Randomization 
 
All randomizations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
carrying out randomizations will be provided at the time of study activation and will also be included 
in the CCTG EDC Generic Data Management Guidebook, posted on the MA.32 trial specific web-
site. If sites experience difficulties accessing the system and/or  randomizing subjects please contact 
the help desk (link in EDC) or the MA.32 Study Coordinator. 
 
All eligible subjects enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG MA.32) 
• 
treatment centre and investigator 
• 
date of REB approval* for study at participating centre 
• 
version of the informed consent that the patient signed 
• 
patient's initials, hospital number (if permitted by the local REB) and CCTG serial number 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential 
questionnaires and tests and actual values 
• 
completed eligibility checklist 
• 
stratification parameters  
 
* 
Initial approval of all studies must be Full Board. 
 
Randomization will be performed electronically. Randomization will be given by the EDC system 
and confirmed by e-mail.  
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all 
subjects entered into the trial. Under no circumstances, therefore, may an allocated 
patient’s data be withdrawn prior to final analysis unless the subject withdraws 
participation from the trial and requests that data collection/submission cease from the 
point in time of withdrawal. 
 
All eligible subjects admitted to the trial will be followed by the coordinating centre. It is 
the responsibility of the physician in charge to satisfy him/herself that the patient is indeed 
eligible before requesting randomization. 
 
All randomized subjects are to be followed until death or until sites are informed by CCTG 
that further follow-up is no longer required. The follow-up requirements for ineligible 
subjects who have received no study treatment whatsoever are submission of the Baseline 
Report plus an annual Short Follow-up Report. Ineligible subjects who have had study 
treatment should also be followed with the Short Follow-up Report to allow for treatment 
and adverse events assessment. 
 
 


 
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7.2 
Stratification 
 
Subjects will be stratified by: 
• 
Receptor Status (ER and/or PgR positive versus both negative) 
• 
BMI (< 30 versus >30 kg/m2) 
• 
HER2 Status (positive versus negative) 
• 
Chemotherapy (any versus none) 
 
CTSU sites should refer to Appendix XI for CTSU-specific procedures. 
ICR-CTSU sites should refer to the ICR-CTSU specific appendix for Group-specific procedures. 
IBCSG sites should refer to the IBCSG-specific appendix for Group-specific procedures. 
 
 


 
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8.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of subjects rests with the individual investigator. 
 
8.1 
Study Treatment Plan 
 
Breast cancers must have been completely resected by lumpectomy (resection margins must be 
clear of invasive cancer) or mastectomy. If there is microscopic residual in situ disease present at 
lumpectomy or total mastectomy margins, further excision is highly recommended. If further 
excision is not undertaken, the patient may still be entered on study, provided that in addition to 
breast or chest wall irradiation, a boost to the tumour bed is delivered.  
 
Radiation is to be administered according to pre-specified institutional guidelines either prior to or 
during protocol treatment. Either neo-adjuvant and/or adjuvant chemotherapy is allowed providing 
the last dose was administered at least 4 weeks prior to randomization. Other adjuvant therapies 
(including endocrine, biologic agents such as trastuzumab or lapatinib or bevacizumab, radiation, 
bisphosphonates) may be given before, during or after randomization and study treatment with 
metformin or placebo. 
 
All subjects (both adjuvant and neo-adjuvant) must have sentinel lymph node biopsy and/or axillary 
lymph node dissection.  
 
Sentinel lymph node biopsy alone is allowed in the following instances: 
a)  sentinel lymph node biopsy is negative: pN0 
b)  sentinel lymph node biopsy is positive for isolated tumour cells only: pN0 (i+) 
c)*  clinically node negative, T1-2 tumours with sentinel lymph node biopsy positive in < 2 lymph 
nodes without extra-capsular extension or matted nodes and undergoing breast conserving 
surgery and tangential whole breast irradiation  
 
(* excludes subjects treated with neo-adjuvant systemic therapy) 
 
All subjects (regardless of randomization) will be given basic information on healthy lifestyle (diet, 
physical activity) developed by the American Cancer Society (www.cancer.org). The information 
to be provided is included as Appendix XII. 
 
8.1.1 
Drug Administration 
 
Arm 
Agent(s) 
Strength 
Route 
Duration 
Schedule 
1 
Metformin 
850 mg 
p.o 
5 years or until 
primary endpoint 
850 mg p.o. b.i.d with food 
(includes 4 week ramp-up*) 
2 
Placebo 
One caplet 
p.o. 
5 years or until 
primary endpoint 
One caplet p.o. b.i.d with food 
(includes 4 week ramp-up*) 
 
 


 
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In accordance with CCTG policy, protocol treatment is to begin within 10 working days of patient 
randomization.  
 
* The “ramp-up” to protocol dose and schedule will occur as follows: 
• 
1 caplet po daily for 4 weeks, then 
• 
1 caplet po bid for the balance of 5 years 
 
Please see protocol section 12.1 for a complete list of criteria for stopping protocol treatment.  
 
8.1.2 
Patient Monitoring 
 
A calendar schedule will be provided for each patient for the ramp-up period and  telephone 
contact will be made with the patient one month after enrolment to assess compliance, toxicity and 
to ensure the patient has increased medication to twice daily. (The calendar is intended only as a 
tool to assist subjects in adjusting to full dose at the correct time after starting study treatment.) A 
record of the telephone contact will be made, by the CRA, on the Telephone Follow-up report. 
(Please see Appendix IV.) Any problems identified by the CRA will be communicated to the 
responsible Investigator. 
 
8.1.3 
Dose Adjustments 
 
The major toxic effects of metformin which limit dose are gastrointestinal (nausea, abdominal 
bloating, diarrhea). During the ramp-up period, subjects experiencing gastrointestinal symptoms 
should be encouraged to take tablets with food. If no improvement, subjects should try taking study 
medication every other day for two weeks, once per day for two weeks and then twice per day 
thereafter.  Subjects not tolerating study medication after this approach may go off study treatment 
but Investigators are urged to re-challenge willing subjects 3 months later. Dose adjustments, for 
reasons of toxicity, will be as in the tables below. (Please note that none of the recommended dose 
adjustments require splitting of study medication pills. Pills are not to be split or crushed, prior to 
taking, for any reason.) Breaks of up to 4 weeks consecutively or 8 weeks overall are allowed to 
ascertain the cause of unpleasant symptoms. Beyond this, treatment is at the discretion of the 
Investigator.  
 
Gastrointestinal Toxicity 
 
Toxicity / Adverse Event 
Grade 
Investigator Action 
Gastrointestinal Toxicity 
of any type 
Grade 1 
Patient should be encouraged to remain on full dose. If patient is 
unwilling, stop study treatment for one week. 
 
For subjects who were unwilling to remain on full dose, after one week 
without study drug, follow the ramp-up procedure. If Grade 1 
symptoms persist or recur during the ramp-up or at full dose and the 
patient is unwilling to continue, follow instructions for Grade 2 
toxicity. 
From the Gastrointestinal 
Category of CTC AE 
 
Nausea 
Distension/Bloating 
Diarrhea 
Gastrointestinal - Other 
Grade 2 
(or higher) 
Reduce to one tablet per day for one week. If symptoms resolve or are 
Grade 1 only, after one week, resume full dose (2 tablets per day). 
 
If symptoms persist or recur at Grade 2 or higher, stop study treatment 
for 4 weeks, then resume study treatment as follows: 
 
Re-start study drug according to original ramp-up schedule (one tablet 
per day for 4 weeks then 2 tablets per day if tolerated). If toxicity 
persists or recurs, the study drug should be adjusted to the maximum 
dose that is tolerated with Grade 1 toxicity or lower. A second attempt 
to increase to full dose should be made 3 months later and if the full 
dose is not tolerated at that time, the maximum tolerated dose should 
be used for the remainder of the 5-year intervention. 
 
 


 
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Other Toxicities / Events 
 
Toxicity / Event 
Grade 
Investigator Action 
Hepatic dysfunction* 
(bilirubin > ULN except 
for Gilbert’s Disease) 
Grade 1 
(or greater) 
Hold study drug for up to 4 weeks. If bilirubin returns to normal 
within that time frame, begin one tablet per day for 4 weeks, then 2 
tablets per day. 
Hepatic dysfunction* 
 
AST or ALT=1.8- 3.0 X 
ULN 
Please consult 
CTC AE for 
precise grading 
Repeat AST & ALT in 2 weeks. If either AST or ALT > 1.8 X ULN, 
continue at discretion of Investigator, monitoring AST & ALT every 
two weeks until both < 1.8 X ULN – then resume annual testing. 
 
If Investigator decides to stop medication , resume once AST &ALT 
< 1.8 X ULN, starting with one tablet per day for 4 weeks, then 
increasing to 2 tablets per day with annual AST & ALT assessments 
Hepatic dysfunction* 
 
AST or ALT > 3.0 X 
ULN 
Please consult 
CTC AE for 
precise grading 
Hold study drug. 
Repeat LFTs in 2 weeks. 
 
If AST and ALT < 1.8 ULN, resume medication. 
Resumption involves 1 tablet per day for 4 weeks, then increase to 2 
tablets per day, at the discretion of the Investigator, with resumption 
of protocol specified monitoring if both AST and ALT remain at < 
1.8 x ULN. 
 
If repeat AST and ALT are 1.8-3.0 x ULN, follow steps as described 
in section above or resume study medication at the discretion of the 
Investigator. 
 
If AST and/or ALT > 3.0 x ULN, initiate workup for liver disease. 
If AST or ALT=1.8-3.0 resume medication at the discretion of the 
investigator. 
Renal dysfunction 
 
Creatinine > 115 μmol/L 
 1.3 mg/dL 
Please consult 
your 
institution’s 
ULN and CTC 
AE for precise 
grade 
Hold study drug for up to 4 weeks. 
 
After resolution of event, using 4-week ramp-up schedule (one caplet 
per day for 4 weeks, then 2 caplet per day) 
Clinical diagnosis of 
congestive heart failure 
> Grade 3 
(Please consult 
CTC AE for 
precise grade) 
Hold study drug for up to 4 weeks. 
 
Re-start may be considered if underlying condition (e.g. acute MI) has 
resolved. If Metformin is started after CHF, the ramp-up schedule (one 
caplet per day for 4 weeks then two caplets per day) should be used. 
Do not re-start if symptoms persist or ongoing treatment of CHF is 
required. 
Acidosis 
(Lactate > 5.0 mM) 
(pH < 7.3) 
Grade 3 
Stop study drug and do not re-start. 
 
Report as a serious adverse event. Please consult protocol section 11. 
Anemia 
Hgb < 110 or MCV > 
105 
> Grade 1 
Perform CBC and serum B12 level. Initiate anemia workup if cause of 
anemia not apparent. Continue at full dose. (Treatment is not held for 
anemia regardless of toxicity grade.) 
Skin Reactions 
 
Major – generalized 
urticaria, bullous rashes, 
exfoliative dermatitis 
Generalized 
Stop study drug. and do not re-start. 
Continued on next page … 
 
 


 
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Other Toxicities / Events (continued) 
Toxicity / Event 
Grade 
Investigator Action 
Stevens Johnson 
Syndrome 
 
Localized 
Localized 
Hold study drug for up to 4 weeks 
if possibly, probably or definitely related to study drug. 
 
When rash clears, one caplet per day for 4 weeks, then 2 caplets per 
day – if rash recurs, and is thought to be possibly, probably or 
definitely related to study medication, discontinue study medication. 
Hospitalization for any 
reason 
As per grade of 
event causing 
hospitalization 
Hold study drug for up to 4 weeks. The Investigator is to determine 
when it is safe to re-start. The drug should be re-started using a 4-week 
ramp-up schedule (one caplet per day for 4 weeks then two caplets per 
day) if the hospitalization resulted in discontinuation of the drug for 2 
weeks or longer. If the discontinuation of the drug was less than 2 
weeks, the drug should be re-started at full dose (two caplets per day) 
without a ramp-up. 
* Be alert to signs of acidosis!: protocol specific biochemistry should be checked annually. If subject develops malaise, nausea, 
dark urine, jaundice or right upper quadrant pain, study medication should be stopped until biochemistry is performed. 
Medication should be resumed according to the algorithms above (if first biochemistry results are normal, resume immediately 
at full dose) 
 
Other Situations 
 
Diagnostic Imaging: 
If the subject is scheduled for any CT scans requiring intravenous contrast material, metformin 
should not be taken for 24 hours prior to the investigation nor for 48 hours after the procedure. 
(This does not include contrast used for MRI or nuclear medicine scans, including MUGA.) Study 
medication may then be resumed at full dose (without ramp-up) provided there is no concern about 
renal function. If there is concern about renal function, creatinine should be checked prior to 
resumption of study medication. 
 
General Anaesthetic: 
If general anaesthetic is required for surgery, study drug should not be taken on the morning of 
surgery nor for 48 hours after anaesthetic and surgery. Study medication may then be resumed at 
full dose (without ramp-up) provided there is no concern about renal function. The drug is restarted 
at full dose if the duration of interruption was less than 2 weeks. If the duration of drug interruption 
was more than 2 weeks, it should be restarted using a 4 week ramp-up schedule (one caplet per day for 
4 weeks, then two caplets per day). If there is concern about renal function, creatinine should be 
checked prior to resumption of study medication. 
 
Any Situation Considered Medically Necessary: 
Study medication may be held in any situation which the Investigator considers it medically 
necessary, for up to 4 weeks, and may be resumed at Investigator discretion, using the 4-week 
ramp-up if re-starting. 
 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events, 
version 4 (CTCAE). Only events of Grade 3, 4 and 5 will be collected. (Please consult Appendix 
V). 
 
 
 


 
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8.1.4 
Concomitant Therapy 
 
Permitted 
Subjects may receive loco-regional radiation, adjuvant endocrine treatment, trastuzumab or other 
biologics or bisphosphonates, at the discretion of their treating physician, before during or after 
randomization and study treatment with metformin or placebo. Chemotherapy (or neoadjuvant 
chemotherapy), if given, must be completed at least 4 weeks prior to randomization.  
 
Not permitted 
Sulfonylureas, thiazolidenediones or insulin for any reason unless these drugs become necessary to 
treat a new diagnosis while on study therapy in which case the patient will discontinue study 
treatment. Subjects should avoid excessive alcohol intake (i.e. less than 3 alcoholic beverages on 
any given day).  
 
8.1.5 
Duration of Therapy 
 
Subjects will take their allocated therapy orally, twice daily, with food.  
 
The DSMC recommended, as an outcome of the second interim analysis, that all ER and PgR 
negative subjects discontinue study medication. Specifically, the results indicated that continuation 
of protocol therapy will not provide additional information about the benefit of metformin in this 
sub-population. Please see protocol section 14 for details.  
 
Treatment will be continued for 5 years in receptor positive (ER and/or PgR positive) subjects 
unless unacceptable toxicity occurs or the subject has recurrent tumour, new invasive primary 
cancer (other than adequately treated basal cell carcinoma or squamous cell carcinoma of the skin), 
or concurrent illness that necessitates withdrawal or subject decides to withdraw from participation 
for any reason.  (For details concerning toxicity and intercurrent illness, please consult protocol 
section 8. For a complete list of general criteria for stopping study treatment, please see protocol 
section 12.1.) 
 
If the subject’s immediate management for the new diagnosis is influenced by the knowledge of 
which treatment she/he was assigned, study medication will be unblinded upon the Investigator’s 
request, by CCTG. 
 
8.1.6 
Blinding/Unblinding 
 
Metformin and matching placebo are identical in appearance as are the bottles in which they are 
provided. Blinding is critical to the integrity of this clinical drug trial. However, in the event of a 
medical emergency in an individual subject, in which knowledge of the investigational product is 
critical to the subject's management, the blind for that subject may be broken by the treating 
physician. Before breaking the blind of an individual subject's blinded treatment, the Investigator 
should have determined that the information is necessary, i.e. that it will alter the subject's 
immediate management. In many cases, particularly when the emergency is clearly not 
investigational product-related, the problem may be properly managed by assuming that the subject 
is receiving active product without the need for unblinding. The need to break the blind must first 
be discussed with the CCTG. For any treatment code unblinding, the reason and parties involved 
must be documented in the patient’s medical record. Treatment identification information should 
be kept confidential and should be disseminated only to those individuals that must be informed 
for medical management of the patient. The CCTG must be notified as soon as possible of any 
emergency situation in which the drug code was broken. 
 
 


 
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To request an unblinding of patient treatment during regular office hours (8am to 6pm eastern time), 
please contact the MA.32 Study Coordinator, at 613-533-6430. For emergency after hours 
unblinding requests: 
Toll Free number: 877-617-2810 (North America Only) 
International Calls: 613-541-3280 
 
The Investigator requesting the unblinding of a patient treatment must provide: 
1) 
the trial code (MA.32); 
2) 
the patient ID number; 
3) 
patient initials; 
4) 
reason for unblinding; 
5) 
the last treatment kit number. 
 
 


 
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9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All subjects entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
Subjects are to be followed every 6 months for the first year and then annually until 5 years from 
randomization while on study treatment. Treatment is for 5 years or until disease 
recurrence/progression, new invasive primary cancer (other than BCC or SCC of the skin that has 
been adequately treated), intolerable toxicity or subject withdrawal for whatever reason. After study 
treatment discontinuation, subjects should be followed annually for delayed/persistent toxicity and 
disease status.  
 
9.1 
Evaluation During Protocol Treatment 
 
Investigations 
Timing 
History and Physical Exam 
including: 
• 
Weight, Waist and Hip Circumference, 
Blood pressure, BMI, Compliance (patient 
reported and pill count), Cardiovascular 
hospitalizations, New diagnosis of diabetes 
• At each clinic visit 
Hematology* 
• 
WBC, Granulocytes, Platelets, 
Hemoglobin, MCV 
• At 6, 12, 24, 36, 48 and 60 
months while on study treatment  
Biochemistry* 
• 
ALT, AST, Alkaline Phosphatase, Serum 
Creatinine, Serum Bilirubin 
• 
Serum Vitamin B12* 
• 
Fasting Glucose, Fasting Insulin (same 
draw; Fasting Glucose measured locally; 
Fasting insulin measured centrally)) 
• At 6, 12, 24, 36, 48 and 60 
months while on study treatment 
• At 12, 36 and 60 months while 
on study treatment  
• At 6 month visit & at 48 months 
(or just prior to end of study 
treatment if not at 48 months)*** 
Radiology 
• 
Annual mammogram (please note that MRI 
cannot be substituted for mammogram but 
may be done in addition to mammogram) 
• Annually from baseline 
mammogram  
Other Investigations 
• 
Serum, plasma, DNA (optional) 
• At 6 month visit & at 48 months 
(or just prior to end of study 
treatment if not at 48 months) 
• 
As needed to assess for 
recurrence/progression 
• As needed, at Investigator 
discretion 
Adverse Events** 
(Appendix V) 
• 
Subjects must be evaluated at each clinic 
visit for adverse events  
• At each clinic visit 
Quality of Life 
(888 patient subset) 
• 
EORTC QLQ-C30, Trial Specific 
Checklist,  
• At 6, 12, 24, 36, 48 and 60 
months while on study treatment  
Physical Activity and Diet 
(Quality of Life subset) 
• 
Physical Activity Items (Nurses’ Health 
Study II), Block Alive Screener  
• At 6, 12, 24, 36, 48 and 60 
months while on study treatment  
* 
Vitamin B12 deficiency should be managed according to Investigator discretion. 
** 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events, version 4. 
*** For subjects who discontinue study treatment anytime prior to 4 years, the mandatory fasting glucose and fasting insulin should 
be drawn just prior to study treatment discontinuation. For subjects who complete 4 years of therapy, a 4-year treatment should 
be done at the 48 month visit. Subjects who have passed the 48 month mark may have their samples drawn at the 60 month visit 
prior to treatment discontinuation.  
 
 


 
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9.2 
Evaluation After Protocol Treatment 
 
Subjects are seen annually, after cessation of study treatment 
 
Prior to reaching primary endpoint 
Investigations 
Timing 
History and Physical 
Exam including: 
• 
Clinical assessment for recurrence/progression 
• 
Weight, BMI, Cardiovascular hospitalizations, New diabetes 
At each clinic visit 
Radiology 
• 
Annual mammogram (Please note that MRI may not be 
substituted for a mammogram but may be done in addition to 
mammogram) 
Annually from 
baseline 
mammogram 
Other Investigations 
• 
As necessary to assess for recurrence/progression, 
Contralateral breast carcinoma, DCIS alone, New invasive 
non-breast primary 
At each clinic visit 
Adverse Events 
Adverse events (related to study treatment only) will be recorded 
and graded according to the NCI Common Terminology Criteria 
for Adverse Events (Version 4 CTCAE - Appendix V). 
At each clinic visit 
There will be no QoL, Physical Activity or Diet Questionnaires after protocol treatment. 
 
After experiencing invasive local/regional recurrence (a primary endpoint) but no distant recurrence 
Investigations 
Timing 
History and Physical 
Exam including: 
• 
Clinical assessment for distant recurrence/progression, 
Contralateral breast carcinoma, New invasive non-breast 
primary 
At each clinic visit 
Radiology 
• 
Annual mammogram (Please note that MRI may not be 
substituted for a mammogram but may be done in addition to 
mammogram) if there is breast tissue remaining 
Annually from 
baseline 
mammogram 
Other Investigations 
• 
As necessary to assess for recurrence/progression, New 
primaries (breast or non-breast) 
At each clinic visit 
Adverse Events 
Adverse events (related to study treatment only) will be recorded 
and graded according to the NCI Common Terminology Criteria 
for Adverse Events (Version 4 CTCAE - Appendix V). 
At each clinic visit 
There will be no QoL, Physical Activity or Diet Questionnaires after local recurrence. 
 
After distant recurrence/progression (a primary endpoint) 
Investigations 
Timing 
History and Physical 
Exam including: 
• 
Clinical assessment 
At each clinic visit 
Other Investigations 
• 
As necessary (& to assess for new invasive non-breast 
primary) 
At each clinic visit 
Adverse Events 
Adverse events (related to study treatment only) will be recorded 
and graded according to the NCI Common Terminology Criteria 
for Adverse Events (Version 4 CTCAE - Appendix V). 
At each clinic visit 
There will be no QoL, Physical Activity or Diet Questionnaires after distant recurrence. 
 
 


 
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After Contralateral Invasive Breast Carcinoma (a primary endpoint) 
Investigations 
Timing 
History and Physical 
Exam including: 
• 
Clinical assessment for local/regional recurrence, distant 
recurrence 
At each clinic visit 
Other Investigations 
• 
Annual mammogram (Please note that MRI may not be 
substituted for a mammogram but may be done in addition to 
mammogram) if there is breast tissue remaining 
• 
As necessary (& to assess for new invasive non-breast 
primary) 
Annually from 
baseline 
mammogram 
Adverse Events 
Adverse events (related to study treatment only) will be recorded 
and graded according to the NCI Common Terminology Criteria 
for Adverse Events (Version 4 CTCAE - Appendix V). 
At each clinic visit 
There will be no QoL, Physical Activity or Diet Questionnaires after distant recurrence. 
 
New invasive non-breast primary, treated with curative intent (a primary endpoint) 
Investigations 
Timing 
History and Physical 
Exam including: 
• 
Clinical assessment for breast recurrence/progression, 
contralateral breast carcinoma and DCIS alone 
At each clinic visit 
Other Investigations 
• 
Annual mammogram (Please note that MRI may not be 
substituted for a mammogram but may be done in addition to 
mammogram) 
• 
Other investigations, as necessary  
Annually from 
baseline 
mammogram 
Adverse Events 
Adverse events (related to study treatment only) will be recorded 
and graded according to the NCI Common Terminology Criteria 
for Adverse Events (Version 4 CTCAE - Appendix V). 
At each clinic visit 
There will be no QoL, Physical Activity or Diet Questionnaires after a new invasive non-breast primary. 
 
Other new invasive non-breast primary, incurable (a primary endpoint) 
Investigations 
Timing 
History and Physical 
Exam including: 
• 
Clinical assessment  
At each clinic visit 
Other Investigations 
• 
As necessary  
At each clinic visit 
Adverse Events 
Adverse events (related to study treatment only) will be recorded 
and graded according to the NCI Common Terminology Criteria 
for Adverse Events (Version 4 CTCAE - Appendix V). 
At each clinic visit 
There will be no QoL, Physical Activity or Diet Questionnaires after a new invasive non-breast primary. 
 
 


 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions of Evaluability 
 
10.1.1 Evaluable for Adverse Events. All subjects will be evaluable for adverse event evaluation from the 
first date of their metformin/placebo. 
 
10.1.2 Evaluable for Quality of Life Assessment. All subjects who have completed the quality of life 
questionnaires are evaluable for quality of life. The quality of life questionnaires are being done in 
a defined sub-set of MA.32 subjects. (Sub-set closed to accrual 2011NOV04; follow-up continues.) 
 
10.1.3 Evaluable for Physical Activity and Nutrition Assessment. All subjects who have completed the 
Physical Activity and Nutrition Questionnaires are evaluable for these items. The Physical Activity 
and Nutrition Questionnaires are being done in a defined sub-set of MA.32 subjects. 
 
10.2 
Criteria for Measurement of Study Endpoints 
 
As invasive disease free survival is an important endpoint in this study, it is vital that it be 
adequately and precisely documented. The definitions used are from the STEEP System [Hudis, 
2007]. 
 
10.2.1 Definitions of Endpoints 
 
Primary Endpoint 
Invasive Disease Free Survival is defined as the time from randomization to the time of any of the 
following events: ipsilateral and contralateral invasive breast tumour, local/regional invasive 
recurrence, distant recurrence, death from breast cancer, death from non-breast cancer cause, death 
from unknown cause, diagnosis of a second primary invasive non-breast cancer (except squamous 
cell carcinoma and basal cell carcinoma of skin, completely excised and presumed cured). 
 
Secondary Endpoints 
Overall Survival is defined as the time from randomization to the time of death from breast cancer, 
death from a non breast cancer cause or death from an unknown cause. 
 
Distant Relapse Free Survival is defined as the time from randomization to the time of distant 
recurrence, death from breast cancer, death from a non breast cancer cause or death from an 
unknown cause. 
 
Breast Cancer Free Interval is defined as the time from randomization to the time of diagnosis of 
invasive ipsilateral breast tumour recurrence, local/regional invasive recurrence, distant recurrence, 
death from breast cancer, invasive contralateral breast cancer, ipsilateral DCIS, contralateral DCIS. 
 
Breast Cancer Specific Mortality is defined as the time from randomization to the time of death 
from breast cancer. 
 
Contralateral Invasive Breast Cancer is defined as the diagnosis of a primary invasive breast 
cancer in the opposite breast after randomization. 
 
Other Medical Endpoints – including one or more of: 
1. Diabetes: initiation of new anti-diabetes medication (or confirmed MD diagnosis of diabetes) 
2. Cardiovascular hospitalization or cardiovascular death (stroke, myocardial infarction) 
3. Changes in BMI (Please see Appendix IX) 


 
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10.3 
Evidence of Disease Recurrence/Progression 
 
As defined below, definite evidence of disease recurrence is required to determine that disease has 
recurred. 
 
Recurrence will be categorized as local, regional or distant. 
 
Local (Breast) Recurrence is defined as recurrence within the breast, following partial mastectomy. 
See 10.5 for management. 
 
Local (Chest Wall) Recurrence is defined as recurrent cutaneous or subcutaneous tumour occurring 
in an area bounded superiorly by the clavicle, inferiorly by a horizontal line at the level of the 
xiphisternum, medially by the midline and laterally by the posterior axillary line. 
 
Regional (Nodal) Recurrence is defined as recurrent tumour in the lymph nodes in the homolateral 
axilla, homolateral supraclavicular fossa or ipsilateral internal mammary chain. 
 
Distant Recurrence is defined as spread of disease beyond the limits specified in those above. 
 
10.3.1 Local - Regional Sites 
 
1. Definite - positive cytology, aspiration or biopsy 
2. Suspicious - a visible or palpable lesion 
 
10.3.2 Distant Recurrence 
 
a) Bone Marrow 
1. Definite - positive cytology, aspiration or biopsy 
2. Suspicious - leukoerythroblastic blood picture 
b) Lungs and Pleural 
1. Definite - 
i) Positive cytology, aspiration or biopsy, or 
ii) Presence of multiple pulmonary nodules which are felt to be consistent with pulmonary 
metastases 
 
Note: If a solitary lung lesion is found and no other lesions are present on lung tomograms, further 
investigation, such as CT scan, biopsy or needle aspiration, or thoracic diseases 
consultation should be performed. 
 
c) Skeletal 
1. Definite - 
i) X-ray evidence of lytic, blastic, or mixed lytic-blastic lesions on skeletal films with or 
without bone scan confirmation or 
ii) Biopsy proof of bone metastases or 
iii) Progressive bone scan changes over at least a four week period showing development 
of new lesions is necessary in asymptomatic subjects with only bone scan 
abnormalities 
 
Note: In the absence of progressive disease by scan a biopsy is strongly recommended. Any 
positive bone scan in joints or in a recent area of trauma (surgical or otherwise) cannot be 
used as a criterion of treatment failure. 
 
 


 
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d) Ascites and Pleural Effusions 
1. Definite - positive cytology or 
2. Suspicious - roentgenographic or clinical evidence 
 
e) Liver 
1. Definite - 
i) Liver enlargement, especially if the liver is nodular, with additional confirmation by an 
abnormal liver scan, ultrasound or CT scan demonstrating solid space occupying lesions 
or 
ii) Liver biopsy confirmation of metastatic disease 
 
Note: If the liver scan, ultrasound or CT scan findings are not definitive a liver biopsy is mandatory. 
 
f) Central Nervous System 
1. Definite - 
i) Positive CT scan or MRI, usually in a patient with neurological symptoms or 
ii) Biopsy or cytology (for a diagnosis of meningeal involvement) 
 
10.4 
Dating of First Recurrence 
 
This should always be based on the onset of a sign but never on the onset of a symptom. The date of 
first detection of a palpable lesion is acceptable only when the diagnosis of tumour involvement is 
subsequently established. 
 
The diagnosis of recurrent disease by radiographs or scans should be dated from the first positive 
record, even if this is determined in retrospect. 
 
Initial recording of dates of first recurrence and death should be made as they occur by those who are 
responsible for the care of the patient. Dates that are based on suspicion alone will be reviewed by 
the CCTG coordinating office in order to establish their accuracy through subsequent behaviour. In 
addition, the case records of those subjects not reported as having recurrent disease will be scrutinized 
regularly to check that review is continuing and to ensure consistent recording. 
 
10.5 
Management Following Recurrence 
 
Subject management following recurrence (breast, chest wall, regional and/or distant) is at the 
discretion of the Investigator but the subject must come off study treatment when recurrence is 
confirmed by the Investigator.  (Subjects need not come off study treatment for new in situ breast 
carcinoma only). 
 
10.6 
Contralateral Breast Carcinoma – Invasive and in situ 
 
A lesion in the opposite breast will be assumed to be a new primary malignancy unless obviously 
contiguous with recurrent chest wall disease or proven on cytology/biopsy to be of metastatic origin. 
Subjects must come off study treatment upon the diagnosis of invasive disease in the contralateral 
breast. (Subjects need not come off study treatment for new in situ breast carcinoma only). 
 
10.7 
Second Malignancy 
 
Subjects developing any new non-breast primary malignancies, except for adequately treated 
superficial squamous or basal cell carcinoma of the skin or in situ carcinoma of the cervix will 
discontinue protocol treatment (the exceptions based on the assumption that disease has been 
completely surgically excised and presumed cured). 
 
 


 
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11.0 
SERIOUS ADVERSE EVENT REPORTING  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4 will be utilized for Adverse Event (AE) reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
(Serious, Unexpected AND Related) 
 
• 
All serious adverse events which are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 11.2 for reporting instructions). These include 
events occurring during the treatment period (until 30 days after last protocol treatment 
administration) and at any time afterwards. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information contained in the Product Monograph. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol agent cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
11.2 
Serious Adverse Event Reporting Instructions 
 
Please report only events that are serious, unexpected AND related to study treatment as serious 
adverse events. All reportable serious adverse events must be reported using a web-based 
Electronic Data Capture (EDC) system being used for this trial. For details about accessing the 
EDC system and completing the on-line SAE report form, please refer to the CCTG Generic Data 
Management Guidebook for EDC Studies posted on the MA.32 section of the CCTG website 
(www.ctg.queensu.ca). 
 
 


 
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Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
MA.32 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2814 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the MA.32 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application.  
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
Reporting Malignancies or Myeloid Dysplasia 
 
Malignancies or myeloid dysplasia that are unexpected AND related to protocol treatment in the 
opinion of the investigator must be reported as Serious Adverse Events as described in Section 11.0 
and 11.2, within 15 working days of when diagnosis is known to the investigator. Other 
malignancies occurring or recurring during the trial, which are considered unrelated or expected 
should only be reported on the case report form. 
 
11.3.1 Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting 
 
a. Pregnancy Prevention 
 
WOCBP and males who are enrolled in the trial must have agreed to use contraceptive 
method(s) as described in Ineligibility Criterion 5.2.8.  Investigators may wish to additionally 
advise the female partners of male participants about pregnancy prevention guidelines when 
appropriate and compliant with local policy.  
 
 


 
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b. Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants, 
and female partners of male participants. Pregnancies occurring up to 30 days after the 
completion of study treatment must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning 
of the pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage.  
 
Once informed consent has been obtained, the form should be updated to provide further 
pregnancy information and to reflect the outcome of the pregnancy. All follow-up reports must 
be submitted to CCTG in a timely manner. For pregnant partner of trial participant (and 
pregnant participants, if required by local policy), a copy of the signed signature page of the 
pregnancy follow-up consent must be submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-
533-2812/safety-desk@ctg.queensu.ca).  
 
If the pregnancy results in death; is life-threatening; requires inpatient hospitalization or 
prolongation of existing hospitalization; results in persistent or significant disability/incapacity; 
is a congenital anomaly/birth defect, then an SAE report must be additionally submitted as 
described above. Please note, hospitalization for labour/delivery alone does not constitute an 
‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
c.  Exposure Reporting (non-study participants) 
The investigator is required to report to CCTG any incidence of exposure to study agent(s). 
Exposure is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- 
study participant (an individual who is not otherwise participating in this clinical trial). An 
example of an exposure includes a non-study participant swallowing study medication. The 
investigator is responsible for determining significance, based on the agent to which the 
individual is exposed.  
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of 
the exposure, using the CCTG Exposure Reporting Form available from the trial webpage.  
 
Once informed consent has been obtained, the form should be updated to provide further 
exposure information and to reflect the outcome of the exposure as the information becomes 
available upon appropriate follow-up of the exposed individual (follow-up for at least 30 days 
after exposure). All follow-up reports must be submitted to CCTG in a timely manner. A copy 
of the signed exposure follow-up consent signature page must also be submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-
533-2812/safety-desk@ctg.queensu.ca).  
 
If the exposure results in death; is life-threatening; requires inpatient hospitalization or 
prolongation of existing hospitalization; results in persistent or significant disability/incapacity; 
is a congenital anomaly/birth defect, then an SAE report must be additionally submitted as 
described above.  
 
 


 
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11.3.4 Blinded Studies and Patient Unblinding  
 
Centre requests for participant unblinding as a result of a pregnancy or exposure are acceptable. 
However, the usual unblinding rules (see section 8.1.6) must be followed. 
 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada (Office of Clinical 
Trials) 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which a causal relationship with protocol treatment can not be ruled out). 
 
11.5 
CCTG Reporting Responsibility to Apotex 
 
All serious adverse events that are judged to be serious, unexpected and related to study treatment 
(that is, regulatory reportable) will also be reported to Apotex, the provider of the metformin and 
placebo for this clinical trial. 
 
11.6 
Reporting Safety Reports to Local Research Ethics Boards 
 
CCTG will notify all Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to the CCTG. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. Investigators must notify their 
Research Ethics Boards (REBs) and file the report with their Product Monograph. The date of REB 
Submission for SAEs and SUs will need to be entered into the CCTG trial MA.32 web based safety 
monitoring utility and documentation of REB submission must be retained in the study binder on 
site. 
 
For this purpose, the REB submission template letter provided by CCTG should be used. Please 
note: 
• 
this letter must be either printed on institutional letterhead or contain the centre 
identification/REB name; 
• 
the date of REB submission must be provided; 
• 
this form must be signed by one of the approved participants (according to the participants list) 
for this trial. 
 
The submission of these events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. 
 
 


 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
Interruption of Discontinuation of Treatment 
 
Subjects whose treatment is interrupted for any reason except intolerable toxicity will be 
encouraged to resume and continue with their assigned therapy. 
 
Compliance (and reasons for non-compliance) should be noted on the follow-up report. A formal 
pill count will be done for this trial. Patient reported compliance will be employed and unused pills 
(returned by the patient at each dispensation of a new treatment kit) will be counted and recorded. 
The visit schedule for those subjects who discontinue therapy should not be modified as endpoints 
will be assessed for as long as the patient can be followed and an intent-to-treat analysis will be 
performed. 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Subjects may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy (Please 
consult protocol section 8). 
• 
Unacceptable toxicity as defined in Section 8  
• 
Intercurrent illness (e.g. including diabetes, congestive heart failure) precluding continuation 
of study medication. (Please consult protocol section 8.) 
• 
Tumour progression or disease recurrence as defined in Section 10.0. 
• 
Development of a new invasive primary cancer (other than basal cell carcinoma or squamous 
cell carcinoma of the skin that has been adequately treated) 
• 
Request by the patient. 
• 
Completion of therapy as outlined in Section 8.0. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if subjects discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
 
12.2 
Therapy After Protocol Treatment is Stopped 
 
Patient management following stoppage of protocol treatment is at the discretion of the 
Investigator. Metformin and matching placebo are identical in appearance as are the bottles in 
which they are provided. Blinding is critical to the integrity of this clinical drug trial. However, in 
the event of a medical emergency in an individual subject, in which knowledge of the 
investigational product is critical to the subject's management, the blind for that subject may be 
broken by the treating physician. Before breaking the blind of an individual subject's blinded 
treatment, the Investigator should have determined that the information is necessary, i.e. that it will 
alter the subject's immediate management. In many cases, particularly when the emergency is 
clearly not investigational product-related, the problem may be properly managed by assuming that 
the subject is receiving active product without the need for unblinding. The need to break the blind 
must first be discussed with the CCTG. For any treatment code unblinding, the reason and parties 
involved must be documented in the patient’s medical record. Treatment identification information 
should be kept confidential and should be disseminated only to those individuals that must be 
informed for medical management of the patient. The CCTG must be notified as soon as possible 
of any emergency situation in which the drug code was broken. See List of Contacts for details. 
 
12.3 
Follow-up Off Protocol Treatment 
 
Follow-up will continue after treatment completion according to the plan described in protocol 
section 9. 
 
 


 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
13.2 
Tissue Collection 
 
The collection of a representative block of the diagnostic tumour tissue (if available) and the 
adjacent normal tissue (part of the standard resection) is an important part of this trial. This is 
mandatory for site participation in the study, but the participation of subjects is optional. Blocks 
will be carefully banked as part of the CCTG tissue/tumour bank at Queen’s University in Kingston, 
Ontario. Tumour blocks will be the preferred material to collect, as one of the objectives will be to 
create tissue micro arrays. These will optimize the amount of tissue available to investigators and 
permit the preservation of the tumour block submitted. If, at any time, the submitting hospital 
requires the block to be returned for medical or legal concerns, it will be returned by courier on 
request. 
 
The tissue may be used by researchers now or in the future to better understand the nature of breast 
cancer and how patients respond to treatment. Samples will be used for research purposes only and 
will not be sold. A scientific review process of any proposals to use the tissue will take place and 
any proposals approved will have undergone ethics approval. Patients will not be identified by 
name. The only identification of tissue will be by a patient study number assigned at the time of 
randomization to the trial the surgical/ histology number and/or patient initials. Material issued to 
researchers will be anonymized and only identified by a coded number. 
 
Diagnostic pathology reports are received as part of the supporting documentation required for this 
trial. Receipt of these will initiate a request directly from the Queen’s Department of Pathology to 
pathology departments for a representative tumour block. 
 
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out 
without the expressed consent of the subject.  
 
All subjects on whom a diagnostic tumour block is collected will be aware of this retrieval and will 
have given their consent. 
 
13.3 
MA.32 Use of Tumour Blocks 
 
As part of the embedded correlative science for the MA.32 protocol, the following research is to 
be conducted on submitted tumour blocks:  
 
Insulin Receptor (IR) 
 
Our core analyses will examine IR expression on formalin fixed, paraffin embedded breast cancer 
tissue collected at breast cancer diagnosis. IR is commonly expressed on breast cancer cells 
[Mulligan, 2007], and is believed to mediate insulin action on breast tissue; activation of the receptor 
by insulin initiates signaling via the PI3Kinase pathway, leading to proliferation. IR expression is 
essential for indirect (insulin dependent) metformin effects. Given reports that IGF-1R may 
dimerize with IR in breast cancer [Frasca, 2003] we will evaluate IGF-1R in secondary analyses. 
 
LKB1 
 
LKB1 expression is key to the ability of metformin to affect AMPK activity within tumors and to 
suppress the growth-promoting outputs of this signaling pathway (i.e. mTOR-regulated protein 
translation). [Lizcano, 2004; Shaw, 2004] LKB1 expression is essential for direct (insulin independent) 
effects of metformin. 


 
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AMEND #1: 2011-AUG-15; AMEND #2: 2012-FEB-20;  
Phosphoantibody Markers of Activation of Key Signaling Pathways 
 
Expression of IR and LKB1 will be indicative of the capacity of tumor cells to respond to indirect 
(insulin and IR mediated) and direct (insulin independent, LKB1 mediated) effects of metformin 
respectively, however, the expression of these factors cannot distinguish whether the pathways 
underling these responses are actually activated. Multiple other genetic factors may alter pathway 
activation. As a result, activation markers of these pathways [PI3K (STMN1), PKB/Akt (P-
PKB/Akt,) mTOR (P-4E-BP1) and IRS-1 (P-IRS-1)] will be evaluated as predictors of metformin 
benefit. If one or more of these biomarkers are activated at breast cancer diagnosis, it is predicted 
that metformin benefit is possible. If none of these pathways is activated, it is predicted that 
metformin benefit will not be seen, regardless of IR and/or LKB1 expression. 
 
Genomic/Gene Expression Profile Predictive of Metformin Benefit  
 
Large-scale genomic studies over the past two decades have identified numerous recurrent genetic 
events in breast cancer, such as the amplification of HER2 oncogene or the mutations of the BRCA1 
and BRCA2 tumor suppressor genes, defining specific subgroups of patients and influencing their 
clinical management. More recent studies are focusing on building a comprehensive, genome-wide 
understanding of various types of breast cancer. We plan to use such analyses to search for a 
genomic/gene expression profile predictive of metformin benefit. In the case of observed 
metformin benefit, we will perform comprehensive genomic/gene expression analysis of peripheral 
blood and available tumour material. Considering rapid technical advances in the genomic analysis 
arena, at the time of analysis, we will choose the most appropriate methodology to delineate the 
genetic/gene expression predictors of metformin benefit.  
 
13.4 
Blood Collection and Analysis 
 
Investigation of a core group of blood variables (at baseline, 6 months after enrolment and at 48 
months of treatment) and tumor related factors (at diagnosis) that will be examined as predictors of 
metformin benefit in this trial is outlined below. We will also collect additional samples that will 
allow us to examine a broader array of both prognostic and predictive factors in future work. The 
blood collection for fasting glucose and insulin is a mandatory part of the baseline, 6-month and 48 
months of treatment measurements of MA.32. 
 
After an overnight fast of at least 12 hours, participants will provide the following blood specimens: 
1 tube for immediate glucose analysis (performed according to established institutional practice), 
light green topped tubes (containing lithium heparin - for plasma), red topped tubes (for serum) and 
lavender topped tube (for DNA). Lavender topped tubes for DNA should be collected even for patients 
who consent to blood banking but refuse genetic testing. DNA may be used to study gene expression 
without fitting the definition of genetic testing. (Please see the MA.32 Sample Consent Form for 
definitions.) The green topped tubes will be centrifuged within half an hour of collection and the plasma 
collected frozen immediately in 1 ml aliquots at -80°C. The redtopped tubes will sit for 30 minutes at 
room temperature and then be centrifuged and the collected serum frozen immediately in 1 ml aliquots 
at -80°C. Lavender topped tubes (whole blood in EDTA) will be collected and frozen at -80°C in 1 ml 
aliquots for subsequent thawing and DNA extraction. Specimens will be stored at participating centers 
immediately after collection and then shipped to a central laboratory, frozen on dry ice, in batches of 10 
sets or more (1 set = entire blood collection at one patient visit), for subsequent storage and ultimate 
analysis. Our plan to collect lymphocytes for DNA at both baseline and 6 months will provide the 
necessary sample to evaluate not only germline DNA but also potential changes in DNA methylation 
as a result of the metformin intervention. 
 
 


 
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13.5 
MA.32 Use of Blood Samples 
 
Insulin (plasma) 
 
Our core analyses will explore the indirect, insulin mediated, effect of metformin as a predictor of 
invasive disease free survival (primarily), overall survival and breast cancer free interval, including 
an evaluation of both baseline fasting insulin (primarily), change in insulin over 6 months 
(secondarily) and at 48 months of treatment. This primary focus on insulin reflects the recognition 
that insulin at diagnosis is a prognostic factor in breast cancer, and it reflects the major impact 
metformin has on insulin levels; our primary hypothesis is that higher insulin level at baseline will 
predict metformin benefit in the overall study population. Additionally, in exploratory analyses we 
will examine the relationship between change in insulin during the first 6 months of metformin 
administration and invasive disease free survival and overall survival in women randomized to 
metformin (change in insulin is expected to occur primarily in the metformin arm). 
 
Glucose (plasma) 
 
Fasting glucose levels have been associated with breast cancer risk in some but not all studies; their 
effect on prognosis is unknown. It is not clear whether the effect on risk is a direct one or whether 
glucose is a surrogate for insulin in these published studies. We plan to examine whether baseline 
glucose predicts metformin benefit independent of insulin or whether glucose modifies effects of 
insulin as a predictor of metformin benefit. We will also investigate Homeostasis Model 
Assessment (HOMA) [Vaccaro O, 2004], an empirically derived estimate of insulin sensitivity 
calculated from a single measure of fasting insulin and glucose that correlates well with the gold 
standard frequently sampled intravenous glucose tolerance test, as a predictor of metformin benefit, 
focusing on whether it provides additional prediction beyond insulin alone. 
 
Research Blood Samples Taken at Baseline and Again at 6 Months  
and at 48 Months of Study Treatment 
 
Type of 
Tube 
One Tube     (7 ml) 
(1.4 teaspoons) 
Light Green Top Tubes 
(3 x 4.5 ml) 
(2.7 teaspoons) 
Red Top Tube 
(2 x 6 ml) 
(2.4 teaspoons) 
Lavender Top Tube  
(1 x 6 ml) 
(1.2 teaspoons) 
To be 
used for 
Plasma for Fasting 
Glucose 
(done locally 
according to 
institution’s 
procedures & 
mandatory) 
Insulin 
(done centrally & 
mandatory) 
 
Plasma for storage for 
future research 
(optional) 
Serum for storage 
for future research 
(optional) 
DNA extraction 
(done centrally & optional) 
Lavender topped tubes for DNA should 
be collected even for patients who 
consent to blood banking but refuse 
genetic testing. DNA may be used to 
study gene expression without fitting 
the definition of genetic testing. (Please 
see the MA.32 Sample Consent Form 
for definitions). 
TOTAL VOLUME DRAWN = 38.5 ML (7.8 Teaspoons, 2.6 Tablespoons) 
 
Please see also Appendix X and Correlative Sciences Lab Manual posted on the web-site Trial Page.  
 
 


 
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13.6 
Central Data Review 
 
CCTG receives core support from the Canadian Cancer Society. To ensure efficient use of limited 
funding, the CCTG has, over the past 40 years, optimized their risk based trial oversight and 
monitoring program. A critical component is central data review of submitted deidentified source 
documents, allowing source data verification and confirmation of key aspects including eligibility, 
endpoints and safety outcomes. Depending on the trial’s design, these source documents may 
include such source documents as surgical and histopathology reports to confirm disease stage and 
type, imaging reports to confirm extent of disease and assess efficacy, or include submission of 
tumour samples (to confirm diagnosis and eligibility or DICOM images (to verify response or 
radiation therapy planning). These source documents are reviewed by experienced data managers 
and physicians and are critical to ensuring the accuracy of the data and consistency of conclusions 
drawn. 
 
The collection of this critical data involves submission of source documents by mail and/or fax. 
 
See Appendix III (Documentation for Study) for details of supporting document requirements for 
this trial and for requirements for the redaction of personal identifiers. Although it remains the 
centres responsibility to ensure adequate redaction of any information provided to CCTG, 
submitted source documents are reviewed prior to acceptance at CCTG; in the case of incomplete 
redaction, documents are destroyed and the site assigned a violation and required to resubmit. 
 
All patients will provide written informed consent for submission of source documents, and the 
rationale and documents to be collected will be detailed in the informed consent document. 
 
 
 


 
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14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
The primary objective of this study is to compare invasive disease-free survival (IDFS) in pre- and 
post-menopausal women with T1-T3, N+/-, ER/PgR+/-, HER2 +/- invasive breast cancer. Eligible 
subjects will be randomized to one of the following two treatment groups: metformin (850 mg po 
bid for 5 years, experimental arm) or placebo (one caplet po bid for 5 years, control arm). Subjects 
will be stratified by: 1) ER and PgR status (both negative vs. either ER or PgR positive), 2) Body 
Mass Index (< 30 kg/m2 versus > 30 kg/m2), 3) HER2 (Positive = 3+ over-expression by IHC in > 
30% of invasive tumour cells OR HER2 gene amplification by FISH/CISH> 6 HER2 gene copies 
per nucleus, OR a FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of > 2.2. All 
other results will be considered negative.) and 4) Chemotherapy administration (any versus none). 
We will also compare overall survival, distant relapse free survival, breast cancer free survival, 
breast cancer specific mortality, incidence of contralateral invasive breast cancer, health-related 
quality of life, body mass index between metformin and placebo arm. The intent-to-treat (ITT) 
population will comprise all randomized patients, will be based on the allocated treatment 
regardless of whether the patient received the assigned treatment, and will be based on the at-
randomization values of the stratification factors. The adverse events in the two different treatment 
groups will also be compared. The embedded correlative science studies are described in Section 
13 of this protocol. 
 
A minimization procedure [White,1978] will be used to allocate patients with equal probabilities to 
one of the two treatment groups. 
 
Based on recommendation from DSMC after the second interim analysis, only the study subjects 
with ER/PgR+ will be included as the primary analysis in the final analysis. 
 
14.2 
Primary Endpoints and Analysis 
 
The primary endpoint of this study is invasive disease-free survival. It is defined as the time from 
randomization to the time of documented ipsilateral and contralateral invasive breast tumour, 
local/regional invasive recurrence, distant recurrence, death from breast cancer, death from non-
breast cause, death from unknown cause, second primary invasive cancer (non-breast, except for 
adequately treated BCC or SCC of the skin). If a subject has not had invasive disease or died at the 
time of data cut-off for final analysis of the primary endpoint, IDFS will be censored on the date of 
last follow-up. The survival experiences of subjects in both treatment arms will be described by the 
Kaplan-Meier method. Stratified two-sided log-rank tests adjusting for stratification factors as 
defined in the protocol will be the primary method to compare IDFS between metformin and 
placebo arm. As an exploratory analysis, a Cox proportional hazards model will be used to identify 
and adjust for factors significantly related to invasive disease-free survival. 
 
All subjects will be evaluated for toxicity from the time of their first oral dose of study medication. 
Toxicities will be graded using the current CTCAE version (as per protocol Appendix V). The 
incidence of toxicities by arm will be summarized by type of adverse event. A Fisher’s Exact Test 
will be used to compare toxicities between two arms. 
 
 


 
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14.3 
Sample Size and Duration of Study 
 
The sample size for this study is calculated in order to compare invasive disease-free survival 
(IDFS) between subjects randomized to receive metformin versus placebo. At the time of study 
initiation, the 5 year IDFS for subjects allocated to the placebo arm was estimated to be 85.0%, 
based on a population of pre- and post-menopausal women with T1-T3, N+/-, ER/PgR +/-, HER2 
+/- invasive breast cancer. With an overall two-sided alpha of 0.05 a total of 431 events were 
required to provide 80% power to detect a hazard ratio (HR) of 0.76 between the two treatment 
arms after taking into account two planned interim analyses. This HR was selected because it was 
the HR seen in the WINS study of dietary fat reduction/weight loss in the adjuvant breast cancer 
setting, described in protocol Section 2.  
 
Analysis of compliance for the first 241 patients was performed. The drug discontinuation rate at 
6 months in MA.32 is 8.3% in the first 241 subjects; an additional 1.7% discontinuation was seen 
beyond 6 months (total 10%). Rates are likely higher on the metformin (vs placebo) arm because 
most discontinuations were due to Gl toxicity. Although MA.32 is a pragmatic study, and thus will 
assess effectiveness that includes non- compliance, we believe these drug discontinuation rates are 
higher than will be seen in future clinical practice (due to investigator inexperience with metformin 
and patient reluctance to continue a drug with side effects in the absence of documented benefit) 
and thus a more conservative HR should be targeted for this study. The issue of drug non-
compliance was discussed by the Trial Committee in December 2011 and the option of enrolling a 
higher risk population to target a more conservative HR was endorsed. This would be achieved by 
restricting enrolment of subjects with T1cN0 tumours to those with ER/PR and HER2 negative 
(triple negative) status and requiring the presence of at least one adverse prognostic factor for T2N0 
tumours (i.e. at least one of: ER and PgR negative, HER2 positive, histologic grade 3, Ki67 > 14%, 
Oncotype Recurrence Score > 25 or lymphovascular invasion). The changes in eligibility criteria 
would increase the IDFS event rate for entire study population from an estimated 15% to 19%. The 
resulting higher event rate (554 events) would allow detection of a HR 0.785 given our current 
sample size of 3582 assuming 3 years of accrual and an additional 3 years of follow-up, with an 
overall two-sided alpha of 0.05 and 80% power after taking into account two interim analyses (see 
Section 14.5 for details). This is the HR one obtains when we adjust our original HR of 0.76 for a 
10% drug discontinuation rate. The HR of 0.785 represents an absolute improvement of 3.7% in 5 
year IDFS from 81% to 84.7% for those allocated to metformin. The total duration of the trial 
would be six years.  
 
Based on the recommendation of DSMC after the second interim analysis, the final analysis will 
include only study subjects who were ER/PgR+ and be performed when 554 events are observed 
from these subjects. Because of the alpha spending during the first two interim analyses, the 
nominal two-sided significant level for the final analysis will be 0.037. With 554 events in the final 
analysis, there will be 78% power to detect the hazard ratio of 0.785 at two-sided 3.7% level or 
80% power to detect a hazard ratio of 0.78. It is expected that additional 4 years of follow-up from 
November 2015 would be required to observe the required number of events. 
 
 


 
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2021 Update 
As of October 31, 2020, the event number for the IDFS endpoint was 446 and an additional 40 
months is estimated to reach the target number of events (554) based on the current event rate. 
Analysis of data based on 446 events is associated with 68% power (reduced 10% from 78%) to 
detect a target HR of 0.785 at two-sided 0.037 level or 80% power to detect a hazard ratio of 0.757. 
The HR of 0.757 represents an absolute improvement of 3.8% in 5 year IDFS from 83.0% to 86.8% 
for ER/PgR+ patients allocated to metformin and approximates the target HR proposed in the 
overall population at the time of study initiation.  
 
Given the estimated retention of power to detect the target HR using a time based analysis with a 
last contact date of October 31 2020 compared to the additional time and resources to reach 554 
events to trigger the final analysis of the primary endpoint the study design will be amended to 
incorporate a time based analysis. The critical p value for the final analysis will be 0.037 to account 
for the prior interim analyses. As of October 31, 2020, the median followup for the patients in the 
hormone receptor positive study population is estimated to be 95 months. The change in study 
design has been endorsed by an independent statistician.  
 
In addition to the time based analysis described above, the protocol will be amended to include two 
new secondary endpoints that provide additional information regarding the anticancer and cancer 
prevention impact of metformin by measurement of breast cancer specific mortality and incidence 
of contralateral invasive breast cancer respectively. 
 
14.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators' meetings. 
 
14.5 
Interim Analysis 
 
Two interim analyses are planned for this study when 185 and 370 events are observed, to allow 
early termination of the study if the results are extreme. Lan-DeMets error spending function will 
be used to assess for superiority, and futility for superiority [Lan 1983]. The early stopping 
boundaries are based on a power family with power 3, which approximates the O’Brien-Flemming 
boundaries [Jennison 2000]. The actual p-values for superiority and futility will be calculated based 
on the number of events observed at the time of interim analysis, controlling the two-sided Type I 
error of 0.05 and the power of 80% at the end of the study. 
 
If exactly 185 events are observed for the first interim analysis, the null hypothesis would be 
rejected early due to evidence of superiority at the first interim analysis if the p-value is less than 
or equal to 0.00185. The alternative hypothesis would be rejected for futility if the p-value is at 
least 0.971. If exactly 370events are observed for the second interim analysis, the nominal critical 
p-values for rejecting the null hypothesis and the alternative hypothesis would be 0.0138 and 0.468, 
respectively. The nominal significant level for the final analysis of the primary endpoint is 0.0463 
when 554events are observed, to maintain the overall two-sided alpha of 0.05. 
 
Results of the interim analysis will be supplied to DSMC who will make their recommendation 
regarding continuation of the trial. 
 
No additional interim analysis will be performed. 
 
 


 
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2021 update: 
After the second interim analysis and the change of the study population to the hormone positive 
patients, no additional interim analysis is planned and the critical p-value for the final analysis will 
be 0.037 as described in Section 14.3. 
 
14.6 
Quality Of Life Analysis 
 
The EORTC QLQ-30 Global Score will be used for our primary assessment of quality of life but 
subscales and specific symptoms (diarrhea, bloating, flatulence, dyspepsia, abdominal cramps, 
nausea and vomiting, taste alteration, limitation of activities because of gastrointestinal symptoms, 
joint/musculoskeletal symptoms) will be used for our secondary hypothesis.  
 
Since QOL is not part of the primary outcome, we will measure QOL on a proportion of 
participants. We want to detect a small to medium effect size of ~0.3 in either the primary 
assessment or the 10 subscales (diarrhea, bloating, flatulence, dyspepsia, abdominal cramps, 
nausea, vomiting, metallic taste, limitation of activities by gastrointestinal symptoms, 
joint/musculoskeletal symptoms) of quality of life in the overall quality of life sub-study 
population. We also want to detect an effect size of 0.5 for these outcomes in each of the sub-study 
groups defined by adjuvant endocrine therapy use at the time of randomization (tamoxifen, 
aromatase inhibitor, no endocrine therapy). With significance at the 5% level and 80% power, we 
will need a total of 296 subjects (148/arm) in each of the 3 hormone therapy defined groups (888 
or 444/arm in the full HRQOL sub-study) to detect an effect size of 0.5 in each hormonal group; 
this sample size will allow us to detect an effect size of 0.289 for the entire HRQOL sub-study 
population. (Although subjects in the Quality of Life sub-group will not be stratified by endocrine 
therapy use, it is expected that, given the diversity inherent in the enrolment process, these three 
groups of subjects will be more or less evenly balanced between the metformin and placebo 
groups.) These estimates have taken into account expected dropouts (10%) and non-completion 
rates (20%). we have applied the Bonferroni correction to account for the multiplicity problem. 
 
 
It is anticipated that approximately 90% of the Quality of Life participants will also contribute 
Physical Activity and Diet Data yielding a sample size of about 800 subjects and an 80% power to 
detect an effect size of 0.304 for either the primary assessment or the 10 subscales. 
 
The EORTC QLQ-C30 and the Trial Specific Checklist will be mandatory prior to randomization, 
at 6 months and then annually in subjects participating in the HRQOL portion of the study. Scoring 
of questionnaires will be conducted by the central office of CCTG according to the scoring manual 
of the EORTC QLQ-C30. The Trial Specific Checklist items will be scored individually. 
 
Analyses of HRQOL data will be conducted and presented according to the standard approach of 
the CCTG. The levels of fatigue and overall QoL will be evaluated according to diet and physical 
activity in the metformin and placebo groups in the subset of QoL participants with diet and 
physical activity assessment. 
 
 


 
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15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group and may be credited 
as authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
 
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the study chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following the analysis of study results the 
draft is not substantially complete, the central office reserves the right to make other arrangements 
to ensure timely publication. 
 
15.3 
Submission of Material for Presentation or Publication 
 
Any manuscripts reporting the results of this clinical trial should be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission for 
publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator 
shall have the right to request that publication be delayed for up to an additional 30 days in order 
to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts should be provided to CTEP for 
forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or publication in 
the proceedings. Press releases and other media presentations must also be forwarded to CTEP 
prior to release.  
 
 


 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
(This section applies to Canadian Sites only; CTSU sites please refer to the CTSU Logistical 
Appendix. ICR-CTSU sites please refer to the ICR- CTSU-specific Appendix. IBCSG sites please 
refer to the IBCSG-specific Appendix.) 
 
16.1 
Institution Eligibility for Participation 
 
Selected member centres in good standing of the CCTG are eligible to participate in this study. 
Any centre joining the CCTG is required to sign a Participating Centre Study Agreement and have 
Standard Operating Procedures regarding the conduct of clinical trials. 
 
The CCTG will submit via fax to Health Canada for each participating Canadian centre prior to 
local activation a completed Health Canada Clinical Trial Site Information Form. 
 
Because this trial is affected by U.S. legislation, U.S. federal regulations for the protection of 
human subjects apply. Canadian and U.S. institutions must have a Federalwide Assurance (FWA) 
number issued by the Office for Human Research Protections (OHRP) of the Department of Health 
and Human Services. By means of this assurance, the institution and its REB agree to abide by U.S. 
standards regarding, for example, constitution of the REB.  
 
16.2 
Investigator Qualifications 
 
For all investigators (principal investigators and co-investigators) the following documentation 
must be on file with the CCTG: 
• 
A current curriculum vitae, updated and submitted within two years at the time of 
randomization. 
• 
Documentation indicating completion of training in the protection of human research 
participants (e.g. NCI U.S. Completion Certificate). 
• 
Completion of the required CCTG GCP training modules. 
• 
A current NCI U.S. investigator number. An NCI U.S. investigator number is obtained by 
completing and signing a FDA 1572 form, a Supplemental Investigator Data Form, and a 
Financial Disclosure Form. These forms and a current CV are submitted to the NCI U.S. by the 
investigator. 
 
For the principal investigator only: 
• 
A Health Canada Qualified Investigator Undertaking Form must be completed and signed by 
the principal investigator of the study at participating Canadian centres and received by the 
CCTG central office before that centre can be locally activated. 
 
16.3 
REB (Research Ethics Board) Approval for Protocols 
 
Each participating centre will have on file with the CCTG central office, as part of its membership/ 
agreement documents, a description of its ethics review process and composition of its REB. 
 
 


 
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REB Composition 
Membership of an REB approving this protocol must be consistent with Canadian regulatory 
requirements, summarized as follows: 
• 
at least 5 members; 
• 
majority of members are Canadian citizens or permanent residents; 
• 
includes 2 members whose primary expertise and experience are in a scientific discipline with 
broad experience in the methods and areas of research to be approved (1 of these is from a 
medical discipline); 
• 
includes 1 member knowledgeable in ethics; 
• 
includes 1 member knowledgeable in Canadian laws relevant to the biomedical research to be 
approved; 
• 
includes 1 member whose primary experience and expertise are in a non-scientific discipline; 
• 
includes 1 member who is from the community or is a representative of an organization 
interested in the areas of research to be approved and who is not affiliated with the CCTG or 
the centre where the clinical trial is to be conducted. 
 
A Health Canada REB Attestation Form must be completed and signed by the REB representative. 
Alternatively, an attestation to the following may be included in the signed local ethics approval 
document: 
• 
The membership of the Research Ethics Board complies with the membership requirements for 
Research Ethics Boards defined in Division 5 of the Food and Drug Regulations; 
• 
The Research Ethics Board carries out its functions in a manner consistent with Good Clinical 
Practice; and 
• 
The Research Ethics Board has reviewed and approved the clinical trial protocol and informed 
consent for the trial which is to be conducted by the qualified investigator named at the 
specified clinical trial site. This approval and the views of this Research Ethics Board have 
been documented in writing. 
 
This documentation must be received by the CCTG central office before the centre can be locally 
activated. 
 
Initial Approval 
Member centres wishing to participate in a trial are required to obtain full board local ethics 
approval of the protocol and consent form (see below) by the appropriate REB.  
 
Annual Re-Approvals 
This trial is NCI US affiliated and therefore U.S. regulations regarding the Protection of Human 
Subjects apply (U.S. Code of Federal Regulations Title 45, Part 46). These regulations require that 
re-approvals of research be conducted at least once per year for as long as data are being submitted 
on trial patients, even through the follow-up period. Furthermore, these regulations require that 
annual re-approvals must be full board as long as the study is open to accrual or patients are 
receiving protocol treatment or undergoing protocol mandated interventions. 
 
Amendments/Administrative Updates 
All amendments or administrative updates to the protocol must undergo review by local REBs. 
Amendments/administrative updates will be circulated to all participating sites in a standard format 
with clear instructions regarding REB review. If full board approval of an amendment is required 
it will be specified. 
 
 


 
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Amendments will be reviewed and approved by Health Canada prior to central implementation of 
the amendment, and by REBs prior to local implementation, EXCEPT when the amendment 
eliminates an immediate hazard to clinical trial subjects. Amendments will be distributed with 
Health Canada REB attestation forms which must be completed. For each amendment CCTG will 
collect documentation of REB approval, a completed REB attestation form. 
 
REB Refusals 
If an REB refuses to approve this protocol (or an amendment/administrative update to this protocol) 
the CCTG must be notified immediately of the date of refusal and the reason(s) for the refusal. 
Notification will then be made to Health Canada. 
 
Serious Adverse Events, Safety Updates, Investigator Brochure Updates and Product Monograph 
Updates 
During the course of the study serious adverse events, safety updates, investigator brochure updates 
or product monographs may be sent to you for reporting to your REB. The date of REB submission 
for these documents will need to be entered into the MA.32 web based safety monitoring utility 
and documentation of REB submission must be retained in the study binder on site.  
 
16.4 
Informed Consent 
 
Informed Consent Document 
The REB of an institution must approve the consent form document which will be used at that 
centre prior to its local activation; changes to the consent form in the course of the study will also 
require REB approval. 
 
It is essential that the consent form contain a clear statement which gives permission for 1) 
information to be sent to and 2) source medical records to be reviewed by the CCTG and other 
agencies as necessary. The consent form must include all ICH-GCP consent elements. In addition, 
the consent form should include all elements required by CCTG policy, and centres receiving funding 
from NCEHR, SSHRC and/or CIHR should include elements from the Tri Council Policy Statement 
(TCPS). 
 
Informed consent forms that do not contain all ICH-GCP required elements will require an 
amendment and will lead to the delay of local activation. A complete list of the elements required 
by regulations, guidelines and CCTG policy can be found by accessing the CCTG website at 
http://www.ctg.queensu.ca/private/ethics/consent_RE_Checklists.html. 
 
Because this study is NCI U.S. affiliated, U.S. regulations regarding consent form content also 
apply.  
 
The sample consent form provided in the protocol includes all the required elements, as well as the 
"additional" and "suggested" elements relevant to this study. REBs must consider the sample 
consent as the basis for review, as this form has been approved by the U.S. National Institutes of 
Health. Significant changes of wording or deletions of the adverse event or alternative therapy 
sections of the sample consent must be justified by the REB in writing; note however that additions 
to these sections are rarely a problem. 
 
 


 
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Consent Process/Patient Eligibility 
Patients who cannot give informed consent (i.e. mentally incompetent patients, or those physically 
incapacitated such as comatose patients) are not to be recruited into the study. Patients competent 
but physically unable to sign the consent form may have the document signed by their nearest 
relative or legal guardian. Each patient will be provided with a full explanation of the study before 
consent is requested. 
 
16.4.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up” consent form will not be required by 
CCTG.  
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure Follow-up” can be found 
on the trial webpage. The appropriate consent form must be used to obtain consent from any non-
trial participant (such as the pregnant partner or exposed individual).  
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 
 
Obtaining Consent for Research on Children  
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/legal guardian.  
 
For reporting an exposure, the parent/guardian is required to sign an “exposure follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
16.5 
Retention of Patient Records and Study Files 
 
ICH Good Clinical Practice guidelines apply to CCTG studies. It is the responsibility of CCTG to 
inform the investigator/institution as to when trial related records no longer need to be retained. 
The investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
 
CCTG will notify all the trial investigators/institutions and all the regulatory authorities if clinical 
development of an investigational product discontinues or when trial related records no longer need 
to be retained. 
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI). Reports are to be 
submitted according to the schedule in Appendix IV (Documentation for Study). 
 
 


 
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16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance programme. The monitors/auditors will require access to 
patient medical records to verify the data, as well as essential documents, standard operating 
procedures (including electronic information), ethics and pharmacy documentation (as applicable) 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. In addition, as this trial is NCI US affiliated, findings 
will be reported to the NCI US Clinical Trials Monitoring Branch as required.  
 
The above mentioned documentation, in addition to any submitted source documents, may be 
accessed remotely in the event of a public health emergency either through remote access to 
Electronic Medical Records or through a secure file sharing portal. 
 
16.8 
Case Report Forms 
 
A list of reports to be submitted, as well as expectation dates, are to be found in Appendix IV – 
DOCUMENTATION FOR STUDY. 


 
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insulin-like growth factor I and insulin-like growth factor binding protein 3 with breast cancer in young women in 
Norway. Cancer Epidemiol Biomarkers Prev 2008; 17: 2097-2100. PMID: 18708402 
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19046439 
 
 


 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET 
Required Investigations 
Pre-
study* 
6 
mo 
12 
mo 
24 
mo 
36 
mo 
48 
mo 
60 
mo 
Post study 
treatment 
History & Physical 
 
 
 
 
 
 
 
 
Waist & Hip Circumference, Blood Pressure 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status 
X 
 
 
 
 
 
 
 
Weight, BMI 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Medical History, Menopausal Status 
X 
 
 
 
 
 
 
 
Concomitant Meds 
X 
 
 
 
 
 
 
 
Hematology* 
 
 
 
 
 
 
 
 
Hemoglobin 
X 
X 
X 
X 
X 
X 
X 
 
WBCs, 
X 
X 
X 
X 
X 
X 
X 
 
Granulocytes 
X 
X 
X 
X 
X 
X 
X 
 
Platelets 
X 
X 
X 
X 
X 
X 
X 
 
MCV 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry* 
 
 
 
 
 
 
 
 
AST 
X 
X 
X 
X 
X 
X 
X 
 
ALT 
X 
X 
X 
X 
X 
X 
X 
 
Alkaline Phosphatase 
X 
X 
X 
X 
X 
X 
X 
 
Serum Creatinine 
X 
X 
X 
X 
X 
X 
X 
 
Serum Bilirubin 
X 
X 
X 
X 
X 
X 
X 
 
Serum Vitamin B12 
X 
 
X 
 
X 
 
X 
 
Fasting Glucose, Fasting Insulin (same draw) 
X 
X 
 
 
 
X 
 
 
Radiology 
 
 
 
 
 
 
 
 
Mammogram 
X 
 
X 
X 
X 
X 
X 
X 
Chest X-ray (or Chest CT) 
X 
 
 
 
 
 
 
 
Bone Scan (as necessary) 
X 
 
 
 
 
 
 
 
CT Abdomen (as necessary) 
X 
 
 
 
 
 
 
 
Other Investigations 
 
 
 
 
 
 
 
 
TNM Classification, Histologic Grade 
X 
 
 
 
 
 
 
 
ER / PgR Status 
X 
 
 
 
 
 
 
 
HER2 Status 
X 
 
 
 
 
 
 
 
Initiation of new anti-diabetes medication (or confirmed 
diagnosis of diabetes). Cardiovascular hospitalization 
(stroke, myocardial infarction) or death 
 
X 
X 
X 
X 
X 
X 
X 
Blood Sample for Correlative Science (serum, plasma, 
DNA) (optional) 
X 
X 
 
 
 
X 
 
 
Adverse Events 
 
 
 
 
 
 
 
 
CTC AE (version 4) Grade 3, 4 and 5 only 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life (888 subjects) sample size achieved 2011NOV04 
 
 
 
 
 
 
 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
 
Trial Specific Checklist 
X 
X 
X 
X 
X 
X 
X 
 
Physical Activity & Diet 
 
 
 
 
 
 
 
 
Block Alive Screener (Diet) 
X 
X 
X 
X 
X 
X 
X 
 
Physical Activity Items (NHS II) 
X 
X 
X 
X 
X 
X 
X 
 
* Please see protocol section 6 for timing of pre-study investigations 


 
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 
 
 


 
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APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Detailed information and instructions about drug distribution, transfer, returns, destruction and 
accountability will be provided in a separate document, in time for you to review this information and 
consider your participation in this clinical trial. 
 
General 
 
In order to initiate study drug distribution, CCTG must receive the address and the name of a contact person 
to whom the study drug will be shipped at each site. This will be accomplished as part of the local activation 
process.  
 
Distribution 
 
Metformin and Placebo will be provided by Apotex Inc. and supplied free-of-charge, through CCTG, to 
study participants. Study drugs will be organized into patient specific treatment “kits”. Each treatment “kit” 
will contain one bottle of either blinded Metformin or Placebo. Participating sites will be pre-stocked with 
treatment kits. In North America once a patient has been successfully randomized through the CCTG 
electronic data capture system, the identity of the treatment kit which should be given to the patient will be 
transmitted back to the submitter. Site Pharmacy stock will be re-supplied automatically as treatment kits 
are used. Kits to be re-supplied to each patient will be identified and communicated to the site automatically 
prior to each patient follow-up visit. All drug orders will be shipped directly to the Pharmacist designated 
responsible for MA.32 Study Drugs. 
 
Each treatment bottle will be labeled with the following: 
 
1. NCIC CTG MA32.  
2. Treatment Box Number 
3. Number of Tablets  
4. Instructions (Safety/Handling) 
5. Storage Instructions  
6. Blank line for Investigator name & phone # 
7. Lot Number/Expiry Date 
8. Blank line for patient initials 
 
Questions about drug orders, transfers, returns, destruction or accountability should be addressed to: 
 
CCTG 
MA.32 Team (RE: Drug Supply & Distribution) 
10 Stuart Street 
Queen’s University 
Kingston Ontario, Canada 
Phone: 613-533-6430 
K7L 3N6 
Fax: 613-533-2814 
 
 
 


 
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Drug Accountability 
 
The Investigator, or a responsible party designated by the Investigator (e.g. the responsible Pharmacist), 
must maintain a careful record of the receipt, disposition return and destruction of drugs received for use in 
this clinical trial using the NCI Investigational Agent Accountability record available on the NCI home 
page (http://ctep.info.nih.gov) or MA.32 Trial Page. (Please note that the original accountability logs 
provided by the study are to be continued for this trial.) As this is a double blinded study, a separate 
Investigational Agent Accountability Record must be maintained for each CCTG patient on this protocol 
as required by regulation.  
 
Subject Compliance 
 
Subjects are to bring study drug bottles to every protocol-mandated visit (to assist in assessing patient –
reported compliance). Both patient reported compliance and a pill count will be employed. Returns and 
destruction of same should be documented in the NCI Accountability Log for each patient. Patient returns 
and expired drug should be destroyed on site as per local standard operating procedures and documented 
on the Investigational Agent Accountability record. Instructions on handling of unused drug will be 
provided by the CCTG at trial closure.  
 
 


 
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APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization and will apply to all randomized patients.  
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except Quality 
of Life, Physical Activity, Diet and SAE reporting. For details of accessing the EDC system and completing 
the on-line Case Report Forms please refer to the “CCTG EDC Generic Data Management Guidebook” 
posted on the MA.32 area of the CCTG web-site (www.ctg.queensu.ca).  
 
The electronic CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Required at 
To be completed 
electronically 
Supporting Documentation* 
Mandatory 
Submission 
To be submitted 
immediately after the report 
they refer to has been 
submitted electronically 
Submission On 
Request 
To be submitted 
immediately after 
request 
Eligibility Checklist 
At time of 
randomization 
At time of 
randomization 
Consent form**, 
copies of protocol 
mandated baseline 
radiology, operative, 
and diagnostic 
pathology reports 
additional clinical, 
laboratory or 
imaging reports 
that may impact 
on decision 
regarding 
eligibility 
Baseline Report 
At time of 
randomization 
Within 6 weeks of 
randomization 
Telephone Follow-up 
Report 
One month after start 
of study drug 
Within 2 weeks of 
telephone contact 
 
 
Correlative Studies 
Report 
(Tumour and Blood) 
At time of 
randomization 
Within 6 weeks of 
drawing of 6 month 
sample 
Diagnostic pathology 
report 
(for tumour tissue 
only) 
 
Treatment Report 
At time of clinic visit 
Within 6 weeks of 
clinic visit 
Mammogram reports 
additional clinical, 
laboratory or 
imaging reports 
that 
may inform 
evaluation of 
safety 
End of Treatment 
Report 
As soon as off 
treatment status is 
confirmed 
Within 2 weeks of 
end of treatment 
 
 
Relapse/Progression 
Report 
Upon disease 
progression 
Within 6 weeks of 
confirmation 
Copies of protocol-
mandated imaging 
and non-protocol 
mandated imaging 
relevant to disease 
assessment , operative 
and pathology reports 
 
table continued on next page … 
 
 


 
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Electronic Folder 
Required at 
To be completed 
electronically 
Supporting Documentation* 
Mandatory 
Submission 
To be submitted 
immediately after the report 
they refer to has been 
submitted electronically 
Submission On 
Request 
To be submitted 
immediately after 
request 
Short Follow-up Report 
Annually after off 
treatment 
Within 6 weeks of 
clinic visit 
Mammogram reports 
(as appropriate – 
please see protocol 
section 9), Radiology 
reports for protocol 
-mandated imaging 
and non-protocol 
mandated imaging if 
relevant to disease 
assessment 
Additional clinical 
,laboratory or 
imaging reports 
that may inform 
evaluation of 
safety 
Death Report 
Upon patient death 
Within 6 weeks of 
patient death 
Autopsy report if 
autopsy was done 
Additional 
clinical, 
laboratory or 
imaging reports 
that may inform 
evaluation of 
cause of death 
SAE Report*** 
Within 24 hours of 
event 
Complete report 
within 10 days 
 
Additional 
clinical, 
laboratory or 
imaging reports 
that may inform 
evaluation of 
safety including, 
admission and 
discharge 
summaries/notes 
*** See section 11.0 Serious Adverse Event Reporting for details. 
** For Canadian centres, it is acceptable to submit only the signature page(s) of the main consent and only the check 
box page(s)/signature page(s) of the optional consent provided that the version date of the consent form is 
indicated. Centres are expected to redact the participant’s name and signature on the submitted copy, leaving only 
a portion visible (e.g. initials or loops) to confirm that a person has signed but that cannot identify that individual. 
*  Source documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, 
and/or serious adverse events. Supporting documents should be submitted immediately after the report they 
refer to has been submitted electronically. EDC forms submitted without supporting documentation are not 
considered submitted and will be reflected in the Centre Performance Index (CPI) as not submitted. All relevant 
patient identifiers, other than the CCTG patient ID assigned at enrollment, and any other prohibited personal 
information must be fully and completely redacted (blacked-out) on all source documentation, per national and 
local privacy protection regulations and requirements,. Acceptable methods include:  
•  fully opaque sticker/tab placed over the identifiers prior to submission 
•  fully opaque black marker; prior to submission please ensure that the information is no longer visible on the 
scanned document  
•  electronic black box placed over identifiers in PDF document that is subsequently printed.  
•  fully opaque black marker; please ensure that the information under the marker cannot be still be seen on the 
scanned document (often markers are translucent and the identifiers can in fact be seen after scanning)  
Note that supporting documents must include the participant’s trial code, CCTG patient serial number, and 
participant initials (or a two/three masking letter code assigned by your centre). 
 
 


 
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The CRFs to be used in this trial outside the EDC system are as follows: 
 
Report 
To be completed 
Due at CCTG 
Supporting Documentation 
Required 
Quality of Life, Physical 
Activity, Diet 
Questionnaires 
At intervals defined in 
Appendix I 
Within 6 weeks of 
completion of 
questionnaires 
 
 
 


 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
 
The descriptions and the grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4 will be utilized for Adverse Event (AE) reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4. Please note that only Grade 3, 4 and 
5 events are to be collected – except if an event qualifies as an SAE or if the event is recorded as a reason 
for going off study treatment. A copy of the CTCAE version 4 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 


 
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APPENDIX VI - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
Data derived from Quality of Life measured in clinical trials can help to select the optimal intervention, 
describe patient’s experience or provide prognostic information. Studies have shown that measuring Quality 
of Life provides additional information compared to measuring adverse events alone. Current literature 
reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or pre-registration (baseline) 
• 
during treatment / follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 


 
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2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, she should still complete the questionnaire prior to 
treatment. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel 
unwell. In that case, you may express sympathy that things are below par, but state that this 
is exactly the information we require if we are to understand more about how quality of 
life is affected. You may also remind them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
4. What If . . .  
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient.  
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over 
the phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 


 
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B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible.  
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion.  
 
5. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
is not literate in either English or French (or other languages that the questionnaire may be available 
in). In other words, if the assistance of a translator is required to comprehend the questions and reply, 
the questionnaires should not be completed. Translation of the questions is not acceptable. Please 
indicate on questionnaire. 
 
6. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then she is NOT eligible and should 
NOT be put on study. 
 
7. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire 
should be read to them and the answers recorded by a health care professional (e.g. preferably the 
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who 
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient 
is completing the questionnaire at home, and a telephone interview by the clinical research associate is 
not possible, then a spouse or friend may read the questions to the patient and record the answers. 
However, this method should be a last resort, and the spouse or friend should be instructed to not coach 
or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 
The Quality of Life Questionnaires will be administered to the first 888 eligible English/French 
speaking subjects. English-speaking subjects from this sub-set of 888 subjects will also do the Physical 
Activity and Diet Questionnaires. (The Physical Activity and Diet Questionnaire are available and 
validated only in English.) 
 


 
 
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Quality of Life Questionnaire – ENGLISH  
 
NCIC CTG Trial: MA.32 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: ____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check (√) 
 Prior to randomization 
During protocol therapy: 
 6 months 
 12 months 
 24 months 
 36 months 
 48 months 
 60 months 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
Was assistance required?___ Yes ___ No 
If yes, reason: ________________________________________ 
Where was questionnaire completed:  home 
 clinic 
 another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy            mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 


 
NCIC CTG Trial MA.32. Quality of Life Questionnaire 
Page 1 of 1 
Quality of Life Questionnaire (MA.32) 
 
The MA.32 study will employ, in a sub-set of 888 subjects, 2 instruments: 
 
1. EORTC QLQ C-30 
2. Trial Specific Checklist (last 7 questions of QoL questionnaire) 
 
The first 888 English or French-speaking eligible subjects to be enrolled will comprise this sub-set of subjects. These 
instruments will all be made available, to active sites, in paper format, for completion by subjects. Links to the instruments 
are provided here to facilitate their presentation to your local REB, with the protocol and consent form, for approval.  
 
The time required for subjects to complete each questionnaire is as follows: 
 
Questionnaire 
Time Required to 
Complete 
EORTC QLQ C-30 
 
http://www.eortc.be/home/qol/downloads/f/C30/QLQ-C30%20English.pdf 
 
http://www.eortc.be/home/qol/downloads/f/C30/QLQ-
C30%20FrenchCanadian.pdf 
 
 
20 minutes 
Trial Specific Checklist 
 
31. Did you have bloating of your abdomen (stomach or belly)?  
 
Avez-vous ressenti un ballonnement à l'abdomen (à l'estomac ou au ventre)? 
32. Did you have pain or cramps in your abdomen (stomach or belly)? 
 
Avez-vous ressenti de la douleur ou des crampes a l'abdomen (a l'estomac 
ou au ventre)?  
33. Did you have heartburn?  
 
Avez-vous ressenti (souffert de) brûlures d’estomac? 
34. Did you have gas?  
 
Avez-vous eu des gaz? 
35. Did you limit your activities because of gastro-intestinal problems?  
 
Avez-vous limité vos activités en raison de problèmes gastro-intestinaux? 
36. Did you have a metallic taste?  
 
Avez-vous eu un goût métallique? 
37. Do you have aching muscles or joints? 
 
Avez-vous ressenti des douleurs aux muscles ou aux jointures? 
 
5 minutes 
 
 


 
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APPENDIX VII - PHYSICAL ACTIVITY AND DIETARY QUESTIONNAIRES 
 
On the same sub-set of 888 MA.32 subjects, physical activity and dietary intake behaviours will also be 
addressed through the use of the following two instruments: 
 
1. Physical Activity Items of the Nurses Health Study II Questionnaire 
2. Block Alive Screener (Diet)  
 
Physical activity patterns and dietary intakes will be assessed in order to measure changes in these 
behaviours over time and to evaluate differences in these changes between Metformin and placebo groups. 
It will then be possible to adjust for changes in diet and physical activity in assessment of study outcomes.  
 
The Physical Activity and Diet Questionnaires will be administered to the English-speaking subjects in the 
888 subject sub-set because the Physical Activity and Diet Questionnaires are available and validated only 
in English.  
 
These instruments will all be made available, to active sites, in paper format, for completion by subjects. 
Copies of the instruments are provided here to facilitate their presentation to your local REB, with the 
protocol and consent form, for approval. 
 
Questionnaire 
Time Required to 
Complete 
Physical Activity Items of the 
Nurses Health Study II Questionnaire 
   
(Sample available in this Appendix) 
 
5 minutes 
Block Alive Screener 
 
(Sample available in this Appendix) 
 
10 minutes 
 
 
 


 
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APPENDIX VIII - 7TH EDITION OF THE TNM CLASSIFICATION OF MALIGNANT TUMOURS 
 
The 7th Edition of the TNM Classification of Malignant Tumours has recently been released. To facilitate 
this process, educational resources have been made available to promote the use of staging (visit 
http://www.cancerstaging.org/staging/posters/breast8.5x11.pdf and 
http://www.cancerstaging.org/staging/changes2010.pdf).  
These staging criteria should be used for new trials. 
 
Oncotype DX analyzes a panel of 21 genes within a tumor to determine a Recurrence Score. The Recurrence 
Score is a number between 0 and 100 that corresponds to a specific likelihood of breast cancer recurrence 
within 10 years of the initial diagnosis. In MA.32, an Oncotype Dx score > 25 is considered an adverse 
prognostic factor when assessing eligibility of women with node negative breast cancer measuring between 
1 and 2 cm.  
 
• 
Recurrence Score lower than 18: This suggests a low risk of recurrence. The benefit of 
chemotherapy is likely to be small and will not outweigh the risks of side effects. 
• 
Recurrence Score between 18 and 31: This score suggests an “intermediate” risk of recurrence. 
It’s unclear whether the benefits of chemotherapy outweigh the risks of side effects. 
• 
Recurrence Score greater than 31: A high risk of recurrence, and the benefits of chemotherapy 
are likely to be greater than the risks of side effects. 
 
Ki67 
Ki67 is a molecule that can be easily detected in growing cells in order to gain an understanding of the rate 
at which the cells within a tumor are growing. 
 
Detection of Ki67 is carried out on biopsies, samples of tumor tissue. The goal of this assay is to evaluate 
an important characteristic of the cells within the tumor, the percentage of tumor cells that are actively 
dividing and giving rise to more cancer cells. The number obtained through this examination is termed the 
S-phase, growth, or proliferative fraction. This information can play an important part in deciding the best 
treatment for a cancer patient. 
 
Estrogen and Progesterone Receptor Positive 
 
Estrogen and progesterone receptor status must be known. (Receptor positive by immunohistochemistry: 
ERICA or PgRICA versus both receptors negative. It is recommended that ER and PgR assays be 
considered positive if there are at least 1% positive tumour nuclei in the sample on testing in the presence 
of expected reactivity of internal [normal epithelial elements] and external control. [Hammond 2010] 
 
 
HER2 Positive versus Negative definition 
 
Positive = 3+ over-expression by IHC in > 30% of invasive tumour cells  
OR 
HER2 gene amplification by FISH/CISH > 6 HER2 gene copies per nucleus 
OR 
a FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of > 2.2 
 
All other results will be considered negative. 
 
 


 
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APPENDIX IX – EVALUATION METHODOLOGIES 
 
It is important that at least one individual, at each participating centre be trained to do the anthropometric 
measurements in a correct and consistent fashion so that the data may be compared over time. While these 
measurements are simple in concept, they should be performed, for this trial, according to the following 
procedures to ensure accuracy and consistency. 
 
Height 
 
Height will be measured in stocking feet using a stadiometer. Height should be recorded in metres.  
 
Weight 
 
Weight will be measured in indoor clothing (without shoes) using an appropriate clinical weight scale. 
Weight should be recorded in kilograms.  
 
Waist and Hip Circumference 
 
The circumference should be measured on subjects without heavy outer garments in a standing position. 
The contents of all pockets must be removed. All tight clothing, including the belt, must be loosened. The 
participant should stand with the feet fairly close together (about 12-15cm) with weight equally distributed 
on each leg. Participants should be asked to breathe out gently at the time of the reading of the measurement 
to prevent them from contracting their muscles or from holding their breath. The tape should be held firmly 
in a horizontal position. It is recommended that the observer is sitting by the participant while taking the 
measurement. 
 
The waist measurement should be recorded at the level midway between the lower rib margin and the iliac 
crest, in centimeters, rounded to the nearest .0 or.5 cm. 
 
The hip measurement should be recorded from the maximum circumference over the largest portion of the 
buttocks, in centimeters rounded to the nearest .0 or.5 cm. 
 
BMI 
 
SI units 
Imperial units 


 
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Blood Pressure 
 
Hypertension – Detection, Diagnosis and Management  
 
Measurements should be taken with a sphygmomanometer known to be accurate and by a health care 
provider or CRA who has been adequately trained in the measurement of blood pressure. A recently 
calibrated aneroid or a validated and recently calibrated electronic device can also be used.  Use the arm 
not affected by surgery. In the case of bilateral breast carcinoma, choose one arm for measurement and use 
it consistently. 
 
Reference: Canadian Hypertension Education Program. 2007 CHEP recommendations for the 
management of hypertension. 2007 (www.hypertension.ca/chep/). 
 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC DISEASE 
 
Clinical Evaluation of Functional Capacity of Patients with Heart Disease in Relation to Ordinary Physical 
Activity 
Class 
Cardiac Symptoms 
Limitations 
Need for 
Additional Rest * 
Physical Ability 
to Work ** 
I 
None 
None 
None 
Full time 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full time 
III 
Defined, with less than 
ordinary activity 
Marked 
Usually moderate 
Usually part time 
IV 
May be present even at 
rest, and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. 
** 
At accustomed occupation or usual tasks. 
Reference: Bruce, RA: Mod Concepts Cardiovasc Dis 25:321, 1956. (Modified from New York Heart Association, 1953) 
 
 


 
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APPENDIX X – CORRELATIVE SCIENCE PROCEDURES, BLOOD SAMPLING, PROCESSING 
AND SHIPPING 
 
Blood 
 
After an overnight fast of at least 12 hours, participants will provide the following blood specimens:  
 
 1 tube for immediate glucose analysis,  
 3 light green topped tubes (containing lithium heparin - for insulin & plasma),  
 1 red topped tube (for serum) and  
 1lavender topped tube (for DNA).  
 
• 
The green topped tubes will be centrifuged within half an hour of collection and the collected 
plasma frozen immediately in 1cc aliquots at -80°C.  
• 
The red topped tube will sit for 30 minutes at room temperature and then centrifuged and the 
collected serum frozen immediately in 1 cc aliquots at -80°C.  
• 
The lavender topped tube (whole blood in EDTA) will be collected and frozen in 1 ml aliquots 
at -80°C for subsequent thawing and DNA extraction.  
 
Specimens will be stored at participating centers immediately after collection and then shipped to a central 
laboratory, frozen on dry ice, in batches of 10 sets or more (1 set = entire blood collection from one patient 
visit), for subsequent storage and ultimate analysis. Our plan to collect lymphocytes for DNA at baseline, 
6 months and at 48 months of treatment will provide the necessary sample to evaluate not only germline 
DNA but also potential changes in DNA methylation as a result of the metformin intervention.  
 
Research Blood Samples Taken at Baseline and Again at 6 Months  
and at 48 Months of Study Treatment 
 
Type of 
Tube 
One Tube     (7 ml) 
(1.4 teaspoons) 
Light Green Top Tubes 
(3 x 4.5 ml) 
(2.7 teaspoons) 
Red Top Tube 
(2 x 6 ml) 
(2.4 teaspoons) 
Lavender Top Tube  
(1 x 6 ml) 
(1.2 teaspoons) 
To be used 
for 
Plasma for Fasting 
Glucose 
(done locally 
according to 
institution’s 
procedures & 
mandatory) 
Insulin 
(done centrally & 
mandatory) 
 
Plasma for storage for 
future research 
(optional) 
Serum for storage 
for future 
research 
(optional) 
DNA extraction 
(done centrally & optional) 
Lavender topped tubes for DNA 
should be collected even for patients 
who consent to blood banking but 
refuse genetic testing. DNA may be 
used to study gene expression without 
fitting the definition of genetic testing. 
(Please see the MA.32 Sample 
Consent Form for definitions. 
TOTAL VOLUME DRAWN = 38.5 ML (7.8 Teaspoons, 2.6 Tablespoons) 
 
 
 


 
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Tumour blocks will be requested by the Queen’s Department of Pathology and instructions will be 
included in the request as to where blocks should be sent. The request will be sent to the person named in 
the Correlative Studies Report. All blood frozen and stored at participating sites will be shipped, in 
batches, at intervals, on dry ice to: 
Attn: Shakeel Virk 
Pathology Coordinator 
Canadian Cancer Trials Group Tumour Bank 
Department of Pathology 
4th Floor Richardson Labs Building 
Stuart Street 
Queen’s University  
Kingston, ON K7L 3N6 
Tel: 613-533-2906 
Fax: 613 548-2486 
 
 


 
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APPENDIX XI – CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES 
 
Registration/Randomization 
 
Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. 
Each investigator must have an NCI investigator number and must maintain an “active” investigator 
registration status through the annual submission of a complete investigator registration packet (FDA Form 
1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and 
Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, 
DCTD, NCI. These forms are available on the CTSU registered member Web site or by calling the PMB at 
301-496-5725 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before 
they can enroll subjects. Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU member web site at 
http://www.ctsu.org  
 
All forms and documents associated with this study can be downloaded from the MA.32 page on the CTSU 
registered member Web site (https://www.ctsu.org). Subjects can be randomized only after pre-treatment 
evaluation is complete, all eligibility criteria have been met, and the study site is listed as ‘approved’ in the 
CTSU RSS. 
 
In order to participate in MA.32, sites must submit the “CCTG MA.32 Application to Participate”, by fax, 
to CCTG. Both the site candidate and the CTSU Regulatory Office will be notified simultaneously by 
CCTG if the site meets the requirements to move forward with site registration. 
 
Requirements for MA.32 site registration: 
 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
• 
IRB-approved consent form  
 
Pre-study requirements for patient enrollment on MA.32 
 
• 
Patient must meet all inclusion criteria, and no exclusion criteria should apply 
• 
Patient has signed and dated all applicable consents and authorization forms 
• 
All baseline laboratory tests and pre-study evaluations performed within the time period specified in 
the protocol. Please consult protocol section 6.0 for baseline investigations and protocol section 13 for 
blood banking and tumour banking information. Please do not send any tumour blocks until requested 
to do so by CCTG.  
• 
Patient completed baseline QOL forms, Physical Activity Questionnaire and Diet Questionnaire per 
protocol section 6.0 and Protocol Appendices VI & VII. 
 
CTSU Procedures for Patient Enrollment 
 
1.  Contact the CTSU Patient Registration Office by calling 1-888-462-3009 between 9:00 a.m. and 5:30 
p.m. Eastern Time, Mon-Fri.. Leave a voicemail to alert the CTSU Patient Registrar that an enrollment 
is forthcoming. For immediate registration needs, e.g. within one hour, call the registrar cell phone at 
1-301-704-2376. 
 
 


 
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2.  Complete the following forms: 
 
CTSU Patient Enrollment Transmittal Form 
Eligibility Checklist  
 
3.  Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 9:00 a.m. and 
5:30 p.m., Mon-Fri, Eastern Time (excluding holidays); however, please be aware that registrations 
received after 5:00 p.m. will be processed the next day. The CTSU registrar will check the investigator 
and site information to ensure that all regulatory requirements have been met. The registrar will also 
check that forms are complete and will follow-up with the site to resolve any discrepancies. 
 
4.  Once investigator eligibility is confirmed and enrollment documents are reviewed for compliance, the 
CTSU registrar will access the CCTG’s on-line registration system, to obtain assignment of a treatment 
arm  and assignment of a unique patient ID (to be used on all future forms and correspondence). The 
CTSU registrar will confirm registration by fax.  
 
Data Submission and Reconciliation 
 
The Medidata RaveTM web-based system will be used for electronic data capture (EDC). management and 
reporting on this trial. All case report forms (CRFs), with the exception of completed Quality of Life 
Questionnaires, Physical activity Questionnaires and Diet Questionnaires, will be electronic. Sites will be 
granted access to the EDC system following approval of all site registration documentation by the CTSU 
office. Questionnaires must either be downloaded from the MA.32 protocol web page located on the CTSU 
registered member web site (https://www.ctsu.org) or will be provided by CCTG to approved sites. Sites 
must use the current form versions and adhere to the instructions and submission scheduled outlined in the 
protocol. Submission of supporting documentation will also be required for this study. Supporting 
documents can be mailed or directly scanned/uploaded into the EDC system based on centre 
preference/capability. Mailed supporting documents should be sent directly to CCTG.  
 
Completed electronic CRFs must be submitted directly to CCTG, electronically, via the EDC system. 
Submit all paper questionnaires and supporting documents directly to the CCTG at the address on the “Final 
Page” of the protocol. Do not send study data to the CTSU.  
 
The CCTG will send query notices and delinquency reports directly to the site for reconciliation. These will 
be issued electronically, either directly through the EDC system (data queries for electronic CRFs) or by e-
mail (data queries for paper questionnaires and delinquency reports). Please send query response and 
delinquent data to the CCTG via the appropriate route (electronic or paper) as applicable in each case, and 
do not copy the CTSU Data Operations. Each site should have a designated CTSU Administrator and Data 
Administrator and must keep their CTEP IAM Account contact information current. This will ensure timely 
communication between the clinical site and the CCTG.  
 
Special Materials or Substudies 
 
Tumour tissue blocks (optional) and blood specimens (mandatory for insulin and glucose level 
determination) will be collected for MA.32 subjects. For details of specimen collection, please see protocol 
section 13 and the Sample Consent Form in Protocol Appendix XII. 
 
Please do not send any tumour blocks until requested by the CCTG to do so.  
 
 


 
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Quality of Life, Physical Activity and Nutrition Sub-studies (Protocol Appendices VI & VII) 
 
Order hard copy booklets from CCTG and submit completed forms, as outlined in the protocol, to CCTG 
at the address appearing on the protocol’s “Final Page”. 
 
Serious Adverse Event (AE) Reporting (Protocol Section 11) 
 
Please consult protocol section 11 for Serious Adverse Event Reporting.  
 
Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, or ALL via the 
NCI/CTEP AML-MDS Report Form in lieu of AdEERS. Submit the completed form and supporting 
documentation as outlined in the protocol.  
 
Drug Procurement (Protocol Appendix III) 
 
1. 
Information on drug formulation, procurement, storage and accountability, administration, and 
potential toxicities are outlined in Appendix III of the protocol and a more detailed guide will be 
provided prior to site activation. Sites will be pre-stocked with an initial supply of blinded 
Metformin/Placebo and re-stocked according to use (which will be monitored by the CCTG “Mango” 
System) 
 
2. 
You may navigate to the drug forms by selecting Pharmacy Forms from the document center tree on 
the MA.32 Web page.  
 
Regulatory and Monitoring 
 
Study Audit 
 
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314 and HHS 
45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program (CTEP) Clinical 
Trials Monitoring Branch (CTMB) guidelines for the conduct of clinical trials and study data validity, all 
protocols approved by NCI/CTEP are subject to audit. 
 
Responsibility for assignment of the audit will be determined by the site’s primary affiliation with a 
Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered through CTSU will 
become the responsibility of the Group receiving credit for the enrollment. For CTSU Independent Clinical 
Research Sites (CICRS), the CTSU will coordinate the entire audit process. 
 
For subjects enrolled through sites affiliated with the CTSU, you may request the accrual be credited to any 
Group for which you have an affiliation provided that Group has an active clinical trials program for the 
primary disease type being addressed by the protocol. Per capita reimbursement will be issued by the 
credited Group provided they have endorsed the trial, or by the CTSU if the Group has not endorsed the 
trial. 
 
Details on audit evaluation components, site selection, patient case selection, materials to be reviewed, site 
preparation, on-site procedures for review and assessment, and results reporting and follow-up can be found 
in the CTMB Monitoring Guidelines and are available for download from the CTEP web page 
http://ctep.cancer.gov/monitoring/guidelines.html. 
 


 
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Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
 
The HIPAA Privacy Rule establishes the conditions under which protected health information may be used 
or disclosed by covered entities for research purposes. Research is defined in the Privacy Rule referenced 
in HHS 45 CFR 164.501. Templated language addressing NCI-U.S. HIPAA guidelines are provided in the 
HIPAA Authorization Form located on the CTSU website.  
 
The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization to 
release Protected Health Information is NOT required from subjects enrolled in clinical trials at non-US 
sites. 
 
Clinical Data Update System (CDUS) Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative CDUS 
data will be submitted quarterly to CTEP by electronic means. The sponsoring Group fulfills this reporting 
obligation by electronically transmitting to CTEP the CDUS data collected from the study-specific case 
report forms. 
 
 


 
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APPENDIX XII - A HEALTHY LIFESTYLE AFTER BREAST CANCER 
 
Both the English and French copies of this document are available and posted on the MA.32 trial webpage. 
 
Many patients with breast cancer are interested in adopting a healthy lifestyle. This often involves changes 
in diet and physical activity. The American Cancer Society has developed information that may be helpful 
to breast cancer patients who would like to make lifestyle changes. This information can be found on the 
American Cancer Society website (www.cancer.org). Four helpful documents are provided here: 
 
1. 
Benefits of Good Nutrition 
2. 
Nutrition After Treatment Ends 
3. 
Make Exercise Work for You 
4. 
Fitting in Fitness 
 
Additional information is available on the American Cancer Society website.  
 
We encourage you to adopt a healthy lifestyle and suggest that you discuss planned changes in lifestyle 
with your health care team so ensure they are right for you. 
 
Benefits of Good Nutrition 
 
Good nutrition is especially important if you have cancer because the illness itself, as well as its treatments, 
can affect your appetite. Cancer and cancer treatments can also affect your body's ability to tolerate certain 
foods and to use nutrients. 
 
The nutrient needs of people with cancer vary from person to person. Your doctor, nurses, and a registered 
dietitian can help you identify your nutrition goals and plan ways to help you meet them. Eating well while 
you are being treated for cancer can help you: 
• 
feel better 
• 
keep up your strength and energy 
• 
keep up your weight and your body’s store of nutrients 
• 
tolerate treatment-related side effects 
• 
lower your risk of infection 
• 
heal and recover quickly 
• 
 
Eating well means eating a variety of foods that will give you the nutrients you need to protect your health 
while fighting cancer. These nutrients include protein, carbohydrates, fat, water, vitamins, and minerals. 
 
Nutrients 
 
Protein 
 
We need protein for growth, to repair body tissue, and to keep our immune systems healthy. When your 
body doesn't get enough protein, it takes you longer to recover from illness and you have lower resistance 
to infection. People with cancer often need more protein than usual. After surgery, chemotherapy, or 
radiation therapy, extra protein is usually needed to heal tissues and to help prevent infection. Good sources 
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Fats 
 
Fats play an important role in nutrition. Fats and oils provide a rich source of energy for the body. They are 
used to store energy, insulate body tissues, and transport some types of vitamins through the blood. They 
also play an important role in food preparation by enhancing food flavor, making baked products tender, 
and conducting heat during cooking. You may have heard that some fats are better for you than others. 
When considering the effects of fats on your heart and cholesterol level, choose unsaturated fats 
(monounsaturated and polyunsaturated). 
 
Monounsaturated fats are found mainly in vegetable oils such as canola, olive, and peanut oils. They are 
liquid at room temperature. 
 
Polyunsaturated fats are found mainly in vegetable oils such as safflower, sunflower, corn, flaxseed, and 
canola oils. Polyunsaturated fats are also the main fats found in seafood. They are liquid or soft at room 
temperature. Certain polyunsaturated fatty acids, such as linoleic acid and alpha-linolenic acid, are called 
essential fatty acids, because the body cannot make them. They are needed to build cells and make 
hormones. Essential fatty acids must come from foods we choose. 
 
Saturated fats (or saturated fatty acids) are mainly found in animal sources such as meat and poultry, 
whole or reduced-fat milk, and butter. Some vegetable oils like coconut, palm kernel oil, and palm oil are 
saturated. Saturated fats are usually solid at room temperature. 
 
Trans fatty acids are formed when vegetable oils are processed into margarine or shortening. Sources of 
trans fats in the diet include snack foods and baked goods made with partially hydrogenated vegetable oil 
or vegetable shortening. Trans fats also are found naturally in some animal products, such as dairy products. 
 
Carbohydrates 
 
Carbohydrates give the body the fuel it needs for physical activity and for proper organ function. There are 
also good and bad sources of carbohydrates. The best sources of carbohydrates -- fruits, vegetables, and 
whole grains -- supply needed vitamins and minerals, fiber, and phytonutrients to the body’s cells. Other 
sources of carbohydrates include bread, potatoes, rice, spaghetti, pasta, cereals, dried beans, corn, peas, and 
beans. Sweets (desserts, candy, and drinks with sugar) can supply carbohydrates, but provide very few 
nutrients. 
 
Water 
 
Water and fluids are vital to our health. All body cells need water to function. If you do not take in enough 
fluids or if you are vomiting or have diarrhea, you may become dehydrated. In general, a person should 
drink about eight 8-oz. glasses of water or clear liquid each day to be sure that all the body cells get the 
fluid they need. 


 
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Vitamins and minerals 
 
Vitamins and minerals are needed for proper growth and development. They also allow the body to use the 
energy (calories) supplied in foods. A person who eats a balanced diet with enough calories and protein 
usually gets plenty of vitamins and minerals. But it can be hard to eat a balanced diet when you are being 
treated for cancer and have treatment side effects that last for long periods of time. When that is the case, 
your doctor or dietitian may suggest a daily multivitamin and mineral supplement. If you are thinking of 
taking a vitamin or supplement, be sure to discuss this with your doctor first. Some people with cancer take 
large amounts of vitamins, minerals, and other dietary supplements to try and boost their immune system 
or even destroy cancer cells. Some of these substances can be harmful, especially when taken in large doses. 
In fact, large doses of some vitamins and minerals may reduce the effectiveness of chemotherapy and 
radiation therapy. During treatment, it may be best to choose one with no more than the Daily Value (DV) 
for all nutrients and one without iron, unless your doctor thinks that you need iron. Again, discuss this with 
your doctor first. 
 
Antioxidants 
 
Antioxidants are substances that protect the body's cells from damage caused by free radicals (by-products 
of the body’s normal processes). Examples of antioxidants include vitamin C, vitamin E, vitamin A (beta 
carotene), and selenium. If you want to take in more antioxidants, health experts recommend eating a variety 
of fruits and vegetables, which are good sources of antioxidants. Taking large doses of antioxidant 
supplements is usually not recommended while having chemotherapy and radiation therapy. Talk with your 
doctor to determine the best time to take antioxidant supplements. 
 
Herbs 
 
Herbs have been used to treat disease for hundreds of years. Today, herbs are found in many products, such 
as pills, liquid extracts, teas, and ointments. While many of these products are harmless and safe to use, 
others can cause severe and harmful side effects. Some may even interfere with proven cancer therapies, 
including chemotherapy, radiation therapy, and recovery from surgery. If you are interested in using 
products containing herbs, talk about it with your doctor or nurse first. 
 
Safety considerations 
 
Many people believe that if they find a pill or supplement in stores , it is safe and effective. The Food and 
Drug Administration (FDA) put out new rules in 2007 to help ensure that supplements contain what their 
labels claim they do. However, some of these rules will not be fully in effect until 2010. Even then, the 
supplement's safety and its effect on the body are not addressed by the new FDA rules. The FDA does not 
require manufacturers of these products to print possible side effects on their labels. The FDA cannot pull 
a dietary supplement or herbal product from the market unless it can prove that the product is unsafe. 
 
Tell your health care team about any herbal products and supplements that you are using or are thinking 
about using. Bring the bottle(s) of the supplement to your doctor to talk about the dose and to be sure that 
the ingredients do not interfere with your health or cancer treatments. Some other safety tips: 
• 
Ask your doctor or nurses for reliable information on dietary supplements. 
• 
Check the product labels for both the quantity and concentration of active ingredients contained in 
each product. 
• 
Stop taking the product immediately and call your doctor if you have side effects such as wheezing, 
itching, numbness, or tingling in your limbs. 


 
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Some people with cancer take large amounts of vitamins, minerals, and other dietary supplements in an 
effort to enhance their immune systems or even destroy cancer cells. Some of these substances can be 
harmful. In fact, large doses of some vitamins and minerals may reduce the cancer-fighting effects of 
chemotherapy and radiation therapy. If you would like to learn more about herbs and supplements, call us 
at 1-800-ACS-2345 or visit our web site at www.cancer.org. 
 
Nutrition After Treatment Ends 
 
Most eating-related side effects of cancer treatments go away after the treatment ends. Sometimes side 
effects such as poor appetite, dry mouth, change in taste or smell, trouble swallowing, or significant weight 
loss may last for some time. If this happens to you, talk to your health care team and work out a plan to 
address the problem.  
As you begin to feel better, you may have questions about eating a healthful diet. Just as you wanted to go 
into treatment with the necessary nutrient stores that your diet could give you, you'll want to do the best for 
yourself at this important time. There's very little research to suggest that the foods you eat will keep your 
cancer from coming back. But eating well will help you regain your strength, rebuild tissue, and feel better 
overall. And certainly, what you eat can help reduce risk for other cancers. 
 
Suggestions for healthy eating after cancer: 
 
• 
Check with your doctor for any food or diet restrictions.  
• 
Ask your dietitian to help you create a nutritious, balanced eating plan.  
• 
Choose a variety of foods from all the food groups. Try to eat at least 5 to 7 servings a day of fruits 
and vegetables, including citrus fruits and dark-green and deep-yellow vegetables.  
• 
Eat plenty of high-fiber foods, such as whole grain breads and cereals.  
• 
Buy a new fruit, vegetable, low-fat food, or whole grain product each time you shop for groceries.  
• 
Decrease the amount of fat in your meals by baking or broiling foods.  
• 
Choose low-fat milk and dairy products.  
• 
Avoid salt-cured, smoked, and pickled foods.  
• 
If you choose to drink, drink alcohol only occasionally.  
• 
If you are overweight, consider losing weight by reducing the amount of fat in your diet and increasing 
your activity. Choose activities that you enjoy. Check with your doctor before starting any exercise 
program.  
• 
See "Nutrition and Physical Activity During and After Cancer Treatment: Answers to Common 
Questions" to help choose foods for a well-balanced meal plan. 
 
Make Exercise Work for You 
 
No matter when you start, exercise improves health. Even people who start exercising later in life appear 
to gain many of the same health benefits as people who've exercised their whole lives, according to research 
at Stanford University School of Medicine. 
 
Physical activity throughout life can help protect against some cancers. For breast and prostate cancer, it 
may help by regulating hormone levels. For colon cancer, physical activity speeds up the digestive process, 
shortening the exposure of the bowel lining to harmful substances Exercise also helps reduce cancer risk 
by helping people maintain a healthy weight. 


 
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Choose Your Game 
 
It's important to enjoy what you're doing so you won't get bored or think of it as a chore. To choose an 
activity that's right for you, ask yourself these questions: 
 
Do you like to be social, or would you prefer time to yourself? 
• 
Social butterflies should try activities that connect them with other people. Try to walk with friends, 
join a team or recreation association, or go line dancing. 
• 
If you need time to yourself, walking, running, swimming, or gardening can give you time to reflect. 
 
Do you need to get energized or wind down? 
• 
For an energy boost, try aerobic activities that get the heart pumping. 
• 
Reduce stress with activities like yoga or tai chi. 
 
Are you goal-oriented, or do you like to stay flexible? 
• 
If you like to feel a sense of accomplishment, choose activities where you can chart and monitor your 
progress like training for a run, or take up an activity with rising skill levels, like martial arts. 
• 
For a more flexible routine, try walking or find an exercise video you can do at home. 
 
Do you want to get away from it all or get involved? 
• 
If you want to get away, choose outdoor activities like hiking, biking, or rollerblading. 
• 
Make your workplace more health conscious with the ACS program Active for Life. Participants 
choose their own physical activities, form teams of coworkers, and enjoy a friendly competition for 
the highest number of minutes spent exercising. 
• 
To get involved in the community, consider building homes for the disadvantaged, participating in 
charity walks and runs, helping an elderly neighbor with yard work, or tidying up a local school.  
 
How Much Activity Should You Be Doing? 
 
That depends on you. 
• 
If you haven't been active, you should start with moderate activities and gradually increase the 
duration, frequency, and intensity as you become more fit. Work your way up to 30 minutes or more 
five or more days a week.  
• 
If you are active but want to do more, increase the intensity, duration, or frequency of what you 
currently do. Moderate to vigorous activity for 45 minutes or more five of more days a week will 
increase your health benefits.  
• 
If you are active and want to maintain your current level of fitness, try adding new activities to your 
routine to use different muscles and keep your interest. 
 
Strike a Balance 
 
Ads for expensive exercise equipment and special diets can make healthy living look complicated. But the 
truth is there's no secret to achieving the weight you want. It is as simple as balancing the calories you burn. 
When that doesn't happen, you gain weight. 
 
Remember that everything you eat contains calories, and everything you do uses calories. For example, if 
you weight 150 pounds and are active, you need approximately 2,250 calories per day to maintain that 
weight, versus 1,950 calories if you are sedentary. 


 
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It helps to know that one pound of body fat equals 3,500 calories. That means that to lose one pound per 
week, you need to reduce your total calories by 500 per day. You can do this by eating 250 fewer calories 
a day, and burning an extra 250 calories through physical activity (e.g. walking 2.5 miles). 
 
To Burn Off a Large Order of Fries (400 Calories) 
 
A 160 pound person could burn off 400 calories in the time and activities shown below: 
 
Activity 
Minutes 
Moderate walking 
95 
Scrubbing Floors 
89 
Dancing 
70 
Bicycling 
39 
Running 
28 
 
To plan the physical activity for weight loss, you'll want a ballpark idea of how many calories are burned 
in different activities. For example, if you weigh 150 pounds and did the following activities for an hour, 
you'd burn 324 calories gardening, 297 in brisk walking, and 216 calories playing with kids. 
 
Less vigorous activities use fewer calories but still help in weight control. For a 150 pound person, an hour 
of strolling uses 206 calories, vacuuming or mopping—150 calories. Watching TV burns only 72 calories 
per hour. Find calorie counts for many other activities with our online calculator. 
 
Staying Motivated 
 
Be specific and choose variety. Rather than having general goals like "getting in shape" or "exercising 
more," choose concrete goals such as walking 30 minutes on Tuesdays and Thursdays, and doing stretching 
exercises five minutes each morning. The more variety you have, the more likely you will continue. A well-
rounded exercise program that includes aerobic exercise, strength training using weights, and flexibility 
exercises - even when performed regularly in small increments - is key, according to the American College 
of Sports Medicine.  
 
Incorporate fitness into your lifestyle. Begin to see exercise as an everyday opportunity. For example, 
use the stairs instead of the elevator, walk during lunch, or bike to work. Combine fitness with your family 
chores and activities, such as raking leaves or gardening. 
 
Motivate yourself. Try visualization techniques to help your motivation. Imagine yourself being in shape 
and how it feels. Create a vision of yourself looking fit. Rather than focusing on feeling out of shape, picture 
yourself feeling energized after your workout. Also, reward yourself when you meet each of your goals. 
 
Get a support system. Build a support system of family, friends, co-workers, and/or neighbors. They can 
help encourage you when your motivation is low. You can also exercise with someone else. Try to find a 
buddy who shares similar fitness interests. Many shopping malls have mall-walker programs where you 
can meet others. 
 
Expect setbacks and prepare for obstacles. Things like time, illness, or bad weather may occasionally 
get in the way. Disruptions are inevitable. Accept them and move on. If you go off your program, you can 
always adapt and resume. Some exercise is always better than none at all.  


 
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If you are a male older than 45 , or a female over 55, and have not been regularly active, or have any health 
concerns, consult your physician before you begin an exercise program. Regardless of your age, if you have 
two or more of the following risk factors, consult your physician:  
• 
High blood pressure  
• 
High cholesterol  
• 
Diabetes  
• 
You currently smoke  
• 
Family history of early onset heart disease (first degree relative with heart disease before age 65 for 
female relatives, or before age 55 for male relatives.) 
 
Fitting in Fitness 
 
Simple Steps Add Up 
 
Did you know you benefit from even small amounts of moderate activity throughout the day? Regular 
physical activity is easier to fit in than you may realize and can significantly lower your lifetime risk for 
cancer --and heart disease and diabetes, too. 
 
You'll find the American Cancer Society's physical activity guidelines for adults and children below. These 
recommendations are based on the latest scientific information to help reduce the risk of developing cancer. 
Read on for ways to fit in fitness that may surprise you, then learn how many calories are burned in common 
activities and exercises. 
 
ACS Physical Activity Guidelines 
 
Adults: Engage in at least 30 minutes of moderate to vigorous activity, above usual activities, on 5 or more 
days of the week; 45 to 60 minutes of intentional physical activity are preferable.  
 
Children and adolescents: Engage in at least 60 minutes per day of moderate to vigorous physical activity 
for at least 5 days per week. 
 
Moderate Activity is anything that makes you breath as hard as you do during a brisk walk. During 
moderate activities, you'll notice a slight increase in heart rate and breathing, but you may not break a sweat. 
 
Vigorous Activities generally engage large muscle groups and cause a noticeable increase in heart rate, 
breathing depth and frequency, and sweating. 
 
Other beneficial activities include those that improve strength and flexibility such as weight lifting, 
stretching, or yoga. 


 
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Examples of Moderate and Vigorous Physical Activities 
  
Moderate Activities  
Vigorous Activities  
Exercise and 
Leisure  
Walking, dancing, leisurely bicycling, 
ice-skating or roller-skating, horseback 
riding, canoeing, yoga  
Jogging or running, fast bicycling, 
circuit weight training, aerobic dance, 
martial arts, jump rope, swimming  
Sports  
Volleyball, golfing, softball, baseball, 
badminton, doubles tennis, downhill 
skiing  
Soccer, field hockey or ice hockey, 
lacrosse, singles tennis, racquetball, 
basketball, cross-country skiing  
Home 
Activities  
Mowing the lawn, general lawn and 
garden maintenance  
Digging, carrying and hauling, 
masonry, carpentry  
Occupational 
Activity  
Walking and lifting as part of the job 
(custodial work, farming, auto or 
machine repair)  
Heavy manual labor (forestry, 
construction, fire fighting)  
 
Active Substitutions 
 
Looking for more ways to work in activity during your day? Think about how much time you spend sitting 
rather than being active. Then consider these simple substitutions that can help you get moving. 
• 
Use stairs rather than an elevator.  
• 
Walk or bike to your destination.  
• 
Exercise at lunch with your workmates, family, or friends.  
• 
Take a 10-minute exercise break at work to stretch or take a quick walk.  
• 
Walk to visit co-workers instead of sending an email.  
• 
Go dancing with your spouse or friends.  
• 
Plan active vacations rather than only driving trips.  
• 
Wear a pedometer every day and watch your daily steps increase.  
• 
Join a sports team.  
• 
Use a stationary bicycle or treadmill while watching TV.  
 
No matter what kind of activity you choose, the important thing is to get moving. Try to fit in at least 30 
minutes of exercise on 5 or more days of the week, and look for other opportunities to be active throughout 
the day. 


 
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APPENDIX XIII - EQUIVALENT HEMATOLOGY UNITS 
 
The following units are equivalent to 109/L: 
 
103/mm3  
103/uL  
103/cmm  
103/cumm  
103/mcL  
1000/mm3  
1000/uL  
1000/cmm  
1000/cumm  
1000/mcL  
K/mm3  
K/uL  
K/cmm  
K/cumm  
K/mcL  
mil/mm3  
mil/uL  
mil/cmm  
mil/cumm 
mil/mcL  
thou/mm3  
thou/uL  
thou/cmm  
thous/cumm  
thous/mcL 
E9/L  
GIGA/L  
For example 
 
if the WBC count is 5.3 x103/uL 
this is the same as 
5.3 x109/L 
 
if platelets are 250 thou/mm3 
this is the same as  
250 x109/L 
The following units are equivalent to cells/mm3: 
 
cells/uL 
cells/cmm 
cells/cumm  
cells/mcL  
/mm3  
/uL  
/cmm  
/cumm  
/mcL  
For example 
 
if the WBC count is 5300 cells/uL 
this is the same as 
5300 cells/mm3 
 
if platelets are 250,000 /uL 
this is the same as  
250,000 cells/mm3 
 
 
 


 
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APPENDIX XIV - EMERGENCY SITUATIONS AND COMPLIANCE 
 
Management of Protocol Variances in Emergency Situations 
 
Compliance with the trial protocol, its amendments and any information that may be added to this document 
or provided as a part of the conduct of this trial as well as any associated sub-studies should be ensured to 
every extent possible, however in emergency situations, specific variances from the protocol that occur as 
a result of efforts to minimize or eliminate hazards and protect the safety and well-being of patients are 
permissible. 
 
In these rare circumstances, minor deviations that do not impact patient safety or willingness to participate 
or trial integrity, which have been justified and documented in the medical record by the QI/SI will not be 
considered to be REB reportable deficiencies requiring action, but must be reported to CCTG (e.g. in 
Electronic Data Capture (EDC) or using trial specific deviation logs as directed by CCTG) within 4 weeks 
of the end of the Emergency Situation, unless otherwise instructed by CCTG, and to your REB at the next 
amendment or annual approval. 
 
Centres should also discuss these reporting requirements with their local REB, and review the trial website 
for additional guidance specific to the trial. 
 
Minor Protocol Deviations: 
• 
Missed or delayed protocol mandated visits or investigations on treatment or in follow up. 
• 
Changes in study drug distribution (e.g. drug distributed remotely or IV drug given at satellite site), 
providing permitted by local SOPs, or written procedure established and is approved by CCTG or 
acceptable per further instruction from CCTG. Note there will be no exceptions for injectable/IV 
investigational agents as must be administered at participating site. 
• 
Alternative methods for safety assessments (e.g. telephone contact, virtual visit, alternative location for 
assessment). 
• 
Patient care and evaluations provided by non-research staff, providing overseen by QI/SI who must 
make all treatment decisions and ensure that all required information and results will be reported to 
allow central data submission. Includes physical exam, clinical laboratory tests, research blood 
collections that can be shipped centrally, imaging, non-investigational drug therapy*, standard radiation 
therapy, surgery, and other interventions that do not require protocol-specified credentialing*.  
*Must be approved by CCTG or acceptable per further instruction from CCTG. 
• 
Re-treatment following extended treatment delays if protocol specifies that excessive delays require 
discontinuation, providing other protocol requirements for discontinuation have not been met and either 
discussed with CCTG or acceptable per further instruction from CCTG. 
 
Note:  
− 
Applicable only to COVID-19 and other CCTG designated emergency situations. 
− 
No waivers will be given for eligibility, including performance of protocol mandated tests/imaging.  
− 
Deficiencies will be issued if patients are enrolled when trial is on accrual hold, for unreported Serious 
Adverse Events as well as changes in drug distribution/administration and/or re-treatment after 
extended treatment delays when not discussed and approved by CCTG or acceptable per further 
instruction from CCTG. 
− 
Deviations or changes that are believed to impact patient safety, compromise the study integrity or 
affect willingness to participate are still considered Major Protocol Violations and must be reported to 
CCTG and your REB. These include more than a minimal delay in protocol therapy administration. 
 


 
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CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
Contact 
Tel. # 
Fax # 
ELIGIBILITY CHECKLIST 
Must be completed prior to 
requesting a randomization. 
Amy Hawkins 
Clinical Trials Assistant 
CCTG 
 
Email: 
ahawkins@ctg.queensu.ca  
613-533-6430 
613-533-2814 
STUDY SUPPLIES 
Guides, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Paul Stos 
Study Coordinator 
CCTG 
 
Email: 
pstos@ctg.queensu.ca 
or: 
Dr. Wendy Parulekar 
Senior Investigator 
CCTG 
 
Email: 
wparulekar@ctg.queensu.ca 
613-533-6430 
416-586-8605 
613-533-2814 
416-586-8659 
STUDY CHAIR 
 
Dr. Pamela Goodwin 
Study Chair 
Email: 
pgoodwin@mtsinai.on.ca 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for 
details of reportable events. 
Dr. Wendy Parulekar 
Senior Investigator 
613-533-6430 
613-533-2814 
or: 
Paul Stos 
Study Coordinator 
CCTG 
613-533-6430 
613-533-2814 
DRUG ORDERING 
See Appendix III for full details. 
Amy Hawkins 
Clinical Trials Assistant(s) 
CCTG 
 
Email: 
ahawkins@ctg.queensu.ca 
 
613-533-6430 
613-533-2814 


 
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CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
AMEND #4: 2016-FEB-04 
Cancer Trials Support Unit (CTSU) Address and Contact Information 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data directly to the 
Lead Cooperative Group unless 
otherwise specified in the 
protocol: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
CTSU Patient Registration 
 
Please consult Appendix XI: Cancer 
Trials Support Unit (CTSU) 
Participation Procedures 
Data management will be 
performed by the CCTG by means 
of a web-based Electronic data 
Capture (EDC) System. Electronic 
case report forms must be 
submitted electronically. Clinical 
reports and supporting 
documentation may be submitted 
by mail to: 
 
NCIC CTG – MA.32  
Cancer Research Institute 
10 Stuart Street, 
Queen’s University 
Kingston, Ontario, Canada  
K7L 3N6 
Phone – 613-533-6430 
Fax – 613-533-2814 
 
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy the CTSU on data 
submissions.  
For patient eligibility or treatment-related questions  
Contact the Study Coordinator of the Coordinating Group.  
 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by 
phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will 
be triaged to the appropriate CTSU representative.  
The CTSU Public Web site is located at: www.ctsu.org  
The CTSU Registered Member Web site is located at https://members.ctsu.org 
 
CTSU logistical information is located in Appendix XI 
 

SAP_001.pdf: 
 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MA.32 
Version: 
V002 
Date: 
2021-12-09 
 
 
 
 
 
 
Statistical Analysis Plan 
Final Analysis 
 
 
A PHASE III RANDOMIZED TRIAL OF METFORMIN VERSUS PLACEBO 
ON RECURRENCE AND SURVIVAL IN EARLY STAGE BREAST CANCER 
 
 
CCTG Protocol Number: MA.32 
 
 
 
 
Prepared by: 
 
Protocol Statistician: Bingshu Chen 
 
 
Reviewed by: 
 
Senior Investigator: Wendy Parulekar 
Study Chair: Pam Goodwin 
 
Date: December 9, 2021 
 
 
 
 
 
 


 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MA.32 
Version: 
V002 
Date: 
2021-12-09 
 
Statistical Analysis Plan For CCTG MA.32 final analysis 
Page 1 
Table of Contents 
1 Introduction: ............................................................................................................................................. 3 
1.1 Objectives ...................................................................................................................................... 3 
1.2 Sample Size Determination ............................................................................................................ 3 
1.3 Timing of the Analyses ................................................................................................................... 3 
1.4 Data Collection .............................................................................................................................. 4 
2 Methods and Analyses .............................................................................................................................. 4 
2.1 Analyses Samples ........................................................................................................................... 4 
2.2 Conventions for Calculating Key Data ............................................................................................ 5 
2.3 Analysis Conventions ..................................................................................................................... 5 
2.4 Randomization and Pre-treatment Characteristics ....................................................................... 5 
2.4.1 Definitions and Variables ............................................................................................................ 5 
2.4.1.1 
Accrual .................................................................................................................................. 5 
2.4.1.2 
Randomization/Stratification ............................................................................................... 5 
2.4.1.4 
Ineligibility and Major Protocol Violations ........................................................................... 6 
2.4.1.4 
Summary of Follow-up ......................................................................................................... 6 
2.4.1.5 
Patient Characteristics .......................................................................................................... 6 
2.4.1.6 
Baseline Cancer Treatment .................................................................................................. 7 
2.4.1.7 
Baseline Hematology/Biochemistry ..................................................................................... 7 
2.4.1.8 
Baseline Non-Hematologic Adverse Events .......................................................................... 7 
2.4.2 Analysis of pre-treatment characteristics ................................................................................... 7 
2.5 Efficacy ........................................................................................................................................... 8 
2.5.1 Definitions and Variables ............................................................................................................ 8 
2.5.1.1 
Invasive Disease-free Survival (IDSF) .................................................................................... 8 
2.5.1.2 
Overall Survival (OS) ............................................................................................................. 8 
2.5.1.3 
Breast Cancer Free Interval (BCFI) ........................................................................................ 8 
2.5.1.4 
Distant Relapse Free Survival (distant RFS) .......................................................................... 8 
2.5.1.5 
Medical events ..................................................................................................................... 9 
2.5.2  Analysis of Key Parameters ...................................................................................................... 10 
2.5.2.1 
Invasive Disease-free Survival ............................................................................................ 10 
2.5.2.2 
Overall Survival, BCFI and distant RFS ................................................................................ 11 
2.6 Drug Exposure Dawn hershman is working on this ..................................................................... 11 
2.7 Safety ........................................................................................................................................... 13 
2.7.1 Definitions and variables .......................................................................................................... 13 
2.7.1.1 
Non-hematologic adverse events ....................................................................................... 13 
2.7.1.2 
Hematology/Biochemistry .................................................................................................. 13 
2.7.1.3 
Serious adverse event ........................................................................................................ 13 
2.8  Off study and death .................................................................................................................... 13 
2.9  Quality of Life .............................................................................................................................. 14 
2.9.1 Definitions and Variables .......................................................................................................... 14 
2.9.1.1. EORTC QLQ-C30 .................................................................................................................... 14 
2.9.2 Analysis ..................................................................................................................................... 16 
2.9.2.1 Determination of Assessment Times ..................................................................................... 16 
2.9.2.2 Calculation of Compliance Rates ........................................................................................... 16 
2.9.2.3 Cross-sectional analysis ......................................................................................................... 16 
2.9.2.4 QOL response analysis ........................................................................................................... 17 


 
Statistical Analysis Plan (SAP) 
Doc. No.: 
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Version: 
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Date: 
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Statistical Analysis Plan For CCTG MA.32 final analysis 
Page 2 
2.9.2.5 QOL subscale trend analysis .................................................................................................. 17 
3 Tables ...................................................................................................................................................... 18 
Table 1 Accrual by centre .................................................................................................................. 18 
Table 2: Accrual by Stratification Factors at Randomization ............................................................. 18 
Table 3: Treatment received .............................................................................................................. 19 
Table 4: Stratifiation factor at randomization vs. at baseline ............................................................ 20 
Table 5: Egilibity status ...................................................................................................................... 21 
Table 6: Summary of Follow-up ......................................................................................................... 22 
Table 7: Patient characteristics .......................................................................................................... 23 
Table 8. Baseline Hematology / Biochemistry ................................................................................... 25 
Table 9. Baseline Non-Hematologic Adverse Event ........................................................................... 25 
Table 10. Log Rank and Cox Regression Model for IDFS Survival ...................................................... 26 
Table 11: IDFS by Subsets .................................................................................................................. 27 
Table 12: IDFS event Summary .......................................................................................................... 28 
Table 13. Log Rank and Cox Regression Model for Overall Survival .................................................. 31 
Table 14: OS by Subsets ..................................................................................................................... 32 
Table 15: Death Summary ................................................................................................................. 33 
Table 16: Drug exposure .................................................................................................................... 34 
Table 17.Non-Hematology adverse events ........................................................................................ 35 
Table 18. Hematology / Biochemistry (Follow-up) ............................................................................ 35 
Table 19. Serious Adverse Events ...................................................................................................... 35 
Table 20. Off protocol treatment ...................................................................................................... 35 
Table 21. Death on Trial ..................................................................................................................... 36 
Figure 1. KM plot for IDFS .................................................................................................................. 36 
Figure 2. KM plot for OS .................................................................................................................... 36 
Figure 3. KM plot for BCFI .................................................................................................................. 36 
Figure 4. KM plot for distant RFS ....................................................................................................... 36 
 
 
 


 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MA.32 
Version: 
V002 
Date: 
2021-12-09 
 
Statistical Analysis Plan For CCTG MA.32 final analysis 
Page 3 
1 Introduction: 
 
MA.32 is a phase III superiority trial comparing invasive disease free survival (IDFS) between subjects 
treated with metformin (850 mg po bid for 5 years) versus placebo in addition to standard adjuvant 
therapy in women with early stage breast caner. This document is to describe the statistical analysis plan 
for the protocol specified final analysis of MA.32. 
 
 
1.1 Objectives  
 
The Primary Objective of the trial is to compare improvement in IDFS between treatment and placebo 
arms in the hormone receptor (ER and PgR) positive breast cancer patients. The Secondary Objectives 
include comparing the following endpoints: Overall Survival (OS), distant disease-free survival,  breast 
cancer free interval (BCFI), Breast Cancer Specific Mortality (BCSM), contralateral breast cancer (Invasive 
and DCIS), changes in body mass index (BMI = weight (kg)/height(m)2),  adverse events, other medical 
endpoints – including a new diagnosis of diabetes mellitus or cardiovascular hospitalization or death, 
health related quality of life, plasma metabolic factors (including insulin, glucose, CRP, leptin and others)  
and molecular markers (including insulin receptor, pAKT and others) of metformin action, insulin 
resistance syndrome.   
 
1.2 Sample Size Determination  
 
With an overall two-sided alpha of 0.05 and 80% power, a total of 554 IDFS events  would allow detection 
of a HR 0.785,  after taking into account two interim analyses (see Section 14.5 of the protocol for details). 
A HR of 0.785 represents an absolute improvement of 3.7% in 5 year IDFS from 81% to 84.7% for those 
allocated to metformin. The original sample size estimation was 3582 women, assuming 3 years of accrual 
and an additional 3 years of follow-up, 3582 women will be accrued. A total of 3649 women were accrued 
to enable international participation The study population for the primary analysis was amended to 
include to the ER/PgR positive patients after the second interim analysis. See 1.3 for details. 
 
1.3 Timing of the Analyses  
 
Original timing of the analysis 
 
Two interim analyses were planned for this study when 185 and 370 events are observed, to allow early 
termination of the study if the results were extreme. Lan-DeMets error spending function was used to 
assess for superiority, and futility for superiority. The early stopping boundaries werebased on a power 
family with power 3, which approximates the O’Brien-Flemming boundaries. The actual p-values for 
superiority and futility were calculated based on the number of events observed at the time of interim 
analysis, controlling the two-sided Type I error of 0.05 and the power of 80% at the end of the study. 
 
If exactly 185 events were observed for the first interim analysis, the null hypothesis would be rejected 
early due to evidence of superiority at the first interim analysis if the p-value is less than or equal to 
0.00185. The alternative hypothesis would be rejected for futility if the p-value was at least 0.971. If 
exactly 370 events were observed for the second interim analysis, the nominal critical p-values for 
rejecting the null hypothesis and the alternative hypothesis would have been 0.0138 and 0.468, 


 
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respectively. The nominal significant level for the final analysis would be 0.0463 when 554 events were 
observed, to maintain the overall two-sided alpha of 0.05. 
 
Revised timing of the analysis 
 
Based on the recommendation of DSMC after the second interim analysis, the final analysis would include 
only study subjects who were ER and/or PgR+ (measured at baseline) and be performed when 554 events 
were observed from these subjects. Because of the alpha spending during the first two interim analyses, 
the nominal two-sided significance level for the final analysis would be 0.037 for the revised study 
population. With 554 events in the final analysis, there would be 78% power to detect the hazard ratio of 
0.785 at two-sided 3.7% level or 80% power to detect a hazard ratio of 0.78. It was expected that 
additional 4 years of follow-up from November 2015 would be required to observe the required number 
of events. The power would be reduced if the number of events did not reach 554. 
 
AS of November 5, 2020, there were 446 IDFS events in the ER and/or PgR piositive group and based on 
the current event rate, it is projected that at least another 3 years of follow-up would be required to 
observe 554 events. With 446 events, the power to detect the hazard ratio of 0.78 would be 70%. The 
power to detect an hazard ratio of 0.757 would be 80%. Because of the relatively moderate loss in the 
power  (from 80% to 70%) of the study, continued decline in the event rate (from 40 per year in 2018, 27 
per year in 2019 and 13 events in the first 10 months of 2020), the Trial Leadership recommended that  a 
time based final analysis be performed in 2021. This request was  was approved by the Cancer Therapy 
Evaluation Program, Central Institutional Review Board with notification and approval by the CCTG 
independent Data Safety Monitoring Committee. The estimated median follow-up of all women at the 
time of final analysis would be be approximately 7.6 years.  
 
The selected clinical cut-off date is October 31st, 2020 and the database was cleaned and locked on  July 
9, 2021. 
 
 
1.4 Data Collection  
 
Data were collected, entered and managed by CCTG, Queen’s University, according to the group standard 
data management procedures.  
 
 
2 Methods and Analyses 
 
2.1 Analyses Samples 
 
Only study subjects who were ER and/or PgR+ (variable measured at baseline) will be included in this 
primary final analysis. There will be parallel analyses in hormone receptor negative subjects and in all 
subjects combined as secondary analyses. The study populations for this analysis will include both the 
intention to treat (ITT) and as treated  populations with data included as specified by the data cutoff date. 
 
Analysis of pretreatment characteristics and all efficacy outcomes such as IDFS and OS, will be based on 
the ITT population, regardless of actual treatment received. An sensitivity analysis for efficacy outcomes 


 
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will be conducted for the as treated population. Those who received at least one dose of protocol therapy 
(i.e. the as treated population) will form the basis of the safety analyses.  
 
We will conduct secondary analyses in ER and PgR negative population and the full study population. The 
results for these two analyses will be provided in a separatestatistical snalysis report (SAR). 
 
 
2.2 Conventions for Calculating Key Data  
 
In general, baseline evaluations are those collected closest, but prior to or on the day of randomization. 
If pre-randomization assessment was not done, a pre-treatment assessment will be used as baseline 
assessment.  
 
When either day or month of a date is missing, the missing day and/or month will be imputed by the 
midpoints within the smallest known interval. For example, if the day of the month is missing for any date 
used in a calculation, the 15th of the month will be used to replace the missing day. If the month and day 
of the year are missing for any date used in a calculation, the first of July of the corresponding year will be 
used to replace the missing data. 
 
2.3 Analysis Conventions  
 
All comparisons between treatment arms will be carried out using a two-sided test at an alpha level of 5% 
unless otherwise specified. For the final analysis of the primary endpoint IDFS, the p-value cutpoint will 
be 0.037 instead of 0.05. No formal adjustments will be made for the multiplicity of inferences for the 
other clinical endpoints.  
 
The following baseline stratification factors that will be used to adjust the analyses where appropriate are 
listed below: 
 
• 
BMI </= 30 versus > 30 (kg/m2) 
• 
HER2 positive versus HER2 negative 
• 
Chemotherapy – any versus none 
 
*Add missing/unknown category whenever appropriate. 
 
 
2.4 Randomization and Pre-treatment Characteristics 
 
2.4.1 Definitions and Variables  
 
2.4.1.1 Accrual 
 
• 
Number (%) of randomized patients per study center and country (table 1). 
 
2.4.1.2 Randomization/Stratification  
 


 
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• 
BMI </= 30 versus > 30 (kg/m2) 
• 
HER2 positive versus HER2 negative 
• 
Chemotherapy – any versus none 
 
A minimization procedure for treatment assignment was used in this study. Stratification factors at 
randomization will be summarized by treatment arm (table 2).  
 
Number and percentage of actual treatment received will be summaried by treatment arm (table 3). 
 
Treatment at randomization will be compared with the actual treatment received to identify any 
discrepancies (table 4). 
 
2.4.1.3 Ineligibility and Major Protocol Violations 
 
Number and percentage  of ineligible patients will be be presented by treatment arm (table 5). 
 
Reasons for ineligibility: percentage for each reason and combination of reasons of ineligibility will be 
presented by treatment arm.  
 
The number and percentage of major protocol violations will be presented by treatment arm. (table 5) 
 
The number and percentage of COVID protocol variances will be presented by treatment arm. (table 5a) 
 
 
 
2.4.1.4 Summary of Follow-up 
 
A table showing the median, min and max follow-up (defined as reverse censoring on IDFS survival) will 
be presented by treatment group and for all patients included in analysis. (table 6) 
 
2.4.1.5 Patient Characteristics  
 
Patient characteristics at baseline are summarized in table 7. 
 
• 
Age 
• 
Height (cm) 
• 
Weight (kg) 
• 
BMI 
• 
Race 
• 
ECOG PS 
• 
Menopausal Status 
• 
Receipt of (neo)adjuvant chemotherapy 
• 
Receipt of (neo)adjuvant hormone therapy 
• 
Hormone receptor status (must be 100% positive) 
• 
cT Stage (neoadjuvant) 
• 
cN Stage (neoadjvuant) 


 
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• 
pT stage (adjuvant) 
• 
pN stage (adjuvant) 
• 
Most extensive primary surgery – breast and axilla separately 
• 
Adj radiotherapy 
• 
HER2 status 
• 
Grade 
• 
Breast cancer sub-type (Ductal vs Lobular) 
• 
Resection margins 
• 
Number of axillary nodes examined 
• 
Number of positive axillary nodes 
• 
Number of sentinel nodes examined 
• 
Number of positive sentinel nodes 
 
*An unknown category will be added when appropriate.  
 
 
2.4.1.6 Baseline Cancer Treatment 
 
Number and percent of patients who received cancer treatment (Chemotherapy, Hormone Therapy 
(Neoadj vs post op), Immunotherapy, Adjuvant therapy, Neo-adjuvant therapy, Radiotherapy, Other 
therapy), Comorbidity (cardiovascular) will be summarized by treatment arm (table 7). 
 
 
 
2.4.1.7 Baseline Hematology/Biochemistry   
 
 
CTC 4.0 grades will be used to summarize the baseline hematology/biochemistry data (% with each CTC 
grades) for the following assessments (table 8):  
 
 
• 
WBC,  
• 
Granulocytes,  
• 
Platelets,  
• 
Hemoglobin 
 
 
2.4.1.8 Baseline Non-Hematologic Adverse Events 
 
CTC 4.0 grades will be used to summarize the baseline Non-Hematologic (number for each CTC grades, 
total number and %) (table 9). 
 
 
2.4.2 Analysis of pre-treatment characteristics 
 
No formal statistical tests will be performed to assess the homogeneity of baseline characteristics 
between the arms. Categorical variables will be tabulated by treatment arm and for all patients. 
Continuous variables (e.g., age) or transformed continuous variables (e.g. insulin level) will be presented 


 
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using summary statistics (n, mean, standard deviation (SD), median, min and max) or specified cutoff 
categories by treatment arm and for all patients. Analyses will be based on all randomized patients by arm 
based on the ITT population. 
 
 
2.5 Efficacy  
 
2.5.1 Definitions and Variables 
 
2.5.1.1 Invasive Disease-free Survival (IDSF) 
 
The primary endpoint of this study is invasive disease-free survival. It is defined as the time in months 
from randomization to the time of documented ipsilateral, contralateral invasive breast tumour, 
local/regional invasive recurrence, distant recurrence, death from breast cancer, death from non-breast 
cancer cause, death from unknown cause, second primary invasive cancer (non-breast, except for 
adequately treated BCC or SCC of the skin). If a subject has not had invasive disease nor died at the time 
of data cut-off for this analysis, IDFS will be censored on the date of last disease assessment. 
 
IDFS Time (months) = 
((date of IDFS event or last disease assessment date - date of randomization) + 1) / 30.4375 
 
2.5.1.2 Overall Survival (OS) 
 
For patients who have died, overall survival is calculated in months from the day of randomization to date 
of death. Otherwise, survival is censored at the last day the patient is known alive (LKA). 
 
OS Time (months) = 
((date of death or LKA - date of randomization) + 1) / 30.4375 
 
2.5.1.3 Breast Cancer Free Interval (BCFI) 
 
Breast Cancer Free Interval is defined as the time from randomization to the time of diagnosis of invasive 
ipsilateral breast tumour recurrence, local/regional invasive recurrence, distant recurrence, death from 
breast cancer, invasive contralateral breast cancer, ipsilateral DCIS, contralateral DCIS. If a subject has not 
had BCFI event at the time of data cut-off for this analysis, or died from other reasons, the BCFI will be 
censored on the date of last disease assessment. 
 
Incidence of contralateral invasive breast cancer is defined as the diagnosis of a primary invasive breast 
cancer in the opposite breast after randomization. 
 
Number of the contralateral breast cancer (invasive and invasive / DCIS) will be reported by treatment 
arms. 
 
Types of BCFI events will be listed by treatment arms. 
 
2.5.1.4 Distant Relapse Free Survival (DRFS) 


 
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Distant Relapse Free Survival (DRFS) is defined as the time from randomization to the time of distant 
recurrence, death from breast cancer, death from a non breast cancer cause or death from an unknown 
cause. If a subject has not had distant RFS event nor died at the time of data cut-off for this analysis, DRFS 
will be censored on the date of last disease assessment. 
 
2.5.1.6 Breast Cancer Specific Mortalityl (BCSM) 
 
Breast cancer specific mortality is defined as the time from randomization to the time of death from breast 
cancer. Patients died from causes other than breast cancer will be treated as a competing event and 
patients who were alive will be censored at the last day the patient is known alive (LKA). 
 
2.5.1.7 IBCFS 
 
IBCFS is defined as the time in months from randomization to the time of documented local/regional 
invasive recurrence, distant recurrence, ipsilateral and contralateral invasive breast tumour, death from 
breast cancer, death from other non-breast cancer cause, death from unknown cause. If a subject has not 
had IBCFS event nor died at the time of data cut-off for this analysis, IBCFS will be censored on the date 
of last disease assessment. 
 
 
2.5.1.7 Medical events 
 
1.Diabetes: initiation of new anti-diabetes medication (or confirmed MD diagnosis of diabetes) 
2.Cardiovascular hospitalization or cardiovascular death (stroke, myocardial infarction) 
 
 
 


 
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2.5.1.9 Summary of events 
 
First Event 
IDFS 
BCFI 
 DRFS 
BCSM 
OS 
IBCFS 
Local or Regional 
Recurrence  
Event 
Event 
 
 
 
Event 
Distant Recurrence Event 
Event 
Event 
 
 
Event 
New primary malignancy  Event 
 
 
 
 
 
Invasive ipsilateral breast 
tumour  
Event 
Event 
 
 
 
Event 
DCIS ipsilateral breast 
tumour(data in   F5, F5s)  
 
Event 
 
 
 
 
Invasive contralateral breast 
tumour  
Event 
Event 
 
 
 
Event 
DCIS contralateral breast 
tumour (data in F5, F5s)  
 
Event 
 
 
 
 
Death (Breast Cancer) Event 
Event 
Event 
Event 
Event 
Event 
Death (Protocol treatment 
of the disease) 
Event 
Event 
Event 
Event 
Event 
Event 
Death (Non-Protocol 
treatment of the disease) 
Event 
Event 
Event 
Event 
Event 
Event 
Death (Others) 
 
Event 
Censor 
Event 
Competing 
Event 
Event 
Event 
Death (Unknown) 
 
Event 
Censor 
Event 
Competing 
Event 
Event 
Event 
None Censor 
Censor 
Censor 
Censor 
Censor 
Censor 
 
 
 
2.5.2  Analysis of Key Parameters  
 
The comparison between treatment arms will be carried out using a two-sided test at an alpha level of 5% 
unless otherwise specified (e.g. 3.7% for IDFS). All efficacy analyses will be presented by treatment arm. 
The CONSORT diagram will be included.  
 
 
2.5.2.1 Invasive Disease-free Survival 
 
A Kaplan-Meier curve for IDFS in each treatment arm will be displayed. The difference between the two 
treatment arms will be tested using the log-rank test stratified by BMI </= 30 versus > 30 (kg/m2), HER2 
positive versus HER2 negative, Chemotherapy – any versus none. 
 
The analysis of IDFS will also be presented for each level of each stratification factor. In addition, as an 
exploratory analysis, a stratified Cox regression model adjusting for other prognostic factors which are 
unbalanced or correlated to the IDFS in univariate analyses will be applied to verify the impact of the 


 
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prognostic factors on the treatment effect and/or identify factors significantly related to the IDFS.  In these 
analyses, the final Cox model will be determined using a stepwise model building procedure with a 
significance level of 0.1 used for entry or removal of variables.  A un-stratified Cox regression model with 
stratification factors as covariates will also be fitted. In all regression analyses, all patients with missing 
value in any covariate will be either excluded from the analysis or imputed to the mean value of that 
covariate. (Table 10 11, 12, Figure 1).  
 
For patients who developed IDFS events, the type of progression events and summary of progression 
will be tabulated (Table 12).  The percentage of patients with new primary malignancy for each arm 
will be reported. 
 
A separate Statistical Analysis Plan is developed for blood variables.  
 
 
2.5.2.2 Overall Survival, BCFI and distant RFS, BCSM IBCFS 
 
The analyses of OS, BCFI, distant RFS, BCSM, IBCFS will be similar to these of IDFS (table 13, 14, 15, Figure 
2, 3, 4 will be repeated). 
 
Cumulative incidence curves will be plotted by treastment arms for breast cancer specific survival (BCSS) 
with death from any causes treated as a competing event.  
 
 
Medical outcomes (cardiovascular, diabetes) will be summary by treatment arm and compared using a 
Chi-squared test. 
 
Sensitivity analyses: 
 
• 
Sensitivity analyses for both IDFS and OS BCFI, distand RFS, BCSS other medical conditions will be 
performed with the as treated population. 
 
 
2.6 Drug Exposure  
 
Drug duration 
 
Duration of drug exposure will be reported as time from date of first dose of protocol therapy to the time 
of last drug dose before the clinical cut-off date. Date of randomization will be used if first dose date is 
unknown. Patients with IDFS event will be censored at the date of IDFS event for the purpose of drug 
exposure duration.  If date of discontinuation is unknown we use drug dispensed. 
 
Min, Median (based on KM method, censored at IDFS date), and Max duration of drug exposure will be 
reported by treatment arm in Table 16a.  
 
Drug duration by SNP status  
 


 
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Drug duration: (off protocol treatment) in relation to SNP status will be reported by treatment arms in the 
subset of patients with available data (Table 16b). 
 
• 
Comparison1: CC or AC vs CC 
• 
Comparison2: CC vs CA vs AA 
 
Drug adherence 
 
Overall drug adherence (compliance) 
 
The overall compliance rate will be calculated for each patient individually then take an average of all 
patients in each arm. 
 
For each patient,  the overall drug compliance rate = 
  
(Total number of kits dispense * 400 - total number of pills returned) divided by (total number of days on 
protocol treatment with full doses * 2 pills per day + 1 pill per day with dose reduction) 
 
Total number of days on protocol therapy = days from randomization to first date of the following event: 
 
(IDFS event, off treatment, or withdrawal of consent ). 
 
Note: If a kit was dispensed and was not returned, then the number of returned pills count will be 
estimated at 400. If a patient was off protocol treatment before IDFS event, then the patient will be 
designated as non-compliant and the drug compliance rate for this patient will be 0%. Numbers and 
percent of non-compliants will be reported for each arm (Table 16c1). 
 
Drug compliance rates over each time priod 
 
In each study period (month 6, years 1, 2, 3, 4, 5) before iDFS event, off protocol treatment or widthdraw 
of consent, the drug adherence rate without adjust for dose reduction is calculated as 
 
Drug adherence rate for each drug kit (%) =  
(Total number of pills dispensed  – Total number of  pills returned) / Total number  pills dispensed 
= (400  – Total number of pills returned)/(400-34.75) 
 
Note: 1) The total number of pills dispense is 400 pills every 6 months and each patient need 365.25 pills 
on average for 6 months on average (2 pills per day). 
2) Some patients returned empty drug kit with will result a drug compliance for a particular kit to be 
greater than 100% (400/365.25 = 109.51%). According to the request from Dawn, this number will be 
capped at 100%. 
 
All kits dispensed between momths 0 to 3 will be considered as drug for months 0 to 6.  
All kits dispensed between momths 4 to 9 will be considered as as drug for months 7 to 12.  
All kits dispensed between momths 10 to 21 will be considered as drug for as months 13 to 24.  
All kits dispensed between momths 22 to 33 will be considered as as drug for months 25 to 36.  


 
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All kits dispensed between momths 34 to 45 will be considered as as drug for months 37 to 48. 
All kits dispensed between momths 46 to 66 will be considered as as drug for months 49 to 60.  
 
The overall adherence without adjust for dose modification rate and the average drug kit compliance rate 
each time period compliance rates and will be reported by treatment arm (Table 16c2). A sensivity analysis 
will be conducted with the assumption that the missing kit was 50% and 100% taken.  
 
Dose Modification 
 
Numbers and percent of patients with at least one drug modification (Yes vs No) will be report by each 
study period (month 6, years 1, 2, 3, 4, 5) and trearment arm (Table 16d).  
 
 
2.7 Safety  
 
2.7.1 Definitions and variables 
 
All toxicity/side effects data collected post randomization will be included in the analyses of toxicities.  
 
2.7.1.1 Non-hematologic adverse events  
 
Non-hematologic adverse events will be summarized according to CTC AE 4.0 (table 19).  
 
Sub group analysis of non-hematologic AE will be  reprted by SNP status(Four more tables for subsets: 
SNP_base = ‘CC’, SNP_base = ‘AC’, SNP_base = ‘AA’, and SNP_base in (‘CC’, ‘CA’) ). 
 
• 
Comparison 1: CC or AC vs AA   
• 
Comparison 2: CC vs AC vs AA  
 
2.7.1.2 Hematology/Biochemistry  
 
Hematology/Biochemistry experienced  will be reported according to CTC AE 4.0 (table 20).  
 
2.7.1.3 Serious adverse event 
 
SAE will be listed by treatment arm (table 21). 
 
2.8  Off protocol therapy and death 
 
Patients off protocol treatment): Number and % of all treated patients. Reason for going off protocol 
therapy (e.g. adverse event, death, progression, etc): Number and  % of all treated patients will be 
presented (table 22). 
 
Deaths within 30 days from last treatment administration. Cause of death within 30 days from last 
treatment administration: Number and  % of all treated patients will be presented (table 23).  
 


 
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2.9  Quality of Life 
 
The EORTC QLQ-30 Global Score will be used for our primary assessment of quality of life but subscales 
and specific symptoms (diarrhea, bloating, flatulence, dyspepsia, abdominal cramps, nausea and vomiting, 
taste alteration, limitation of activities because of gastrointestinal symptoms, joint/musculoskeletal 
symptoms) will be used for our secondary hypothesis. 
 
2.9.1 Definitions and Variables 
 
2.9.1.1. EORTC QLQ-C30 
 
There are five functional domains and three symptom domains that can be derived from EORTC QLQ-C30 
(see below for definitions). If the number of unanswered questions in each domain is within a limit 
specified with the definition for each domain, the score is calculated as below: 
 
For function domains of Physical, Emotional, Cognitive and Social: 
 
Score=100-(((Total score for the answered questions/(Total questions answered))-1)*100/3). 
 
 
For symptom domains: 
 
Score=(((Total for the answered questions/(Total questions answered))-1)*100/3) 
 
Otherwise, the score will be recorded as “missing”. For each single item, the score will be recorded as 
“missing” if the answer to this item is missing. 
 
Functional Domains: 
Physical: 
Questions: 1, 2, 3, 4, 5, 6, 7 
 
Score=missing if number of above questions not answered is greater than 3;  
Emotional: 
Questions: 21, 22, 23, 24 
 
Score=missing if number of above questions not answered is greater than 2;  
Cognitive: 
Questions: 20, 25 
 
Score=missing if number of above questions not answered is greater than 0;  
Social: 
Questions: 26, 27 
 
Score=missing if number of above questions not answered is greater than 0;  
 
Symptom Domains: 
 
Fatigue: 
Questions: 10, 12, 18 
 
Score=missing if number of above questions not answered is greater than 1;  
 
Nausea and vomiting: 
Questions: 14, 15 
 
Score=missing if number of above questions not answered is greater than 0;  
 
Pain: 
Questions: 9, 19 
 
Score=missing if number of above questions not answered is greater than 0. 
 


 
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There are also six single items in EORTC QLQ-C30 pertaining to common symptoms and one global 
assessment that can be derived from EORTC QLQ-C30. The single items are: 
 
Single Items: 
 
Dyspnea: 
Question 8; 
 
Sleep/Insomnia: 
Question 11; 
 
Appetite: 
Question 13; 
 
Constipation: 
Question 16; 
 
Diarrhea: 
Question 17; 
 
Financial: 
Question 28. 
 
They are all scored using the following formula: 
 
Score= (Answer to the question-1)*100/3. 
 
The Global Assessment includes Questions 29 and 30. If number of the questions not answered is greater 
than 0, its score will be “missing”; Otherwise, 
 
Score= ((Total for the answered questions/(Total questions answered))-1)*100/6. 
 
For functional domains, a higher score indicates better functioning but for symptoms domains, a higher 
scores indicate higher (worse) symptoms. 
 
Trial specific checklist: 
 
The following trial specific checklist were collected: 
 
31. Did you have bloating of your abdomen (stomach or belly)?  
32. Did you have pain or cramps in your abdomen (stomach or belly)?  
33. Did you have heartburn?  
34. Did you have gas?  
35. Did you limit your activities because of gastro-intestinal problems?  
36. Did you have a metallic taste?  
37. Do you have aching muscles or joints?  
Exploaraory Analysis 
QLQ-C30 Summary Score =  
(PF + RF + SF + EF + CF + 100-Fatigue + 100-Pain + 100-Nausea/Vomiting + 100-Dyspnoea + 100-Sleeping 
Disturbances + 100 Appetite Loss + 100-Constipation + 100-Diarrhoea)/13 
Only calculated if all 13 scores available; Scale scores based on completed items (at least 50% 
completed)  
 
 
A frequency table to to answer of each question will be listed at baseline and each of the follow-up time.  
 


 
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2.9.2 Analysis 
 
All analyses on quality of life scores will be exploratory and will include all randomized patients with QoL 
data. Report number included in the QOL substudy (888). 
 
The patient characteristics between QOL participants with those who did not participate will be reported.  
Table 7 will be repeated for patients in QoL study vs patients did not in the QoL study.  
 
Repeat Table 7 again for all Canadian population. 
 
The patient characteristics (Table 7) among the following three groups: no endocrine therapy, tamoxifen 
and aromatase inhibitor will also be reported. 
 
The time point of the primary QOL endpoint will be 12 months after randomization. 
 
2.9.2.1 Determination of Assessment Times 
 
The following will be the scheme to determining the time frame of a QOL assessment:  
1) Baseline: Baseline evaluation is the QOL questionnaire collected closest, but prior to, the first day 
of starting study treatment/randomization; 
2) Monnth 6 evaluation: If the QOL is assessed between month 3 and month 9 
3) Monnth 12 evaluation: If the QOL is assessed between month 10 and month 18 
4) Monnth 24 evaluation: If the QOL is assessed between month 19 and month 30 
5) Monnth 36 evaluation: If the QOL is assessed between month 31 and month 42 
6) Monnth 48 evaluation: If the QOL is assessed between month 43 and month 54 
7) Monnth 60 evaluation: If the QOL is assessed between month 55 and month 66 
 
 
2.9.2.2 Calculation of Compliance Rates  
 
The following method will be used to calculate the compliance rates of QOL assessment. The compliance 
rate is calculated as the number of forms received out of the number of forms expected at each 
assessment point defined based on the following principles: 
 
1) At baseline: the number of forms expected is the total number of patients who are eligible for the 
study and required to fill out QOL questionnaires.  
2) FU period: the number expected at each assessment is the number of patients with baseline data 
minus the number of patients who have off the protocol treatment, died or progressed during 
that and previous follow up period (with assessment window defined by 2.9.2.1). 
 
2.9.2.3 Cross-sectional analysis 
 
The mean and standard deviation of QOL scores at baseline and mean and standard deviation of QOL 
change scores from baseline at each assessment time will be calculated. Then Wilcoxon Rank-Sum test is 


 
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used to compare two treatment arms in terms of change in QOL score at each assessment time from 
baseline.  
 
Mean change in scores over time will be analyzed using generalized linear mixed model. The treatment 
arms, patient substudy groups defined by adjuvant endocrine therapy use at the time of randomization 
(tamoxifen, aromatase inhibitor, no endocrine therapy), and qol assessment time point will be used as 
covariates in this analysis. The interactions between treatment arms and qol assessment time (up to 60 
months) will be tested using a likelihood ratio method. 
 
2.9.2.4 QOL response analysis 
 
QOL response is calculated as follows for a functional domain: A change score of 10 points from baseline 
was defined as clinically relevant. Patients will be assessed as improved if they have reported a score of 
10-points or better than baseline at any time of the QOL assessment. Conversely, patients will be assessed 
as worsened if there is a reported score that is at least 10 points worse than baseline at any time of the 
QOL assessments without meeting the criteria for improved. Patients whose scores are intermediate 
between these values at every QOL assessment will be considered as stable. In contrast to functional 
domains, for the determination of patient’s QOL response, classification of patients into improved and 
worsened categories is reversed for symptom domains and single items. A Chi-square test will be 
performed to compare the distributions of these three categories between two arms (improved, stable 
or worse). 
 
2.9.2.5 QOL subscale trend analysis  
 
Plots of QoL score over time by treatment arms over time (From baseline to month 60) will be reported 
for gloval QOL, each subscales and symptoms items.  
 
 
Note: Physical Activity Items of the Nurses Health Study II Questionnaire and Block Alive Screener (Diet) 
will be analyzed in a saperate analysis report after the finish of the final analysis of MA.32. The levels 
of fatigue and overall QoL will be evaluated according to diet and physical activity in the metformin and 
placebo groups in the subset of QoL participants with diet and physical activity assessment. 
 
 


 
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3 Tables 
 
Table 1 Accrual by centre 
 
Centre 
Number of accrual (%) 
 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
xxxx 
XX (XX) 
XX (XX) 
XX (XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2: Accrual by Stratification Factors at Randomization  
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
ER and/or PgR 
 
 
 
Positive 
** (**) 
** (**) 
** (**) 
Both Negative 
** (**) 
** (**) 
** (**) 
 
 
 
 
BMI 
 
 
 
</=30 
 
 
 
>30 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
HER2 
 
 
 
Positive 
 
 
 
Negative 
 
 
 
 
 
 
 
Chemotherapy 
 
 
 
Any 
 
 
 
None 
 
 
 
Source:  Centralized Randomization File 
 
 
 


 
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Table 3: Treatment received  
 
 
Number of accrual (%) 
Actual treatment 
received 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
 
 
 
 
Metformin 
XX (XX) 
XX (XX) 
XX (XX) 
Placebo 
 
 
 
No treatment 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 4: Stratifiation factor at randomization vs. at baseline  
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
At randomization 
At baseline 
Metformin 
N = *** 
Placebo 
N = *** 
 
 
 
 
BMI 
 
** (**) 
** (**) 
</=30 
</=30 
** (**) 
** (**) 
</=30 
>30 
 
 
>30 
</=30 
 
 
>30 
>30 
 
 
 
 
 
 
HER2 
 
 
 
Positive 
Positive 
 
 
Positive 
Negative 
 
 
Negative 
Positive 
 
 
Negative 
Negative 
 
 
 
 
 
 
Chemotherapy 
 
 
 
Any 
Any 
 
 
Any 
None 
 
 
None 
Any 
 
 
None 
None 
 
 
 
 
 
 


 
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Table 5: Eligibility status  
 
Total patients allocated 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
 
 
 
 
 
 
 
 
Ineligible 
XX (XX) 
 
 
Total eligible patients 
XX (XX) 
 
 
 
 
 
 
REASONS FOR INELIGIBILITY 
 
 
 
Reason 1  
XX (XX) 
 
 
Reason 2  
XX (XX) 
 
 
 
 
 
 
Major Protocol Violations 
 
 
 
XXX 
 
 
 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5a: COVID-19 Protocol variance 
 
 
Total patients allocated 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
 
 
 
 
 
 
 
 
Protocol variance due to 
COVID19 
 
 
 
Alternate patient 
assessment  
(Phone or virtual visit) 
 
 
 
Missed study Visit 
 
 
 
Delayed response 
assessment 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 6: Summary of Follow-up  
 
 
Data set:  All Randomized Patients 
 
Number of patients 
 
Placebo 
N = *** 
Metformin 
N = *** 
Total 
N = *** 
Median* 
*** 
*** 
*** 
Min 
**  
** 
** 
Max 
**  
** 
** 
Median Follow-up based on inverse OS 
 
 


 
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Table 7: Patient characteristics 
 
All randomized patients 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
AGE 
 
 
 
<=39 
XX (XX) 
 
 
40-49 
XX (XX) 
 
 
50-59 
 
 
 
60-69 
 
 
 
>=70 
XX (XX) 
 
 
Median (Range) 
XX (XX) 
 
 
 
 
 
 
Gender 
 
 
 
M 
 
 
 
F 
 
 
 
 
 
 
 
Race 
 
 
 
Asian 
 
 
 
Black or African American 
 
 
 
etc 
 
 
 
 
 
 
 
ECOG PS 
 
 
 
0  
 
 
1  
 
 
2  
 
 
 
 
 
 
MENOPAUSAL STATUS 
 
 
 
As in meeting book  
 
 
 
 
 
 
Weight (median, range) 
 
 
 
 
 
 
 
Height (median, range) 
 
 
 
 
 
 
 
BMI 
 
 
 
</=30  
 
 
>30  
 
 
Mean (SD)  
 
 
 
 
 
 
HORMONE RECEPTOR STATUS 
 
 
 
ER-positive and/or PgR-
positive (100%) 
 
 
 
  
 
 
 
 
 
 
T stage (Neo-adjuvant) 
 
 
 
cT1  
 
 


 
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cT2  
 
 
cT3  
 
 
N Stage (Neo-adjuvant) 
 
 
 
cN0  
 
 
cN1  
 
 
cN2  
 
 
T stage (adjuvant) 
  
 
pT1 
  
 
pT2  
 
 
pT3  
 
 
 
 
 
 
N Stage  
 
 
 
pN0  
 
 
pN1  
 
 
pN2  
 
 
pN3  
 
 
Adj radiotherapy 
 
 
 
No  
 
 
Yes  
 
 
 
 
 
 
HER2 
 
 
 
Negative  
 
 
Positive  
 
 
 
 
 
 
Adjuvant Horome Threapy 
 
 
 
No  
 
 
Yes  
 
 
 
 
 
 
Adjuvant Herceptin 
 
 
 
No  
 
 
Yes  
 
 
 
 
 
 
Adjuvant chemotherapy 
 
 
 
No  
 
 
Yes  
 
 
  
 
 
Nodes 
 
 
 
Negative  
 
 
Positive  
 
 
 
 
 
 
Anti-Cancer treatment 
 
 
 
Yes  
 
 
No  
 
 
Cardiviscular (Yes vs No) 
 
 
 


 
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Yes  
 
 
No  
 
 
Grade 
 
 
 
I  
 
 
II  
 
 
III  
 
 
  
 
 
Breast cancer subtype 
 
 
 
Ductal  
 
 
Lobular  
 
 
  
 
 
Resection margins 
 
 
 
  
 
 
Number of axillary nodes 
examined  
 
 
 
  
 
 
Number of positive axillary 
nodes 
 
 
 
  
 
 
Number of sentinel nodes 
examined  
 
 
 
 
 
 
 
Number of positive sentinel 
nodes 
 
 
 
  
 
 
  
 
 
 
 
Table 8. Baseline Hematology / Biochemistry 
 
CTC AE 4.0 Hematology / Biochemistry table 
 
 
Table 9. Baseline Non-Hematologic Adverse Event 
 
CTC AE 4.0 Non-Hematologic Adverse Event table 
 
 
 
 


 
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Table 10. Log Rank and Cox Regression Model for IDFS Survival 
 
Data set:  All Randomized Patients 
 
 
Univariate 
HR (95% CI) 
Log-rank  
p-value 
Multivariate 
HR(95% CI) (1) 
Multivariate 
p-value 
Treatment (Metformin vs. 
Placebo) (stratified) 
*** 
*** 
-- 
-- 
Treatment (Metformin vs. 
Placebo) (un-stratified) 
 
 
 
 
 
 
 
 
 
BMI </= 30 versus > 30 
(kg/m2) 
 
 
 
 
HER2 positive versus HER2 
negative 
 
 
 
 
Chemotherapy – any versus 
none 
 
 
 
 
 
 
 
 
 
(1) Based on Cox Model with all factors included. 
 
 
 


 
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Table 11: IDFS by Subsets 
 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
Metformin 
N (# of event) 
Placebo 
N (# of event) 
HR 
(95% C.I) 
ER and/or PgR 
 
 
 
Positive 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
 
BMI 
 
 
 
</=30 
 
 
 
>30 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
HER2 
 
 
 
Positive 
 
 
 
Negative 
 
 
 
 
 
 
 
Chemotherapy 
 
 
 
Any 
 
 
 
None 
 
 
 
 
 
 
 
Hormone therapy 
 
 
 
Any 
 
 
 
None 
 
 
 
 
 
 
 


 
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Table 12: IDFS event Summary 
 
 
Data set:  All randomized Patients 
 
Number of Patients 
Metformin 
N = *** 
Placebo 
N = *** 
 
 
 
Patients with IDFS event 
***  
 
*** 
Local or Regional Recurrence  
** 
** 
Distant Recurrence 
** 
** 
New primary (Non-BC) malignancy  
 
 
Invasive contralateral breast tumour  
** 
** 
Death (cause 1) 
** 
** 
Death (cause 2) 
** 
** 
… 
 
 
 
 
 
Patients who were censored 
 
*** (**) 
*** (**) 
   Reason Censored 
 
 
No IDFS event  
** 
** 
Withdrawal of Consent  
** 
** 
 
 
 


 
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Table 12a: BCFI event by arm  
 
 
 
 
Data set:  All randomized Patients 
 
Number of Patients 
Metformin 
N = *** 
Placebo 
N = *** 
 
 
 
Patients with BCFI event 
***  
 
*** 
Local or Regional Recurrence  
** 
** 
Distant Recurrence 
** 
** 
 
 
 
Invasive ipsilateral breast tumour  
** 
** 
DCIS ipsilateral breast tumour  
** 
** 
Invasive contralateral breast tumour  
** 
** 
DCIS contralateral breast tumour 
** 
** 
Death(related to disease or treatment) 
 
 
Death (Breast Cancer) 
** 
** 
Death (AE related to Protocol treatment) 
** 
** 
Death (Related to non-Protocol treatment) 
** 
** 
 
 
 
 
 
 
 


 
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Table 12b: IBCFS event by arm  
 
 
 
 
Data set:  All randomized Patients 
 
Number of Patients 
Metformin 
N = *** 
Placebo 
N = *** 
 
 
 
Patients with IBCFS event 
***  
 
*** 
Local or Regional Recurrence  
** 
** 
Distant Recurrence 
** 
** 
 
 
 
Invasive ipsilateral breast tumour  
** 
** 
 
 
 
Invasive contralateral breast tumour  
** 
** 
 
 
 
Deaths (All) 
 
 
Death (Breast Cancer) 
** 
** 
Death (AE related to Protocol treatment) 
** 
** 
Death (Related to non-Protocol treatment) 
** 
** 
 
 
 
Death (Cardiovascular Disease) 
** 
** 
Death (Other condition) 
** 
** 
Death (Unknown) 
** 
** 
 
 
 


 
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Table 13. Log Rank and Cox Regression Model for Overall Survival 
 
Data set:  All Randomized Patients 
 
Univariate 
HR (95% CI) 
Log-rank  
p-value 
Multivariate 
HR(95% CI) (1) 
Multivariate 
p-value 
Treatment (Metformin vs. 
Placebo) (stratified) 
*** (*, *) 
*** 
*** (*, *) 
*** 
Treatment (Metformin vs. 
Placebo) (un-stratified) 
*** (*, *) 
*** 
*** (*, *) 
*** 
 
 
 
 
 
BMI < /=30 versus > 30 
(kg/m2) 
*** (*, *) 
*** 
*** (*, *) 
*** 
HER2 positive versus HER2 
negative 
*** (*, *) 
*** 
*** (*, *) 
*** 
Chemotherapy – any versus 
none 
*** (*, *) 
*** 
*** (*, *) 
*** 
Other factors… 
 
 
 
 
 
 
 
 
 
 
 
(1) Based on Cox Model with all factors included. 
 
Similar tables will be reported for BCFI and distant RFS . 
 


 
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Table 14: OS by Subsets 
 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
Metformin 
N (# of event) 
Placebo 
N (# of event) 
HR 
(95% C.I) 
ER and/or PgR 
 
 
 
Positive 
** (**) 
** (**) 
** (*, *) 
 
 
 
 
 
 
 
 
BMI 
 
 
 
</=30 
 
 
 
>/=30 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
HER2 
 
 
 
Positive 
 
 
 
Negative 
 
 
 
 
 
 
 
Chemotherapy 
 
 
 
Any 
 
 
 
None 
 
 
 
 
Similar tables will be reported for BCFI and distant RFS . 
 
 
 
 


 
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Table 15: Death Summary 
 
 
Number of Patients (%) 
Data set:  All randomized Patients 
Metformin 
N =  
Placebo 
N =  
Total 
N =  
 
 
 
 
Patients who died 
 
 
 
 
 
 
 
Cause of Death  
 
 
 
Death (Breast Cancer)  
 
 
Death (AE related to 
Protocol treatment)  
 
 
Death (Related to non-
Protocol treatment)  
 
 
  
 
 
Cardiovascular Disease 
 
 
 
Other condition or 
circumstance   
 
 
Unknown 
 
 
 
 
 
 
 
Patients who were censored  
 
 
  
 
 
Reason Censored  
 
 
Still Alive   
 
 
Withdrawal of Consent   
 
 
 
 


 
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Table 16a: Drug exposure 
 
 
Data set:  All treated Patients 
 
Number of patients 
 
Placebo 
N = *** 
Metformin 
N = *** 
Total 
N = *** 
Median* 
*** 
*** 
*** 
Min 
**  
** 
** 
Max 
**  
** 
** 
* Based on KM method, censored at IDSF event date 
 
 
Table 16b: Duration of treatment by SNP status 
 
Repeat table 20 here using the following subgroup of patients  
SNP_base = ‘CA’ or ‘CC’ vs ‘AA’ 
SNP_base = ‘AA’, vs SNP_base = ‘CA’, vs SNP_base = ’CC’, 
 
 
Table 16c: Drug adherence 
 
 
Data set:  All treated Patients 
 
Number of patients 
Median (Min, Max) 
Placebo 
N = *** 
Metformin 
N = *** 
Total 
N = *** 
Year 1 (0-365 days) 
Median (Min, Max) 
*** 
*** 
Year 2  
*** 
*** 
*** 
Year 3  
*** 
*** 
*** 
Year 4  
*** 
*** 
*** 
Year 5  
*** 
*** 
*** 
Over all 
 
 
 
 
 
Table 16d: Drug dose modification 
 
 


 
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Data set:  All treated Patients 
 
Number of patients 
Dose modification 
Placebo 
N = *** 
Metformin 
N = *** 
Total 
N = *** 
Yes 
** (**) 
** (**) 
** (**) 
No 
** (**) 
** (**) 
** (**) 
 
 
 
 
Repeat this for each study period (years 1 to 5) and overall (0 to 5 years) 
 
 
 
Table 17.Non-Hematology adverse events 
 
CTC AE 4.0 Non-Hematology  adverse events table. 
 
Repeat table 17 here using following subgroup of patients  
SNP_base = ‘CA’ or ‘CC’ vs ‘AA’ 
SNP_base = ‘AA’, vs SNP_base = ‘CA’, vs SNP_base = ’CC’, 
 
 
 
Table 18. Hematology / Biochemistry (Follow-up) 
 
CTC AE 4.0 Hematology / Biochemistry table 
 
 
Table 19. Serious Adverse Events 
 
As in meeting book table. 
 
 
Table 20. Off protocol treatment 
 
Data set:  All treated Patients 
 
Number of patients 
Off treatment 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
Cause1 
*** 
*** 
*** 
2 
**  
** 
** 
3 
 
 
 
4 
 
 
 
 
 


 
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Table 21. Death on Trial within 30 days of last treatment  
 
Data set:  All Randomized Patients 
 
Number of patients 
Cause of Death 
Metformin 
N = *** 
Placebo 
N = *** 
Total 
N = *** 
Cause1 
*** 
*** 
*** 
2 
**  
** 
** 
3 
 
 
 
4 
 
 
 
 
 
 
Figure 1. KM plot for IDFS 
 
 
Figure 2. KM plot for OS 
 
 
Figure 3. KM plot for BCFI 
 
 
Figure 4. KM plot for DRFS 
 
 
Figure 5. Cumulative incidence plot for BCSM  
 
 
Figure 6. KM plot for IBCFS  
 
 
Figure 7a. KM plot for contralateral BC (invasive only) 
 
 
Figure 7b. KM plot for contralateral BC (invasive and DCIS )