Conditions: Diabetes Mellitus, Type 2 Cardiovascular Diseases Risk Factors
Keywords: Diabetes Type 2 diabetes mellitus Cardiovascular risk Cardiovascular outcomes Canagliflozin (JNJ-28431754) Placebo
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4330
Healthy volunteers: no

Brief summary:
The study will assess canagliflozin (JNJ-28431754) in the treatment of patients with type 2 diabetes mellitus (T2DM) with regard to cardiovascular (CV) risk for major adverse cardiac events (MACE). Other objectives include evaluating the overall safety, tolerability, and effectiveness of canagliflozin.

The data from this study will be combined with the data from CANVAS-R study (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, NCT01989754) in a pre-specified integrated analysis of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin.

Detailed description:
The study will evaluate canagliflozin compared to placebo on CV events including CV death, heart attack, and stroke in patients with T2DM, whose diabetes is not well controlled at the beginning of the study and who have a history of CV events or have a high risk for CV events. The study includes 3 substudies which will compare the effectiveness of lowering blood glucose and assess the safety of canagliflozin relative to placebo in patients receiving specific commonly-used diabetes agents. 4,330 participants will be randomly assigned to treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) or placebo, in a 1:1:1 ratio. This study was originally designed to last for up to 9 years. As per FDA post-marketing requirements for canagliflozin, the study's last subject last visit will now occur when enough MACE events (ie, CV death, nonfatal myocardial infarction, nonfatal stroke) are accumulated between the CANVAS (this study) and CANVAS-R studies. The completion target was reached in February 2017.

Arms:
arm 1: Each patient will receive placebo (inactive medication) on background standard of care for diabetes once daily for the duration of the study arm 2: Each patient will receive canagliflozin (JNJ-28431754) 100 mg once daily on background standard of care for diabetes once daily for the duration of the study arm 3: Each patient will receive canagliflozin (JNJ-28431754) 300 mg once daily on background standard of care for diabetes once daily for the duration of the study

Interventions: intervention 1: Placebo intervention 2: Canagliflozin (JNJ-28431754) 100 mg intervention 3: Canagliflozin (JNJ-28431754) 300 mg
Intervention descriptions: intervention 1: One placebo capsule taken orally (by mouth) once daily intervention 2: One 100 mg capsule taken orally (by mouth) once daily intervention 3: One 300 mg capsule taken orally (by mouth) once daily

Protocol document:
Prot_000.pdf: 
FINAL – 28 April 2016
1
Janssen Research & Development*
Clinical Protocol
A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of 
the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With 
Type 2 Diabetes Mellitus
The CANVAS Trial
(CANagliflozin cardioVascular Assessment Study)
Protocol 28431754DIA3008; Phase 3
AMENDMENT INT-8
JNJ-28431754 (canagliflozin)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; or Janssen Research & Development, LLC. 
The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is 
identified on the Contact Information page that accompanies the protocol.
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
Issue/Report Date:
5 May 2016
Prepared by:
Janssen Research & Development, LLC
Document No.:
EDMS-ERI-13522077:12.0
(Legacy No.:
EDMS-PSDB-9584804)
Eudract No.:
2009-012140-16
Compliance:  This study will be conducted in compliance with this protocol, Good Clinical Practice, and applicable 
regulatory requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential 
and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to 
whom the information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you 
that is indicated as privileged or confidential.
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INVESTIGATOR AGREEMENT
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TABLE OF CONTENTS
LIST OF IN-TEXT TABLES AND FIGURES ............................................................................6
PROTOCOL AMENDMENTS ...................................................................................................7
SYNOPSIS ..............................................................................................................................24
TIME AND EVENTS SCHEDULE...........................................................................................30
POSTTREATMENT TIME AND EVENTS SCHEDULE – SUBJECTS WHO 
PREMATURELY DISCONTINUE STUDY MEDICATION.........................................34
ABBREVIATIONS................................................................................................................... 35
1.
INTRODUCTION........................................................................................................37
1.1.
Background.................................................................................................................39
1.1.1.
Brief Overview of Nonclinical Studies ........................................................39
1.1.2.
Clinical Studies...........................................................................................39
1.2.
Overall Rationale and Goals for the Study.................................................................44
2.
OBJECTIVES AND HYPOTHESES ..........................................................................47
2.1.
Objectives................................................................................................................... 47
2.1.1.
Primary Objectives .....................................................................................47
2.1.2.
Secondary Objectives ................................................................................47
2.2.
Hypotheses.................................................................................................................48
2.2.1.
Primary Hypothesis ....................................................................................48
2.2.2.
Secondary Hypotheses ..............................................................................48
2.3.
Substudies: Objectives and Hypotheses....................................................................48
2.4.
Medical Resource Utilization Objective ......................................................................50
3.
OVERVIEW OF STUDY DESIGN ..............................................................................50
3.1.
Study Design ..............................................................................................................51
3.2.
Study Design Rationale..............................................................................................55
4.
STUDY POPULATION...............................................................................................59
4.1.
General Considerations..............................................................................................59
4.2.
Inclusion Criteria.........................................................................................................60
4.3.
Exclusion Criteria........................................................................................................62
4.4.
Prohibitions and Restrictions......................................................................................64
4.5.
Rescreening................................................................................................................65
5.
TREATMENT ALLOCATION.....................................................................................65
6.
DOSAGE AND ADMINISTRATION...........................................................................67
6.1.
Study Drugs................................................................................................................67
6.2.
Concomitant Antihyperglycemic and Other Therapies...............................................68
6.2.1.
Management of Glycemic Control and CV Risk Factors............................68
6.2.2.
Glycemic Rescue Therapy Through Week 18 Criteria and 
Implementation...........................................................................................70
7.
TREATMENT COMPLIANCE ....................................................................................70
8.
PRESTUDY AND CONCOMITANT THERAPY.........................................................71
9.
STUDY EVALUATIONS.............................................................................................71
9.1.
Study Procedures .......................................................................................................71
9.1.1.
Overview ....................................................................................................71
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9.1.2.
Pretreatment Phase ...................................................................................73
9.1.3.
Double-Blind Treatment Phase..................................................................74
9.1.4.
End-of-Treatment/Early Withdrawal...........................................................75
9.1.5.
Posttreatment Phase (Follow-Up)..............................................................75
9.2.
Reporting/Adjudication of Events in the CV Composite Endpoint and Other 
Events for Adjudication...............................................................................................76
9.3.
Study Management: Committees ...............................................................................77
9.3.1.
Academic Research Organization..............................................................77
9.3.2.
Steering Committee....................................................................................77
9.3.3.
Medical Safety Review Committee ............................................................77
9.3.4.
Independent Data Monitoring Committee ..................................................77
9.3.5.
Endpoint Adjudication Committee..............................................................77
9.4.
Safety Evaluations......................................................................................................77
9.5.
Measures of Efficacy/Efficacy Endpoints ...................................................................82
9.6.
Pharmacogenomic Evaluations..................................................................................83
9.7.
Exploratory Evaluations..............................................................................................83
9.8.
Medical Resource Utilization ......................................................................................84
10.
SUBJECT COMPLETION/WITHDRAWAL ...............................................................84
10.1.
Completion.................................................................................................................. 84
10.2.
Withdrawal From Study Drug .....................................................................................84
10.3.
Reinstitution of Subjects Who Have Prematurely Discontinued Double-Blind 
Study Drug to Active Status........................................................................................86
10.4.
Measures to Re-establish Contact in Subjects Lost to Follow-up..............................86
11.
STATISTICAL METHODS .........................................................................................87
11.1.
Analysis Sets .............................................................................................................. 87
11.2.
Handling of Dose in Analysis......................................................................................87
11.3.
Sample Size Determination........................................................................................87
11.4.
Safety Analyses..........................................................................................................88
11.5.
CV Outcomes and Efficacy Analyses.........................................................................89
11.5.1.
CV Outcomes (Primary Efficacy Endpoint) ................................................89
11.5.2.
Major Secondary Efficacy Endpoints .........................................................90
11.5.3.
Multiplicity Adjustment................................................................................90
11.5.4.
Additional Secondary Efficacy Endpoints...................................................91
11.6.
Medical Resource Utilization Analyses ......................................................................91
11.7.
Interim Analyses of CANVAS .....................................................................................91
11.7.1.
Interim Analyses for Health Authority Submissions ................................... 91
11.8.
Meta-Analysis to Support Regulatory Requirements .................................................91
11.8.1.
Meta-Analysis Pre-Regulatory Approval ....................................................91
11.8.2.
Meta-Analysis Post-Regulatory Approval...................................................92
11.9.
Glycemic Efficacy Substudies ....................................................................................93
11.9.1.
Analysis Sets..............................................................................................93
11.9.2.
Sample Size Determination........................................................................93
11.9.3.
Efficacy Analyses .......................................................................................93
11.9.4.
Multiplicity Adjustment................................................................................94
11.9.5.
Safety Analyses..........................................................................................95
12.
ADVERSE EVENT REPORTING...............................................................................95
12.1.
Definitions................................................................................................................... 97
12.1.1.
Adverse Event Definitions and Classifications...........................................97
12.1.2.
Attribution Definitions .................................................................................98
12.1.3.
Severity Criteria..........................................................................................99
12.2.
Procedures ................................................................................................................. 99
12.2.1.
All Adverse Events .....................................................................................99
12.2.2.
Serious Adverse Events...........................................................................101
12.2.3.
Pregnancy ................................................................................................102
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12.3.
Contacting Sponsor Regarding Safety.....................................................................102
13.
PRODUCT QUALITY COMPLAINT HANDLING ....................................................102
13.1.
Procedures ...............................................................................................................102
13.2.
Contacting Sponsor Regarding Product Quality.......................................................102
14.
STUDY DRUG INFORMATION ...............................................................................103
14.1.
Physical Description of Study Drug(s)......................................................................103
14.2.
Packaging.................................................................................................................103
14.3.
Labeling .................................................................................................................... 103
14.4.
Preparation, Handling, and Storage .........................................................................103
14.5.
Drug Accountability...................................................................................................103
15.
STUDY-SPECIFIC MATERIALS..............................................................................104
16.
ETHICAL ASPECTS ................................................................................................104
16.1.
Study-Specific Design Considerations .....................................................................104
16.2.
Regulatory Ethics Compliance .................................................................................107
16.2.1.
Investigator Responsibilities.....................................................................107
16.2.2.
Independent Ethics Committee or Institutional Review Board (IEC/IRB) 107
16.2.3.
Informed Consent.....................................................................................108
16.2.4.
Privacy of Personal Data..........................................................................109
16.2.5.
Country Selection.....................................................................................110
17.
ADMINISTRATIVE REQUIREMENTS.....................................................................110
17.1.
Protocol Amendments ..............................................................................................110
17.2.
Regulatory Documentation.......................................................................................111
17.2.1.
Regulatory Approval/Notification..............................................................111
17.2.2.
Required Prestudy Documentation ..........................................................111
17.3.
Subject Identification, Enrollment, and Screening Logs...........................................112
17.4.
Source Documentation.............................................................................................112
17.5.
Case Report Form Completion.................................................................................113
17.6.
Data Quality Assurance/Quality Control...................................................................113
17.7.
Record Retention......................................................................................................114
17.8.
Monitoring................................................................................................................. 114
17.9.
Study Completion/Termination .................................................................................115
17.9.1.
Study Completion.....................................................................................115
17.9.2.
Study Termination ....................................................................................115
17.10.
On-Site Audits...........................................................................................................115
17.11.
Use of Information and Publication ..........................................................................116
REFERENCES ...................................................................................................................... 118
Attachment 1: 
Sulfonylurea Monotherapy Doses for Stratification Purposes .............. 120
Attachment 2:
Hypoglycemia: Definitions, Symptoms, and Treatment........................121
Attachment 3: 
New York Heart Association Classification of Cardiac Disease ........... 122
Attachment 4:
Optional Specimens for Exploratory Research - Sample Collection 
and Handling.........................................................................................123
Attachment 5:
Pharmacogenomic Sample Collection and Shipment Procedure......... 125
Attachment 6: 
Clinical Laboratory Tests ......................................................................126
Attachment 7:
Algorithm for Monitoring Abnormal Liver Function Tests......................127
Attachment 8: 
Candidate Gene List for Part 1 of Pharmacogenomics ........................128
Attachment 9:
Medical Resource Utilization Review....................................................129
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LAST PAGE .......................................................................................................................... 129
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:  
Adverse Event Collection Requirements .............................................................79
FIGURES
Figure 1:  Study Design Outline ...........................................................................................52
Figure 2:  Follow-up of Randomized Subjects With Respect to the GTED..........................54
Figure 3:  Testing Sequences for Substudy Secondary Efficacy Endpoints........................95
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
14 Aug 2009
Amendment INT-1
16 Sep 2009
Amendment INT-2
27 Apr 2010
Amendment INT-3
11 Mar 2011
Amendment INT-4
08 Sep 2011
Amendment INT-5
13 Dec 2012
Amendment INT-6
08 November 2013
Amendment INT-7
23 September 2015
Amendment INT-8
5 May 2016
Amendments are listed beginning with the most recent amendment.
Amendment INT-8 (5 May 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The primary reason to amend the study protocol  is to include 
new safety information and guidance regarding subject management surrounding the event of lower-
extremity amputations.
Applicable Section(s)
Description of Change(s)
Rationale: Decision to continue adjudication of hospitalized heart failure, VTE, and fracture events.
Section 9.2  
Reporting/Adjudication of 
Events in the CV Composite 
Endpoint and Other Events for 
Adjudication
The note that adjudication of hospitalized heart failure VTE, and fracture 
events would conclude with implementation of INT-6 was removed, 
since adjudication of these cases is continuing.
Rationale: Include guidance regarding subject management surrounding the event of lower-extremity 
amputations.
Time and Events Schedule
footnote “j”; footnote “v”; 
Time and Events Schedule 
(posttreatment) footnote “c”;
Section 12.2.1 All Adverse 
Events
Added foot examination to be consistent with standard diabetes treatment 
guidelines. Added guidance regarding foot care and reducing risk of 
amputation.
Rationale: To address a request from a Health Authority.
Time and Events Schedule 
(posttreatment)
Added collection of AHAs after study drug discontinuation.
Rationale: To address a request from a Health Authority.
Section 9.4. Safety 
Evaluations
Events with characteristics of diabetic ketoacidosis will be adjudicated by 
an ad hoc adjudication committee, to verify whether or not the event 
meets a specified definition of DKA.
In addition other categories of events (eg, renal) may undergo 
adjudication as necessary based on regulatory agency requests or to 
supplement data analyses.
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Applicable Section(s)
Description of Change(s)
Rationale: Include new safety information and guidance regarding subject management surrounding the 
event of lower-extremity amputations
Section 1.1.2. Clinical Studies;
Section 6.1. Study Drug; 
Time and Events Schedule 
footnote “u”;
Section 9.4. Safety 
Evaluations; Table 1;
Added amputation data from IDMC.
Added statement that study drug should be interrupted for subjects who
develop conditions that are associated with or leading to amputation.    
An additional AE of special interest was added, “amputation”. 
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-7 (23 September 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment
The primary reason for the amendment is to reflect a request by Health Authorities to amend the study 
protocol to include diabetic ketoacidosis (DKA) safety information and handling of subjects surrounding 
this event. 
Applicable Section(s)
Description of Change(s)
Rationale: Balanitis was added as an AE of interest and DKA as an AE of special interest to obtain and 
collect safety information surrounding these events.
Time and Events Schedule 
footnote "u"; Section, Section 
9.4. Safety Evaluations; Table 1
An additional AE of interest was added, "male genital infections 
(balanitis, phimosis, events leading to circumcision)", and an AE of 
special interest, "diabetic ketoacidosis"; “other designated forms” was 
added; “In addition, non-serious adverse events” was added; and the 
statement “If adverse events of interest are identified in the future, 
guidance concerning the reporting of those events may be provided to 
investigators via appropriately-documented study communications” was 
added. A directive for reporting DKA to the sponsor within 24 hours was 
added.   
Rationale: To provide the most up to date data results of safety findings. 
Section 1.1.2. Clinical Studies
Additional paragraph added stating additional AE results as of 
11 May 2015.
Rationale: To ensure consistency with the Investigator’s Brochure. 
Section 1.1.2. Clinical Studies
Wording updated regarding bone fracture events consistent with the 
Investigator’s Brochure.
Rationale: To provide clarification on drug discontinuation.
Section 6.1. Study Drugs
Additional wording added to last paragraph to clarify study drug 
discontinuation.
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Applicable Section(s)
Description of Change(s)
Rationale: To include a serious adverse event of biochemically-confirmed diabetic ketoacidosis (DKA) to 
the list of reasons for withdrawal from study drug.
Section 10.2. Withdrawal from 
Study Drug
The sentence "The subject experiences a serious adverse event of 
biochemically-confirmed (eg, pH, serum ketones, anion gap) diabetic 
ketoacidosis (DKA)." was added. 
Rationale: Consistent with changes relative to DKA.
Section 12.2.1. All Adverse 
Events
A description of diabetic ketoacidosis was added: “Study research staff 
should make study subjects aware of potential signs and symptoms of 
diabetic ketoacidosis such as difficulty breathing, nausea, vomiting, 
abdominal pain, feeling confused, fruity-smelling breath, and unusual 
fatigue or sleepiness. Study subjects should be instructed to contact the 
site if they experience such symptoms.  If the investigator suspects these 
symptoms may be related to diabetic ketoacidosis (even if the subject’s 
blood glucose levels are less than 250 mg/dL ([13.9 mmol/L]), testing for 
urine or blood ketones should be considered.”
Rationale: Consistent with prior reduction in amount of plasma being stored; allows potential use of smaller 
collection tube.
Attachment 4
Modified the archive specimen volume collection language.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical or formatting changes were made.
Amendment INT-6 (08 November 2013)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:
The primary reason for the amendment is to reflect the changes required for compliance with the United 
States (US) Food and Drug Administration (FDA) post-marketing requirements for canagliflozin. According 
to these requirements, a post-approval cardiovascular (CV) meta-analysis will occur when at least 688 
MACE events (ie, CV death, nonfatal myocardial infarction, nonfatal stroke) are accumulated from 
CANVAS plus a planned study evaluating renal events (CANVAS-R; A Randomized, Multicenter, Double-
Blind, Parallel, Placebo-Controlled Study of the Effects of Canagliflozin on Renal Endpoints in Adult 
Subjects With Type 2 Diabetes Mellitus; 28431754DIA4003).  Per the post-marketing requirement, the FDA 
believes it is most appropriate to characterize CV safety based on a composite of major adverse 
cardiovascular events (MACE) (not MACE plus hospitalized unstable angina) and using a population at high 
CV risk (ie, similar to the patients currently enrolled in CANVAS). In addition to the above-mentioned 
meta-analysis, the US FDA is requiring enhanced pharmacovigilance on select adverse events of interest, 
which are now described in INT-6. Since the safety profile of canagliflozin was well-established in the 
Phase 3 program, adverse event collection is being limited in INT-6 to serious adverse events, adverse 
events that result in study drug discontinuation, and adverse events of interest (as described in the protocol).
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Applicable Section(s)
Description of Change(s)
Rationale:
This change was made to comply with US FDA post-marketing requirements for 
canagliflozin.
Synopsis; 1.2. Overall 
Rationale and Goals for the 
Study; 3. Overview Of Study 
Design; 11.3. Sample Size 
Determination; 11.8.2.
Meta-Analysis 
Post-Regulatory Approval
Synopsis; 2.1.1. Primary 
Objectives
The post-approval meta-analyses across all Phase 3 studies for assessment 
of CV safety when 500 and 700 events in the CV composite endpoint 
occur will no longer be done. Instead the post-approval CV meta-analysis 
will occur when at least 688 MACE events (ie, CV death, nonfatal 
myocardial infarction, nonfatal stroke) are accumulated from the 
CANVAS (28437154DIA3008) study plus a planned study evaluating 
renal outcomes (CANVAS-R; A Randomized, Multicenter, Double-Blind, 
Parallel, Placebo-Controlled Study of the Effects of Canagliflozin on 
Renal Endpoints in Adult Subjects With Type 2 Diabetes Mellitus; 
28431754DIA4003). The projected date of occurrence (April 2017) of the 
total number of required events was added. 
A statement was added indicating that the data from CANVAS 
(28431754DIA3008) will be combined with CANVAS-R 
(28431754DIA4003) to meet US FDA post-marketing requirements for 
canagliflozin.
Rationale:
This section was updated to reflect the current status of the study.
Synopsis; 1.2. Overall 
Rationale and Goals for the 
Study
The description of the pre-approval CV meta-analysis was modified 
indicating that it has already been conducted. 
Rationale:
Hospitalized unstable angina is no longer part of the pre-specified CV composite 
endpoint, which now focuses only on MACE events (ie, CV death, nonfatal myocardial infarction, and 
nonfatal stroke). Hospitalized heart failure events observed in the ongoing CANVAS study occur 
infrequently due to the nature of the population enrolled which contains no subjects with NYHA Class IV 
heart failure and few subjects with NYHA Class III.  
With respect to venous thromboembolism and fracture events, there is a high concordance rate between 
investigator-reported events and adjudication committee confirmed events, such that the adjudication of 
these events does not impact the assessment of these events.  Nevertheless, all reported venous 
thromboembolism and fracture events will be reported and captured by investigators.   
It is not anticipated that proposed changes to adjudication will impact procedures conducted by 
investigators.  Data collection remains unchanged, with investigators still being required to provide the 
same level of data.
Safety analyses will be conducted using investigator-reported safety results for hospitalized unstable 
angina, hospitalized heart failure, venous thromboembolism, and fracture events.  
9.2. Reporting/Adjudication 
of Events in the CV 
Composite Endpoint and 
Other Events for 
Adjudication; Synopsis; 9.4. 
Safety Evaluations; 12. 
Adverse Event Reporting
For events of hospitalized unstable angina and hospitalized heart failure, 
adjudication will conclude with implementation of amendment INT-6. 
However, investigators will continue to report such events that are serious 
or that lead to study drug discontinuation on the eCRF.  
For events of venous thromboembolism and fractures, adjudication will 
conclude. However, investigators will continue to report all events of 
venous thromboembolism and fractures on the eCRF. The implementation 
date to end adjudication of these events will be documented in an update to 
the adjudication charter(s).   
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Applicable Section(s)
Description of Change(s)
Rationale:
This change is consistent with US FDA post-marketing requirements for canagliflozin, 
and the circumstances outlined in INT-5.
Synopsis
The text describing the safety and tolerability assessments was modified to 
specify that CV safety will be assessed as part of the meta-analysis of 
CANVAS and CANVAS-R.
Rationale:
Because the safety profile of canagliflozin was well-established in the Phase 3 program, 
adverse event collection is being limited in INT-6 to serious adverse events, adverse events that result in 
study drug discontinuation, and events of interest specified by the US FDA in their post-marketing 
requirements for canagliflozin. In addition, this process is consistent with the protocol (Section 9.4), which
previously indicated (as of INT-2), “After the decision to re-open enrollment (and recruit Cohort B), for 
subjects continuing from the initial cohort (Cohort A) and subjects entered in the subsequent cohort 
(Cohort B), only serious adverse events, adverse events resulting in study drug discontinuation, and 
selected adverse events will be collected on CRFs.”
Time and Events Schedule
(new footnote “u”); 3.
Overview Of Study Design; 
9.4. Safety Evaluations; 11.4.
Safety Analyses; 12. Adverse 
Event Reporting
Only serious adverse events, adverse events resulting in study drug 
discontinuation, and adverse events of interest will be recorded on eCRFs. 
Adverse events of interest include: all malignancies, fatal pancreatitis, 
hemorrhagic/necrotizing pancreatitis, severe hypersensitivity reactions 
(eg, angioedema, anaphylaxis, Stevens-Johnson syndrome), 
photosensitivity reactions, serious adverse events of hepatic injury, 
nephrotoxicity/acute kidney injury, venous thromboembolic events, 
fractures, and pregnancy. Information on these events of interest will also 
be recorded on a supplemental electronic case report form (eCRF) for any 
event that is serious or that leads to study drug discontinuation. The only 
exceptions to the adverse event collection described above are for 
malignancies, photosensitivity reactions, fractures, and venous 
thromboembolic events for which information on non-serious adverse 
events will also be recorded on the supplemental eCRF pages (in addition 
to the information collected on serious adverse events and adverse events 
leading to study drug discontinuation).
Also, as noted above, events of hospitalized unstable angina and 
hospitalized heart failure, will be reported the adverse event/serious 
adverse event eCRF if such events are serious or lead to study drug 
discontinuation (see Section 9.4. Safety Evaluations). 
Rationale:
This change is consistent with US FDA post-marketing requirements for canagliflozin in 
that only serious hypoglycemia events and those resulting in study drug discontinuation will be collected. 
This decision also reflects the fact that extensive safety data regarding hypoglycemia were collected in the 
canagliflozin Phase 3 program.  The focus going forward will be on more clinically relevant hypoglycemia 
events and not all events.  As noted above, because the safety profile of canagliflozin was well-established 
in the Phase 3 program, adverse event collection is being limited in INT-6 to serious adverse events, 
adverse events that result in study drug discontinuation, and events of interest specified by the US FDA in 
their post-marketing requirements for canagliflozin. In addition, this process is consistent with the protocol 
(Section 9.4), which previously indicated (as of INT-2), “After the decision to re-open enrollment (and 
recruit Cohort B), for subjects continuing from the initial cohort (Cohort A) and subjects entered in the 
subsequent cohort (Cohort B), only serious adverse events, adverse events resulting in study drug 
discontinuation, and selected adverse events will be collected on CRFs.”
12.2.4. Hypoglycemia; 
related text in Section 11.4. 
Safety Analyses
Section or text regarding hypoglycemia was deleted.
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Applicable Section(s)
Description of Change(s)
Rationale: 
The decision to stop routine annual central ECGs was made due to there being no ECG 
signal from the extensive Phase 3 program. 
Synopsis; Time and Events 
Schedule; 3.1. Overview of 
Study Design; 9.4. Safety 
Evaluations; 11.4. Safety 
Analyses
Routine central ECGs will no longer be collected after Week 52. 
Rationale: 
The urine pregnancy test requirement was removed, but the provision remains for 
investigators to continue testing if locally required or clinically warranted for individual subjects.
Time and Events Schedule; 
9.4. Safety Evaluations; 11.4.
Safety Analyses
Urine pregnancy testing will no longer be required on a routine basis 
post-baseline, but the provision remains for investigators to continue 
testing women of childbearing potential if locally required or clinically 
warranted for individual subjects. 
Rationale: 
The total blood collection was decreased because the collection volumes for exploratory 
samples have been decreased based on the projected need for minimal additional retention samples.
16.1. Study-Specific Design 
Considerations
The total blood volume collected over the course of the study was lowered
from 875 mL to 850 mL.
Rationale: More recent information regarding canagliflozin has become available since the CANVAS 
protocol was drafted. The description of pharmacokinetic, pharmacodynamic, efficacy, and safety 
information was outdated.
Introduction
The introduction was updated to reflect the current benefit/risk profile of 
canagliflozin and its marketing approval in the United States and other 
countries.
The background section was updated to describe the exposure in the 
Phase 1, 2, and 3 studies as of the end of 2012. The pharmacokinetic, 
pharmacodynamic, efficacy, and safety information was updated with 
current information.
Rationale:
This change was made to correct a typographical error in INT-5 and clarify that the 
primary objective will be assessed using the ITT analysis set.  Selected secondary objectives may be 
assessed using the mITT analysis (if appropriate) to comply with US FDA post-marketing requirements for 
canagliflozin.
Synopsis; 3. Overview of 
Study Design; 11.1. Analysis 
Sets; 11.4. Safety Analyses
The modified intent-to-treat (mITT) analysis set definition is now
randomized subjects who receive at least one dose of study drug (original 
definition) plus their data occurring between first dose and last dose plus 
30 days.
A statement was added that alignment of the analysis of the secondary 
endpoints with the ITT and mITT analysis sets will be detailed in the study 
statistical analysis plan (SAP).
Rationale:
This section was updated to allow investigators more flexibility in scheduling subject 
contacts.
Time and Events Schedule
Visits at 13-week in-clinic visits after Week 52 are no longer required and 
will now be performed as a telephone contact. An in-clinic visit at 
13-week intervals may be performed at the investigator’s discretion to 
resupply study drug. 
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Applicable Section(s)
Description of Change(s)
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, spelling or template changes were made.
Amendment INT-5 (13 December 2012)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:
The CANVAS (DIA3008) study is being modified because the sponsor has been unblinded to the results of 
the analysis of the study’s primary cardiovascular (CV) endpoint (MACE events), which was part of a 
cross-program CV meta-analysis. Originally, the cross-program CV meta-analysis results (and results from 
CANVAS) were only to be unblinded to the canagliflozin program Independent Data Monitoring 
Committee (IDMC) and a limited number of sponsor personnel not involved with the canagliflozin 
program, and then submitted to Health Agencies (who were to be requested to avoid public disclosure). 
The release of these CV meta-analysis results to the sponsor was based upon the observed small 
dose-related increase in LDL-cholesterol (4.4% and 8.0% for canagliflozin 100 mg and 300 mg, 
respectively, relative to placebo) observed in Phase 3 studies. This allowed an assessment by the sponsor of 
the LDL-C changes in the context of the CV meta-analysis results, including the hazard ratio (HR) for the 
composite MACE plus hospitalized unstable angina endpoint. Due to the release of the unblinded CV 
endpoint results from CANVAS, the study Steering Committee has determined that the second cohort 
(Cohort B), originally planned for future enrollment in CANVAS, would not be conducted; this decision 
was based upon the assessment that the unblinding interim primary endpoint (MACE CV HR) data from 
the ongoing CANVAS study did not allow a definitive assessment of the study objective. The Steering 
Committee indicated that a separate CV outcome study should be conducted to provide a definitive 
assessment of CV risk. After review of the CV HR results, the Steering Committee in concert with the 
sponsor (and after IDMC review) has recommended continuing CANVAS with the original cohort 
(Cohort A, which completed enrollment in March 2011) so as to provide an initial assessment of the 
study’s primary objective of CV benefit. This initial assessment will provide important information 
supporting a subsequent separate CV outcome study, and will also support assessment of other study 
objectives.
Applicable Section(s)
Description of Change(s)
Rationale: Comprehensive follow-up of subjects who discontinue is important for analysis of the study 
results; these changes provide mechanisms for enhancing follow-up.
Synopsis;
Time and Events 
Schedule
Added mention of provision for alternative posttreatment follow-up options; 
added specific mention of expectation that the investigator will make every 
effort to ascertain the vital status of all subjects at the end of the study, including 
using all reasonable means to contact the subject, family members, the subject’s 
physicians and medical records, and the use of locator agencies and checking 
public records, as allowed by local law.
Rationale: Refer to overall reason for amendment.
1.2. Overall Rationale 
and Goals for the 
Study; 
2.3. Substudies: 
In light of overall reason for amendment, removed mention of Cohorts A and B.
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Applicable Section(s)
Description of Change(s)
Objectives and 
Hypotheses
3. Overview of Study 
Design;
3.1. Study Design;
3.2. Study Design 
Rationale;
4. Study Population;
4.1. General 
Considerations;
5. Treatment 
Allocation;
6.1. Study Drugs;
6.2.1.Management of 
Glycemic Control and 
CV Risk Factors;
6.2.2. Glycemic Rescue 
Therapy;
9.1.2. Pretreatment 
Phase;
9.1.3. Double-Blind 
Treatment Phase;
9.1.4. End of-
Treatment/Early 
Withdrawal;
9.4. Safety Evaluations;
9.8. Medical Resource 
Utilization;
10.2. Withdrawal from 
the Study;
11. Statistical Methods;
12.2.2 Serious adverse 
experiences
Rationale: Refer to overall reason for amendment.
Synopsis; 3. Overview 
of Study Design; 
3.1 Study Design; 
11.3 Sample Size 
Determination; 
11.8.2. Meta-Analysis 
Post-Regulatory 
Approval
In light of overall reason for amendment, removed mention of Cohorts A and B 
and associated statements in the analysis; revised wording regarding 
meta-analyses to meet the CI <1.3 requirement for the upper bound of the 95% 
CI for the CV HR.
Rationale: Comprehensive follow-up of subjects who discontinue is important for analysis of the study 
results; these changes provide mechanisms for enhancing follow-up
Synopsis; Time and 
Events Schedule; 
9.1.4 End-of-
Treatment/Early 
Withdrawal; 10.2 
Withdrawal From the 
Study
Provided for subject to allow contacting physicians and medical records to 
follow-up subjects who cannot be contacted; added provision if the site of the 
study doctor closes, and the study doctor cannot reach the subject to inform 
him/her, the contact information will be transferred to another site where a new 
study doctor will consult with family members, the subject’s physicians and 
medical records, or public records, including the use of locator agencies as 
permitted by local law, to determine the subject’s endpoint status.
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Applicable Section(s)
Description of Change(s)
9.8 Medical Resource 
Utilization
Removed erroneous mention of collecting hospitalization information on MRU 
forms.
Rationale: The sponsor has been unblinded to the results of the analysis of the study’s primary 
cardiovascular endpoint (MACE events), which was part of a cross-program CV meta-analysis. Originally, 
the cross-program CV meta-analysis results (and results from CANVAS) were only to be unblinded to the 
canagliflozin program Independent Data Monitoring Committee and a limited number of sponsor personnel 
not involved with the canagliflozin program, and then submitted to Health Authorities. Since the scope of 
unblinding within the sponsor organization is broader than originally planned, a more limited firewall is 
implemented involving individuals within the sponsor responsible for submitting events to the Endpoint 
Adjudication Committee.
11.8.1. Meta-analysis 
Pre-Regulatory 
Approval
Description of the firewall to maintain data integrity has been edited.
Rationale: Study drug supplies may be supplied in bottles rather than blister packs in the future.
14.2. Packaging
Provided for use of bottles.
Rationale: Company name and sponsorship statement updated due to the recent change in various legal 
entity names.
Title Page; 
Attachment 4
Changed name from Johnson and Johnson Pharmaceutical Research and 
Development to Janssen Research and Development.
Amendment INT-4 (8 September 2011)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reasons for the amendment are (1) to remove the 
pre-planned adaption to re-estimate the sample size for Cohort B and (2) to specify that an interim analysis 
of the ongoing CANVAS (DIA3008) study will be required for reporting of safety data in the initial 
canagliflozin marketing applications. 
Applicable Section(s)
Description of Change(s)
Rationale: In discussions between the sponsor and the CANVAS Steering Committee, a fixed sample size 
approach has been chosen as this is a more statistically and analytically sound approach, relative to 
adaptation, to re-estimate sample size.
Synopsis;
1.2. Overall Rationale 
and Goals for the 
Study; 
3. Overview of Study 
Design;
3.2. Study Design 
Rationale;
11.9. Feasibility 
Assessment
The pre-planned adaptation to re-estimate the sample size for Cohort B will no 
longer be conducted. The description of the prior adaptive design was modified to 
reflect the fixed sample size of the 2 sequential cohorts.
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Applicable Section(s)
Description of Change(s)
Rationale: Since CANVAS (DIA3008) contributes a substantial amount of placebo-controlled, safety data 
in a high-risk population to the overall canagliflozin development program, health authorities will be 
expecting to review unblinded data from this study in order to make a determination of overall safety and 
efficacy of this compound and ultimately a decision on the approvability of canagliflozin.
11.7.1. Interim 
Analyses for Health 
Authority 
Submissions
New section added. Text added to the protocol indicating that an unblinded 
interim analyses of CANVAS data will be done to prepare an interim safety report 
in support of the initial health authority filing.
Rationale: Recently published literature with other drugs in the SGLT2 inhibitor class suggest that the 
observed standard deviation with respect to HbA1c change from baseline in subjects taking sulfonylureas is 
less than originally anticipated in the protocol. The new data would allow for an assessment of the primary 
substudy endpoint (ie, change in HbA1c from baseline) in the sulfonylurea substudy using a smaller 
samples size than originally planned, ie, approximately 50 subjects per group (instead of 86 subjects per 
group) while retaining adequate power.
11.10.2. Sample Size 
Determination;
References
Added a reference to support the analysis of the sulfonylurea substudy with at 
least 50 subjects per group.
Rationale: An evaluation of intermediate endpoints to assess the feasibility in enrolling Cohort B involves 
modeling the effects on surrogate markers, such as blood pressure, body weight, and fasting lipids, in order 
to derive a predicted HR. Such an evaluation is beyond the current scope of the IDMC’s responsibility,
which is focused on ensuring the safety of subjects enrolled in the study.
Synopsis; 
4.1. General 
Considerations;
11.3.2. Subsequent 
Cohort (Cohort B);
11.7.2.
Interim 
Analysis to Assess the 
Feasibility in 
Initiating Cohort B;
11.9. Feasibility 
Assessment
A CV risk factor evaluation committee was formed to evaluate the effects of 
canagliflozin on intermediate outcomes (eg, blood pressure, fasting lipids, body 
weight).
Rationale: The investigator should be allowed to retain some autonomy in their clinical diagnoses which 
may or may not coincide with the Adjudication Committee’s clinical diagnosis.
12. Adverse Event 
Reporting
Added a stipulation that any nonfatal CV event in the composite endpoint initially 
classified as a serious adverse event, but subsequently determined by the 
Endpoint Adjudication Committee as meeting the definition of a study endpoint, 
will be reviewed on an individual basis by the sponsor to determine whether or 
not such an event should be reported by the investigator on the CV events eCRF 
page (and removed from the adverse event/serious adverse event eCRF page). 
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Amendment INT-3 (11 Mar 2011)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reasons for the amendment are (1) to describe 
procedures associated with the use of rosiglitazone in light of recent regulatory actions and (2) to add to the 
follow-up provisions for subjects who discontinue double-blind study drug prior to completion of the 
study.
Applicable Section(s)
INT-3 Description of Change(s)
Rationale: Addition of new nonclinical study results.
1.1.1. Brief Overview 
of Nonclinical Studies
The results of genotoxicity and carcinogenicity studies in rats were included.
Rationale: Rosiglitazone has been withdrawn or restrictions have been placed on its use in several markets 
worldwide.
2.3. Substudies: 
Objectives and 
Hypotheses 
(Cohort A);
3.1. Study Design;
4.1. General 
Considerations;
4.2. Inclusion 
Criteria;
5. Treatment 
Allocation
Rosiglitazone was removed from the list of approved background AHAs. 
4.1. General 
Considerations
Procedures for handling subjects taking rosiglitazone were added. 
4.3. Exclusion 
Criteria –
Medications/
Therapies
Rosiglitazone was added to the list of exclusionary medications. 
Rationale: Additional follow-up measures for subjects who discontinue double-blind study drug early will 
allow for a more comprehensive safety dataset.
Posttreatment Time & 
Events Schedule
Added new Posttreatment Time & Events Schedule for subjects who 
prematurely discontinue study medication.
Rationale: Additional information regarding superficial genital adverse events in men will be collected in 
the canagliflozin development program to better characterize this recently identified adverse drug reaction.
3.1. Study Design;
3.2. Study Design 
Rationale;
12. Adverse Event 
Reporting
Superficial genital adverse events in men were added to the list of selected 
adverse events.
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Applicable Section(s)
INT-3 Description of Change(s)
Rationale: The exclusion criterion related to thyroid stimulating hormone (TSH) was modified in INT-2,
and measurement of TSH at Run-in is no longer necessary.
Time & Events 
Schedule; 
Attachment 6
Thyroid stimulating hormone was removed as a procedure at the Week -2 (Run-in 
Start) visit.
Rationale: Pharmacogenomic samples will continue to be collected as planned; however, the analyses of 
those samples will not be prespecified in the statistical methods section of the protocol.
11.11. 
Pharmacogenomic 
Analyses
This section was removed from the protocol.
Rationale: Updates need to align with other canagliflozin Phase 3 protocols.
3.2. Study Design 
Rationale;
9.1.1. Overview;
9.7. Exploratory 
Evaluations
Description of the exploratory samples was aligned with the global canagliflozin 
Phase 3 protocols.
3.1. Study Design; 
3.2. Study Design 
Rationale;
12. Adverse Event 
Reporting
Hypoglycemia was removed from the list of selected adverse events for editorial 
reasons because additional information is collected on all hypoglycemic episodes, 
irrespective of whether the episode is considered an adverse event.
Rationale: Flexibility for first morning void collection was needed for subjects with atypical sleep 
patterns.
Time & Events 
Schedule; 
9.4. Safety 
Evaluations
Added a clarification that for subjects working a night shift, or who otherwise 
have atypical sleep patterns, the first morning void collection should be made at 
the end of the subject’s usual sleep period.
Rationale: Clarification of blood pressure and body weight measurements were needed.
9.4. Safety 
Evaluations
Specified that blood pressure will be measured 3 times in both arms at the 
screening visit.
Specified that if disrobing for weighing is logistically impossible, the subject 
must be dressed as lightly as possible, with consistency from visit to visit.
Rationale: Subjects for whom study drug is interrupted as a result of an adverse event, a life event (eg, 
temporary relocation to care for an ill family member), or another unforeseen circumstance may need to 
return to active status (ie, re-start double-blind study drug).
10.3. Reinstitution of 
Subjects who Have 
Prematurely 
Discontinued Double-
blind Study Drug to 
Active Status
New section added.
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Applicable Section(s)
INT-3 Description of Change(s)
Rationale: The per-protocol analysis set definition was too restrictive based upon ICH definition of major 
protocol deviations.
11.10.1. Analysis Sets
Clarified that having no major protocol deviations to be included in the per-
protocol analysis set means having no deviations that may affect the interpretation 
of the primary efficacy endpoint.
Rationale: Follow-up telephone contact may not always be possible.
Throughout the 
protocol
Noted that if a telephone contact or study visit is not possible, follow-up 
information may be collected via email or other electronic means.
Amendment INT-2 (27 April 2010)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reasons for the amendment are to (1) add additional 
data that demonstrated no clinically meaningful photosensitizing potential of canagliflozin in humans and 
to remove the photoprotection prohibition; and (2) add additional data of co-administration of digoxin and 
canagliflozin and the removal of digoxin as a prohibited medication.
Applicable Section(s)
INT-2 Description of Change(s)
Rationale: Additional studies that evaluated the photosensitizing potential of canagliflozin in humans have 
been completed.
1.1.2. Clinical 
Studies;
3.2. Study Design 
Rationale
Findings of the photosensitivity studies in Caucasian subjects were added, 
demonstrating that canagliflozin 100 mg or 300 mg once daily, the clinical doses 
used in the Phase 3 studies, had no delayed photosensitizing effect at any 
wavebands representing the terrestrial solar spectrum.
4.4. Prohibitions and 
Restrictions 
Instructions that subjects should use photoprotective measures were removed.
16.1. Study-Specific 
Design 
Considerations
Instructions that subjects should use photoprotective measures were removed. 
Text stating that the photosensitivity studies support safe participation of subjects 
in these Phase 3 studies without specific photoprotection precautions was added.
Rationale: A Phase 1 drug-drug interaction study with digoxin has been completed.
1.1.2. Clinical Studies
A description of the main pharmacokinetic findings from the study was added.
4.3. Exclusion 
Criteria; 
4.4. Prohibitions and 
Restrictions
Digoxin was removed as a prohibited medication and subjects will no longer be 
excluded for taking this medication.
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Applicable Section(s)
INT-2 Description of Change(s)
Rationale: Study oversight committee structure and responsibilities were modified with input from 
Steering Committee.
9.3.4. Executive 
Committee; 
throughout the 
protocol
Section removed. “Executive” Committee changed to “Steering” Committee 
throughout the protocol.
Rationale: Clarification regarding the meta-analysis for pre-regulatory approval could occur with as few as 
80 events and as many as 160 events.
11.8.1. Meta-analysis 
Pre-Regulatory 
Approval
The maximum number of expected events in the first meta-analysis for CV safety 
was modified from 140 to an approximate range of 140 to 160 (with the number 
from the CANVAS study changed from 100 to a range of 110 to 120). In no event 
would the meta-analysis to support regulatory approval occur with fewer than 80 
events. 
Rationale: Follow-up contact in other Phase 3 protocols is 30 days after last dose of study drug in 
accordance with requirements for SAE reporting. 
Throughout the 
protocol
Follow-up contact after last dose of study drug was changed from 28 to 30 days. 
The collection time frame after last dose of study medication for CV events for 
the CV analysis was changed from 28 to 30 days. The time frame for reporting 
SAEs after last dose of study drug was changed from 28 to 30 days.
12.2.1. All Adverse 
Events
Corrected the time point at which the 30-day reporting period for SAEs starts 
(changed to the “last dose of study medication” instead of “last follow-up 
contact”).
Rationale: Description of events that require additional data collection was revised to be consistent with 
program-wide data collection.
3.1. Study Design; 
3.2. Study Design 
Rationale; 
9.4. Safety 
Evaluation; 
12. Adverse Events
Events of increased ALT !3-fold the upper limit of normal (ULN) were removed 
from the events that require a separate section in the eCRFs for collection of 
additional information. Clarification was added that investigators may be 
contacted and requested to provide additional information regarding such events 
and that subjects will be monitored and managed according to the algorithm in 
Attachment 7.
Rationale: Additional Phase 1 studies have been completed.
1.1.2. Clinical Studies
The number of subjects who participated in the Phase 1/1b studies was updated.
Rationale: Single-blind placebo capsules were described as “tablets” in error.
Synopsis; 
3.1. Study Design; 
4.2. Inclusion 
Criteria; 
6.1. Study Drugs; 
9.1.2. Pretreatment; 
9.1.3. Double-blind 
Treatment
Single-blind placebo “tablets” were changed to single-blind placebo “capsules.”
Clarification was added that subjects are to take one single-blind capsule once 
daily during the 2-week run-in period.
Rationale: Hematology was not originally included at end-of-treatment/early withdrawal visit, but is 
needed for optimal safety monitoring.
Time and Events 
Schedule
Hematology was added at end-of-treatment/early withdrawal visit.
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Applicable Section(s)
INT-2 Description of Change(s)
Rationale: Input from the Steering Committee was received after further review of data from other CV 
outcomes trials.
4.2. Inclusion Criteria
The blood pressure criterion was modified to clarify that the value should be an 
average of 3 readings recorded at the screening visit. 
Rationale: The standard exclusion criteria wording has been modified in other issued canagliflozin Phase 3 
protocols.
4.3. Exclusion Criteria
Thyroid exclusion criterion was modified for consistency with the other 
protocols.
4.3. Exclusion Criteria
The laboratory exclusion criterion for subjects taking metformin was modified to 
a serum creatinine level of !1.4 mg/dL (124 ∀mol/L) for men or !1.3 mg/dL 
(115 ∀mol/L) for women and with no contraindication to the use of metformin 
(including eGFR) based on the label of the country of the investigational site.
4.3. Exclusion Criteria; 
5. Treatment 
Allocation
The definition of a stable dose of insulin was modified from a #10% change to a 
#15% change.
Rationale: The standard prohibition and restrictions wording has been modified in other canagliflozin 
Phase 3 protocols.
4.4. Prohibitions and 
Restrictions
A bullet was added with instructions that subjects should not collect first morning 
void during acute illness with fever.
Rationale: For consistency with standards of care for glycemic rescue in clinical trials and with other 
canagliflozin Phase 3 protocols. 
6.2.2. Glycemic 
Rescue Therapy 
Through Week 18 for 
Initial Cohort (Cohort 
A): Criteria and 
Implementation
The time points for rescue were modified: “Week 4” was changed to “Week 6.”
Rationale: Health authorities have requested that a “firewall” be established to ensure data integrity in the 
CANVAS study.
11.8.1. Meta-analysis 
Pre-Regulatory 
Approval
Description of the firewall to maintain data integrity has been added.
Rationale: Additional canagliflozin Phase 3 protocols have been issued and program-wide wording and 
standards have been established for consistency.
Throughout the 
protocol
Updates were made for consistency with the other Phase 3 protocols.
Section 1. 
Introduction; 
References
References added.
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Amendment INT-1 (16 September 2009)
The overall reason for the amendment: Protocol was amended to further clarify the interim analysis and 
adaptation plan for the study. 
Applicable Section(s)
INT-1 Description of Change(s)
Rationale: Description of the criteria for adaptation and the potential for enrollment of a second cohort of 
subjects was clarified. In addition, the roles of the Independent Data Monitoring Committee (IDMC) and 
Executive Committee in the interim analysis and adaptation of the study were clarified. 
Synopsis Overview of 
Study Design;
1.2. Overall Rationale; 
3. Overview of Study 
Design; 3.1. Study 
Design; 3.2 Study 
Design Rationale; 
9.3.5. IDMC; 11.3 
Sample Size 
Determination; 11.7
Interim Analysis
Updated Text
Rationale: Description of the initial cohort (referred to as Cohort A) and the subsequent cohort (referred to 
as Cohort B) was modified for clarity.
Throughout the 
protocol
Previously described as Cohort A and Cohort B; now described as initial cohort 
(Cohort A) and subsequent cohort (Cohort B). 
Rationale: First morning void urine collection was added to run-in visit to provide additional baseline data 
for comparison with treated values.
Time and Events 
Schedule
Rationale: Description of the inclusion and exclusion criteria and prohibitions and restrictions were 
aligned with other Phase 3 studies in the canagliflozin development program for consistency.
4.1. Inclusion Criteria; 
4.2. Exclusion Criteria; 
4.4 Prohibitions and 
Restrictions
Minor changes to the text were made.
Rationale: The study drug kit number will be automatically recorded.
5. Treatment 
Allocation
Deleted statement that the study drug kit number will be entered in the electronic 
case report form (CRF) when the drug is assigned. 
Rationale: Clarification regarding urinalysis by a local laboratory for safety reasons was needed.
5. Treatment 
Allocation
Added a statement that if urinalysis must be performed locally for appropriate 
subject management (eg, to evaluate a potential infection), investigators should 
request microscopic rather than dipstick urinalysis (if microscopic evaluation is 
considered clinically sufficient).
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Applicable Section(s)
INT-1 Description of Change(s)
Rationale: Consideration was needed for subjects who do not meet screening adjustment/optimization of 
lipid altering or blood pressure-lowering medications.
9.1.1. Overview, 9.1.2. 
Pretreatment
Added text stating that if additional time in run-in is required for 
adjustment/optimization of lipid altering or blood pressure-lowering 
medications, (so as to avoid the need for adjustment of these medications after 
randomization), the 2-week placebo run-in may be extended by having the 
subject continue single-blind placebo up to 2 additional weeks (note: the single-
blind placebo package contains sufficient drug supply for additional time period)
Rationale: Exploratory samples were under 2 different informed consents; modifications to the description 
were made to simplify the consent process and include the samples for exploratory research under a single
informed consent.
9.1.1. Overview; 
Attachment 4
Modified text to clarify that one set of plasma, serum, and urine samples will be 
collected at baseline and all 52-week intervals from subjects who consent to this 
component of the study to allow for exploratory research related to canagliflozin 
or biomarker analyses.
Rationale: Hypoglycemic events will be captured as non-serious adverse events in addition to recording 
the information on the hypoglycemia section of the eCRF.
9.4. Safety evaluations; 
12.2.4. Hypoglycemia
Added text stating that information on possible hypoglycemic events will be 
collected on a separate hypoglycemia eCRF page, and hypoglycemic events 
should be recorded on the adverse event eCRF, if considered an adverse event by 
the investigator.
Rationale: Clarification of certain procedures and corresponding analyses was needed.
9.4. Safety evaluations; 
9.5. Efficacy 
Evaluations; 11. 
Statistical Methods
∃
Physical examinations elaborated; estimated glomerular filtration rate 
(eGFR) evaluations moved from safety to efficacy; Medical Resource 
Utilization evaluation removed from follow-up telephone contact 
procedures.
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SYNOPSIS
A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of 
JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus (CANVAS: 
CANagliflozin cardioVascular Assessment Study)
EUDRACT number: 2009-012140-16
Canagliflozin (JNJ-28431754) is an orally active inhibitor of the sodium-glucose co-transporter 2 (SGLT2) 
that is being developed as an oral antihyperglycemic agent (AHA) for the treatment of patients with type 2 
diabetes mellitus (T2DM). Canagliflozin is selective for inhibition for SGLT2 relative to sodium-glucose 
co-transporter 1 (SGLT1). The initial goals of this study (CANVAS) were to assess the overall safety and 
tolerability of canagliflozin and to demonstrate a reduction in major adverse cardiovascular events (MACE) 
with canagliflozin treatment.
Prior clinical studies of canagliflozin in patients with T2DM have demonstrated improvements in glycemic 
control (with reductions in hemoglobin A1c [HbA1c] and fasting plasma glucose [FPG]), reduction in body 
weight, and trends towards improvements in other cardiovascular (CV) disease risk factors (including 
increases in high-density lipoprotein cholesterol [HDL-C], decreases in triglyceride levels, and decreases in 
blood pressure, especially at the 300-mg dose), with generally good tolerance and appropriate safety to 
support continued clinical development of this medication. With improved glycemic control, which itself 
may provide a benefit in CV risk, and the trends towards benefit on other CV risk factors including body 
weight, the potential for a benefit of long-term treatment with canagliflozin on CV disease is raised. 
The present study was intended to assess if treatment of subjects with T2DM with canagliflozin reduces 
CV risk for MACE (including CV death, nonfatal myocardial infarction [MI], and nonfatal stroke) and to 
achieve a number of other important goals. These include the assessment of overall safety and tolerability, 
glycemic efficacy (in the overall study population and in subjects on specific AHAs), long-term effects on 
beta-cell function, and long-term effects on renal function with canagliflozin treatment. This study also 
provides key support for a cross-canagliflozin program assessment of CV safety, examining a composite 
endpoint of MACE plus hospitalized unstable angina (pre-approval CV safety assessment) and MACE 
(post-approval CV safety assessment). Subsequent to the initial plan it has been necessary to modify the 
design of the study. 
The data from this study will be combined with the data from another large-scale study of the effects of 
canagliflozin compared to placebo (CANVAS-R; A Randomized, Multicenter, Double-Blind, Parallel, 
Placebo-Controlled Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects With 
Type 2 Diabetes Mellitus; 28431754DIA4003) in a pre-specified meta-analysis of CV safety outcomes, to 
satisfy post-approval United States (US) Food and Drug Administration (FDA) post-marketing 
requirements for canagliflozin.
OBJECTIVES AND HYPOTHESES
Primary Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history or high risk of CV disease:
∃
to assess the effect of canagliflozin plus standard of care relative to placebo plus standard of care on 
CV risk as measured by the hazard ratio (HR) for a composite endpoint (MACE including CV death, 
nonfatal MI, and nonfatal stroke)
∃
to assess the safety and tolerability of canagliflozin plus standard of care relative to placebo plus 
standard of care 
The data from this study will be combined with the data from CANVAS-R in a pre-specified meta-analysis 
of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin.
Secondary Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history or high risk of CV disease:
∃
to assess the effect of canagliflozin plus standard of care relative to placebo plus standard of care on:
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–
fasting measures of beta-cell function (homeostasis model assessment [HOMA]-B and the 
proinsulin/insulin ratio) (Note: this assessment will be conducted in a subset of subjects at sites 
that elect to participate, including only subjects who are not receiving insulin at randomization).
–
the proportion of subjects with progression of albuminuria (progression defined as !1 step 
increase, ie, no albuminuria to micro- or macro-albuminuria or from micro-albuminuria to 
macro-albuminuria)
–
the urinary albumin/creatinine ratio
–
renal function (as measured by the change from baseline in estimated glomerular filtration rate 
[eGFR])
∃
to assess the effect of canagliflozin relative to placebo after 18 weeks and at the end of the treatment 
period on:
–
glycemic efficacy (HbA1c and FPG)
–
body weight 
–
blood pressure (systolic and diastolic)
–
fasting plasma lipids (triglycerides, HDL-C, low-density lipoprotein cholesterol [LDL-C], total 
cholesterol, and the ratio of LDL-C to HDL-C)
Hypotheses
Primary hypothesis
In subjects with T2DM with inadequate glycemic control who have a history of or a high risk of CV 
disease, relative to placebo plus standard of care, canagliflozin plus standard of care reduces CV risk (as 
measured by the HR for a composite endpoint including CV death, nonfatal MI, and nonfatal stroke). 
Secondary hypotheses
In subjects with T2DM, with inadequate glycemic control, who have a history of or a high risk of CV 
disease, relative to placebo plus standard of care, canagliflozin plus standard of care at the end of the 
treatment period:
∃
improves beta-cell function (change from baseline in HOMA-B)
∃
reduces progression of albuminuria (ie, proportion of subjects with a !1-step progression of 
albuminuria measured by the urine albumin/creatinine ratio)
(See protocol body for objectives and hypotheses for substudies examining the efficacy and safety of 
canagliflozin in combination with specific AHAs.)
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, 3 parallel-group, multicenter study to evaluate the 
safety, tolerability, and CV risk with canagliflozin plus standard of care compared with placebo plus 
standard of care in subjects with T2DM, on a wide range of antihyperglycemic therapies, who have either a 
history or high risk of CV disease. Although the effects of canagliflozin on several CV risk factors 
(eg, glycemic control, body weight, blood pressure) appear favorable in short-term studies, the longer-term 
benefits on CV risk factors are currently unknown; in addition, Phase 3 results demonstrated a small 
increase in LDL-C, without a change in the LDL-C to HDL-C ratio. Note that results from this study, 
integrated with cross-Phase 3 program results, were included in a pre-approval meta-analysis to evaluate 
CV safety (as required by the US FDA Guidance for Industry: Diabetes Mellitus - Evaluating 
Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes) by examining the composite 
of MACE plus hospitalized unstable angina (referred to as the pre-approval CV safety endpoint). This CV 
meta-analysis was conducted in 2012 (addressing the US FDA filing requirement that the upper bound of 
the 2-sided 95% confidence interval (CI) around the CV HR is <1.8); this meta-analysis confirmed the 
requirement, showing the upper bound was <1.8.
This study was originally designed to include 2 sequential cohorts, with up to 18,500 subjects and a study 
duration for individual subjects of up to approximately 8 years. The study will now recruit only the initial 
4,330 subjects who were randomly assigned to treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) 
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or placebo, in a 1:1:1 ratio. The study’s last subject last visit will occur when at least 688 MACE events 
(ie, CV death, nonfatal myocardial infarction, nonfatal stroke) are accumulated between the CANVAS and 
CANVAS-R studies which is projected to occur prior to April 2017. 
The study was modified (as of amendment INT-5) because the cross-program meta-analysis of the 
pre-approval CV safety endpoint was unblinded to the sponsor to prepare regulatory submissions 
(originally this was to be unblinded to the study IDMC only); this was done based upon a decision by the 
sponsor, so that the impact of the small dose-related increase in LDL-C observed with canagliflozin 
treatment in Phase 3 program on the CV HR could be evaluated. Due to the unblinding of these CV 
endpoint results, the study Steering Committee noted that the addition to the CANVAS trial of the planned 
second cohort of subjects would not provide a robust assessment of the primary CV protection hypothesis.
The CANVAS study has additional objectives including the assessment of overall safety and tolerability of 
canagliflozin. The study also includes several substudies intended to provide additional information about 
the efficacy and safety of canagliflozin compared to placebo in combination with specific AHAs. 
In this study, investigators will be counseled to assure appropriate management of CV risk factors 
(eg, blood pressure and lipids) according to standard guidelines (eg, the American Diabetes Association 
[ADA] or other local diabetes guidelines) for the care of patients with T2DM. In addition, after a relatively 
brief period during which the subject’s antihyperglycemic regimen is to be kept stable (described in the 
section below), investigators will attempt to achieve good glycemic control, consistent with standard 
diabetes guidelines, individualized as considered clinically appropriate, with up-titration or stepwise 
addition of AHA therapies. Thus, this study will examine the impact on CV risk, and the safety and 
tolerability of treatment with canagliflozin along with standard of care for CV risk factor and glycemic 
management relative to placebo with standard of care management.
STUDY POPULATION
Men or women with T2DM who have inadequate glycemic control (HbA1c !7.0 and #10.5%), not on an 
AHA or on an AHA in monotherapy or combination therapy, and who have known CV disease or who 
have 2 or more risk factors for CV events are eligible.
STRATIFICATION FOR SUBSTUDIES 
Subjects will have within-subgroup balanced (1:1:1) randomization to each of the 3 treatment groups 
within 6 predefined strata based upon AHA medication(s) that the subject is receiving at the run-in visit and 
will be continuing at entry into the double-blind treatment phase (the strata are defined in the main body of 
the protocol).
DOSAGE AND ADMINISTRATION 
Study Drugs
Upon successful completion of screening, all potentially eligible individuals will enter a 2-week run-in 
period, during which they will receive single-blind placebo capsules (one capsule to be administered 
once-daily). 
Subjects will be randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups: canagliflozin 100 mg, 
canagliflozin 300 mg, or matching placebo. Subjects will be counseled to take their dose of canagliflozin or 
matching placebo once daily, before the first meal of the day, according to their randomized treatment 
assignment, for the duration of the study or until early discontinuation. 
Concomitant Antihyperglycemic and Other Therapies
Detailed instructions are provided in the main protocol for management of (1) glycemic control and CV 
risk factors, and (2) glycemic rescue therapy through Week 18.
EFFICACY AND SAFETY OUTCOME DEFINITIONS/EVALUATION CRITERIA
Primary MACE Outcome
The hypothesis of CV risk reduction for canagliflozin will be evaluated based upon the events in the CV 
composite endpoint of MACE (CV death, nonfatal MI, nonfatal stroke). An independent Endpoint 
Adjudication Committee will assess all events that could potentially be in the specified CV endpoint and 
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only those events where the committee, using methodology and definitions defined in the committee’s 
charter, determines a specified endpoint has occurred will be included in the primary analysis. The 
independent Endpoint Adjudication Committee will apply the endpoint definitions contained in its charter 
and classify the outcome events while blinded to treatment assignment. 
Secondary Efficacy Endpoints 
Secondary measures of efficacy include beta-cell function (HOMA-B; in subjects who are not receiving 
insulin) and progression of albuminuria (based upon categories determined by urinary albumin/creatinine 
ratio). 
Additional efficacy endpoints of interest will include the following: changes from baseline to end-of-
treatment in the proinsulin/insulin ratio (in a subset of subjects), urinary albumin/creatinine ratio, and 
eGFR; changes from baseline to Week 18 in HbA1c, FPG, systolic and diastolic blood pressure, and body 
weight; and percent change from baseline to Week 18 in fasting plasma lipids (triglycerides, HDL-C, 
LDL-C, total cholesterol, and the ratio of LDL-C to HDL-C).
Measurements to assess HOMA-B and the proinsulin/insulin ratio will be collected in a subset of subjects 
of approximately 1,200 subjects (at sites that elect to participate) who are not receiving insulin at baseline.
Safety and Tolerability Assessments 
The safety and tolerability assessments will include an evaluation of serious adverse events, adverse events 
of interest, discontinuation due to adverse events, clinical laboratory tests, vital signs (pulse, blood 
pressure), and body weight.  Cardiovascular safety will be assessed as a part of the meta-analysis of 
CANVAS and CANVAS-R.
STATISTICAL METHODS
Analysis Sets
The ITT analysis set includes all subjects who are randomly assigned to a treatment group. The assessment 
of the primary objective will be based upon this analysis set. The primary CV analysis will be based on the 
time to the first occurrence of any component of the MACE composite endpoint. The modified ITT (mITT) 
analysis set includes the randomized subjects who receive at least one dose of study drug and their data 
occurring between first dose and last dose plus 30 days.
The alignment of the analysis of the secondary endpoints with the ITT and mITT analysis sets will be 
detailed in the study statistical analysis plan (SAP).
Sample Size Determination
The sample size for the recruitment of the initial 4,500 subjects was based upon having a sufficient number 
of participants to support, in concert with the other controlled clinical trials in the canagliflozin 
development program, a detailed pre-approval assessment of the safety and tolerability of canagliflozin. 
Data from this initial cohort were exported and integrated with data from other Phase 3 well-controlled 
studies to support a planned, pre-approval meta-analysis to demonstrate that the upper bound of the 2-sided 
95% CI for the CV HR of canagliflozin relative to control in composite endpoint events (MACE and 
hospitalized unstable angina) was <1.8, as part of the current US regulatory requirements for filing. The 
FDA post-marketing requirements for canagliflozin demand a subsequent estimate of CV safety that will be
performed on data from CANVAS and CANVAS-R, when sufficient events have occurred to demonstrate 
that the upper bound of  the 95% CI HR is <1.3 based on MACE (excluding hospitalized unstable angina).
The assumed per annum event rate is 2.25% and the per annum dropout rate is 5% with an enrollment 
period of 1.5 years, 4,500 randomized subjects were projected to contribute sufficient CV events to support 
the pre-approval meta-analysis. The original phased recruitment strategy allowed for an interim assessment 
of study feasibility to demonstrate the primary hypothesis of CV benefit using the results of the interim 
analysis. Results from the interim analysis (after approximately 2 to 4 years from study initiation, eg, at 
approximately the time of US regulatory approval) were planned to be evaluated by a CV risk factor 
evaluation committee to assess the effect of canagliflozin on CV risk factors (to predict the likely effect of 
canagliflozin on CV events) and determine the point estimate for the HR for MACE. The data on the 
observed point estimate for the CV HR for MACE were to have been reviewed by the IDMC only and not 
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made more broadly available. Re-opening of enrollment was to have proceeded if the effects on the 
intermediate outcomes (ie, CV risk factors) suggested that canagliflozin compared with placebo would 
result in an HR of 0.85 or less (for MACE) and if the observed HR was 0.95 or less. If recruitment did 
proceed, an additional 14,000 subjects would have been enrolled into Cohort B. However, for the reason 
outlined above, this second cohort will no longer be recruited.
Without the recruitment of the second cohort of 14,000 subjects, CANVAS study power is reduced from 
the originally planned 90% power to detect a HR of 0.85 or less. It is now projected that at the completion 
of the study there will be about 400 MACE events recorded within CANVAS, which will provide 33% 
power to detect a HR of 0.85 or less, 55% power to detect a HR of 0.80 or less, and 76% power to detect a 
HR of 0.75 or less using a 2-sided test with 0.05 alpha.
Safety and Tolerability Analysis
Safety and tolerability will be evaluated by summarizing and comparing the incidence of serious adverse 
events and adverse events of interest, discontinuation rate due to adverse events, clinically important 
changes in clinical laboratory tests, vital signs (pulse, blood pressure), and body weight between 
randomized groups. There will be no imputation for missing values for clinical laboratory test results or 
vital sign measurements in the analyses.
CV Outcomes (Primary Efficacy Endpoint)
The primary endpoint for CV benefit will be time to MACE, which is calculated as the time from 
randomization to the first occurrence of MACE. The statistical hypothesis will be: 
H0(1.0): the HR =1.0, versus H1(1.0): the HR ≠1.0.
The primary analysis will be based on the ITT analysis set based upon events determined by the EAC to 
meet prespecified criteria. The primary comparison of canagliflozin to placebo will be based on the HR 
estimate derived from a Cox proportional hazards model with terms for treatment and history of a previous 
CV event as fixed effects. 
The assumption of the proportional HR will be examined. In case the assumption is deemed not reasonable, 
sensitivity analyses that do not rely on the constant HR assumption will be conducted to verify the results 
of the primary analysis. Additionally, the HR and its 2-sided 95% CIs versus placebo will be assessed for 
each dose of canagliflozin. For individual components of the composite CV endpoint, the HR and its 
2-sided 95% CIs of canagliflozin combined doses relative to placebo will also be assessed.
Sensitivity analyses including CV endpoint events that occur within 30 days of the last dose of blinded 
study medication will be done.
The effects of different baseline demographic variables (eg, age, race, sex) as well as other important 
baseline disease characteristics (eg, history of prior CV disease, key concomitant therapy use, and 
region) on the primary endpoint will be explored; a detailed discussion of subgroup analyses will be 
provided in a SAP for this study which will be finalized before the first interim analysis.
Major Secondary Efficacy Analysis
Changes from baseline in the continuous variables of HOMA-B and the proinsulin/insulin ratio, HbA1c, 
FPG, blood pressure, body weight, albuminuria, and eGFR, and percent change in fasting lipids will be 
analyzed using an analysis of covariance (ANCOVA) model with treatment (canagliflozin 100 mg, 
canagliflozin 300 mg, or placebo), and stratification factors as a fixed effect and the corresponding baseline 
value as a covariate. The treatment difference (each dose of canagliflozin minus placebo) in the 
least-squares means and the 2-sided 95% CI will be estimated based on this model. The analyses for 
beta-cell function will be conducted on subjects not receiving insulin at randomization and, for subjects 
who are started on insulin during the study, the last data point before the initiation of insulin will be 
included for these analyses.
The categorical secondary efficacy endpoint is the proportion of subjects with progression of albuminuria 
(defined as !1 step increase, ie, no albuminuria to micro- or macro-albuminuria or from micro-albuminuria 
to macro-albuminuria). The proportion of subjects with progression of albuminuria will be analyzed using 
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the logistic model with treatment (canagliflozin 100 mg, canagliflozin 300 mg or placebo) and stratification 
factors as a fixed effect.
Multiplicity Adjustment
To ensure the family-wise Type I error rate (alpha level) in this study is at most 5%, a gatekeeping 
procedure will be applied in testing the primary and secondary hypotheses.
Interim Analysis
Interim analyses of CANVAS will be done to prepare: (1) an interim safety report in support of the initial 
health authority filing, (2) the 18-week substudy reports, and (3) the CV safety meta-analyses (based on 
adjudicated data). The interim data from the CANVAS study will primarily supplement the safety and 
tolerability data generated from other studies in the canagliflozin development program.
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TIME AND EVENTS SCHEDULE
Phase
Pretreatment
Double-Blind Treatment
Procedures and Evaluations
Screening
Run-
ina
Baseline
13-week 
intervalsv
26-week
intervals
52-week 
intervals
Weekd
-3
-2
Day 1
2, 4 
(TC)e
6
9 
(TC)e 12
18
26
39
52
65 to end
78 to end
104 to
endu
EOT or 
EWb
Follow-up Contactc
30 days after last dose 
of study drugc
Pretreatment/Administrative
Informed consentf
X
Pharmacogenomic consentf, q
X
Inclusion/exclusion criteria
X
X
X
Medical history and demographics
X
X
Prestudy therapyg
X
X
X
Run-in compliance assessment
X
Randomize
X
Pretreatment Procedures
Follicle stimulating hormone (if 
necessary per inclusion criteria)
X
Counseling for diet & exercise and
for hypoglycemia recognition & 
treatmenth
X
Dispense glucose testing supplies 
and first subject diary
X
Study Drug
Dispense single-blind placebo 
X
Administer/dispense double-blind 
study drug
X
X
X
X
X
X
Xv
X
X
Procedures
Physical examinationi
X
Vital signs,j weight, foot 
examinationj
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-lead ECG (central reading)
X
X
Provide container for urine 
collection for first morning void 
X
X
X
X
Xk
Xk
Medical resource utilizationl
X
X
X
X
X
X
X
X
X
X
NOTE: Footnotes are provided after the table.
CV=cardiovascular; EOT=end-of-treatment; EW=early withdrawal; HbA1c= hemoglobin A1c; SMBG=self-monitored blood glucose; TC=telephone contact
(Continued)
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TIME AND EVENTS SCHEDULE (CONTINUED)
Phase
Pretreatment
Double-Blind Treatment
Procedures and Evaluations
Screening
Run-
ina
Baseline
13-week 
intervalsv
26-week
intervals
52-week 
intervals
Weekd
-3
-2
Day 1
2, 4 
(TC)e
6
9 
(TC)e 12
18
26
39
52
65 to end
78 to end
104 to 
end
EOT 
or 
EWb
Follow-up Contactc
30 days after last dose 
of study drugc
Clinical Laboratory Assessments
Hematologym
X
X
X
X
X
X
Urinalysism
X
X
X
X
X
X
Serum chemistrym
X
X
X
X
X
X
X
X
X
HbA1c 
X
X
X
X
X
X
X
X
X
X
Fasting plasma glucosem
X
X
X
X
X
X
X
X
X
Fasting fingerstick glucosem
X
Fasting serum C-peptide, insulin, 
proinsulinm, o(subset of subjects at 
sites that elect to participate) 
X
X
X
X
Fasting lipidsm
Xn
Xn
X
X
X
X
X
First morning void urine for 
albumin/creatinine ratiom, p
X
X
X
X
X
X
Plasma, serum, and urine samples 
for exploratory analysism
X
X
X
X
Pharmacogenomic specimenq
X
Urine pregnancy testr
X
X
Ongoing Review
Review/discuss subject diary and 
SMBG resultss
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapyt
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events u
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Events in CV composite endpoint
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NOTE: Footnotes are provided after the table.
CV=cardiovascular; EOT=end-of-treatment; EW=early withdrawal; HbA1c= hemoglobin A1c; SMBG=self-monitored blood glucose; TC=telephone contact
(Continued)
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TIME AND EVENTS SCHEDULE (CONTINUED)
a Following the run-in visit, there will be a single-blind, placebo run-in period, during which therapy for diabetes should remain stable and therapy for CV risk factors 
(eg, blood pressure, fasting lipids) will be optimized as needed, at the investigator's discretion. Subjects who fail protocol-specified screening criteria for study entry 
may be rescreened, at the discretion of the investigator as described in Section 4.5, Rescreening. 
b End-of-treatment/early withdrawal evaluations will be performed when the double-blind treatment phase of the study is ended or at the time the subject discontinues 
the double-blind study drug or is withdrawn from the study. Evaluations will be performed as soon as possible after stopping the study drug. Subjects who 
discontinue double-blind treatment for any reason will have a posttreatment follow-up contact and visits according to the Posttreatment Time and Events Schedule 
for the duration of the study, until completion of the study. It is the expectation that the investigator will make every effort to ascertain the vital status of all subjects 
at the end of the study, including using all reasonable means to contact the subject, family members, the subject’s physicians and medical records, and the use of 
locator agencies and checking public records, as allowed by local law.
c A telephone follow-up contact (or optional study visit, at the discretion of the investigator) will be conducted for all subjects approximately 30 days (and no more 
than 42 days) after the last dose of study drug. If a telephone contact or study visit is not possible, follow-up information may be collected via email or other 
electronic or non-electronic means.
d After Week 65, on those occasions when the 13- 26-, and/or 52-week-interval visits overlap each other, the visit with the more comprehensive procedures will be 
followed.
e Telephone contact (or an optional, unscheduled site visit, at the discretion of the investigator) will be made at Weeks 2, 4, and 9 to check the subject’s status, 
including discussing the subject’s diary entries and any CV events or adverse events. If a telephone contact or study visit is not possible, follow-up information may 
be collected via email or other electronic or non-electronic means.
f See Section 16.2.3, Informed Consent, for details. The informed consent form must be signed before any study procedure is performed.
g Record as prestudy therapy any medications taken from 30 days before screening (except for AHAs; record AHAs taken within 12 months of screening).
h Subjects will receive information regarding the symptoms of and treatment for hypoglycemia. Signs and symptoms of hypoglycemia (and concurrent fingerstick 
glucose measurement, if available) should be captured in the subject diary, which should be brought to the study center for review by research study staff.
i Full physical examination will include a full review of body systems (vital signs, as below, head and neck, eyes, chest and lungs, breast, CV, extremities and back, 
abdomen, and neurological examination). A pelvic/genitourinary system examination (ie, prostate, rectal, and gynecologic examinations) should be performed if 
considered clinically appropriate by the investigator. 
j Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 3 blood pressure measurements (sitting position, after sitting for 
5 minutes; record 3 consecutive blood pressure readings, at intervals of at least 1 minute apart). Consistent with standard diabetes treatment guidelines, all study 
participants should be provided with routine preventative foot care and early intervention for foot problems (see Section 12.2.1 All Adverse Events for further detail).
k Only required before a 52-week interval visit, regardless of whether the subject is coming for in-clinic visits every 13 or 26 weeks.
l Medical resource utilization (MRU) data should be collected in the subject diary. A sample list of MRU questions contained in the diary is provided in Attachment 9.
m Specific details about specimen collection, storage, packaging, and shipping will be provided in operations manuals. For fasting plasma glucose, insulin, proinsulin, 
C-peptide, and lipids, subjects must be fasting for at least 8 hours before blood sample collection, except for the screening visit when nonfasting blood samples may 
be collected. The first morning void specimens will be used to measure albumin and creatinine. A set of plasma, serum, and urine samples for exploratory analysis 
will be collected at each specified time point. (Specific details about specimen collection, storage, packaging, and shipping are provided in Attachment 4.) The urine 
collections for routine urinalyses and exploratory specimens should be obtained from a spot urine specimen in the clinic. 
(Continued)
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TIME AND EVENTS SCHEDULE (CONTINUED)
n If the subject is fasting at the screening visit, the lipid profile can be obtained at that time point; otherwise, fasting lipid profile should be obtained at the Week -2 
visit.
o C-peptide, insulin, and proinsulin measurements will be performed on a subset of subjects (at sites that elect to participate) who are not receiving insulin at baseline; 
if a subject starts insulin therapy after baseline, no further assessments of these analytes will be made for that subject.
p The subject will provide a urine specimen from the first morning void on the morning of the clinic visit. If the subject does not provide the morning void collection 
on the day of the visit, the subject may bring a first morning void specimen to the investigational site during the subsequent week. For subjects working a night shift, 
or who otherwise have atypical sleep patterns, the collection should be made at the end of the subject’s usual sleep period.
q Subject participation in the pharmacogenomics component of the study is optional. A 10-mL blood sample will be collected only from subjects who give informed 
consent for the pharmacogenomics component of the study to allow for pharmacogenomic research, as necessary (where local regulations permit). A sample may be 
collected at any point in time during the study if not obtained at baseline.
r If positive, the subject is not eligible to enter or continue in the study. A urine pregnancy test will be performed at all specified pre-randomization clinic visits, unless 
a serum pregnancy test is preferred at the discretion of the investigator or if required by local regulations. Serum or urine pregnancy tests may be performed in 
women (unless they are surgically sterile or unless there is a documented history of their postmenopausal status), as determined by the investigator or required by 
local regulations, to establish the absence of pregnancy at any time during the study. 
s See Section 9.1.1, Overview, for diary procedures.
t Concomitant therapy includes all medications taken after the initiation of double-blind study medication (Day 1); after study drug discontinuation, use of AHA 
therapies will be recorded at the final visit or contact.
u Only serious adverse events, adverse events resulting in study drug discontinuation, and adverse events of interest will be recorded on eCRFs. Adverse events of 
interest include: all malignancies, fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, severe hypersensitivity reactions (eg, angioedema, anaphylaxis, Stevens-
Johnson syndrome), photosensitivity reactions, serious adverse events of hepatic injury, nephrotoxicity/acute kidney injury, venous thromboembolic events, fractures, 
male genital infections (balanitis, phimosis, events leading to circumcision), and pregnancy. Information on these events will be recorded on a supplemental eCRF or 
other designated forms for any event that is serious or that leads to study drug discontinuation. In addition, non-serious adverse events of malignancies, 
photosensitivity reactions, fractures, venous thromboembolic events, and male genital infections (balanitis, phimosis, events leading to circumcision) and amputation
for which information on non-serious adverse events will also be recorded on the supplemental CRF pages or other designated forms (in addition to the information 
collected on serious AEs and AEs leading to study drug discontinuation). Diabetic ketoacidosis has been designated an adverse event of special interest and therefore 
adverse events related to DKA, ketoacidosis, metabolic acidosis or acidosis need to be reported to the sponsor within 24 hours of becoming aware of the event, which 
is the same timeframe for reporting of serious adverse events. These adverse events must be reported using a supplemental DKA Reporting form, to complement 
standard information collected on the eCRF AE/SAE page. Amputation has also been designated as an adverse event of special interest and therefore amputations
need to be reported to the sponsor within 24 hours of becoming aware of the event. If adverse events of interest are identified in the future, guidance concerning the 
reporting of those events may be provided to investigators via appropriately-documented study communications. Details regarding adverse event collections are 
provided in Section 9.4, Safety Evaluations.
v Every 13-week in-clinic visits are no longer required and may be changed to every 26-week in-clinic visits (at the option of the investigator). Accordingly, study drug 
may be supplied every 13 or 26 weeks. If in-clinic visits are changed to a every 26 week frequency, a telephone contact should occur in between the 26-week in-
clinic visits such that there will be a contact with the subject every 13 weeks (in-clinic visit alternating with telephone contacts). At each telephone contact, 
investigators should ask subjects about any foot problems and remind them about routine preventative foot care and early intervention for foot problems.
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POSTTREATMENT TIME AND EVENTS SCHEDULE – SUBJECTS WHO PREMATURELY DISCONTINUE STUDY 
MEDICATION
Phase
Double-Blind Visit Schedule (Posttreatment)
- Starting at the nearest post-randomization week after the Follow-up Contact Visit -
Procedures and Evaluations
TC or clinic visit at 26-week
intervals
Clinic visit at 52-week 
intervals
Weeka
2, 4 
(TC)b
6
9 
(TC)b
12
18
26
39
52
78 to end e
104 to end e
Procedures
Vital signs, weight, Foot examinationc
X
X
X
X
X
X
X (foot examination only)
X
Provide container for urine collection for first morning void 
X
X
Serum creatinine
X
X
X
X
X
HbA1c
X
X
X
X
X
X
Fasting serum lipids
X
X
X
First morning void urine for albumin/creatinine ratiod
X
X
X
Ongoing review
Serious adverse events and adverse events of fracture
X
X
X
X
X
X
X
X
X
X
AHA agents after study drug discontinuation
At final visit or contact
Events in CV composite endpoint
X
X
X
X
X
X
X
X
X
X
a After Week 78, on those occasions when the 26- and/or 52-week-interval visits overlap each other, the visit with the more comprehensive procedures will be followed.
b Telephone contact (or an optional, unscheduled site visit, at the discretion of the investigator) will be made at Weeks 2, 4, and 9 to check the subject’s status, including discussing the 
subject’s diary entries and any CV events or adverse events. If a telephone contact or study visit is not possible, follow-up information may be collected via email or other electronic or 
non-electronic means.
c Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 3 blood pressure measurements (sitting position, after sitting for 5 minutes; record 
3 consecutive blood pressure readings, at intervals of at least 1 minute apart). At each visit or telephone contact, investigators should ask subjects about any foot problems and remind 
them about routine preventative foot care and early intervention for foot problems.
d Specific details about specimen collection, storage, packaging, and shipping will be provided in operations manuals. The first morning void specimens will be used to measure albumin 
and creatinine. The subject will provide a urine specimen from the first morning void on the morning of the clinic visit. If the subject does not provide the morning void collection on the 
day of the visit, the subject may bring a first morning void specimen to the investigational site during the subsequent week. For subjects working a night shift, or who otherwise have 
atypical sleep patterns, the collection should be made at the end of the subject’s usual sleep period.
e It is the expectation that the investigator will make every effort to ascertain the vital status of all subjects at the end of the study, including using all reasonable means to contact the 
subject, family members, the subject’s physicians and medical records, and the use of locator agencies and checking public records, as allowed by local law.
Note: Alternate follow-up provisions may be used by the investigator if necessary (see Section 9.1.4).
CV=cardiovascular; TC=telephone contact.
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ABBREVIATIONS
ADA
American Diabetes Association
AHA
antihyperglycemic agent
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARO
Academic Research Organization
AST
aspartate aminotransferase
BMI
body mass index
CPK
creatine phosphokinase
CI
confidence interval
CV
cardiovascular
CYP
cytochrome P450
DKA
diabetic ketoacidosis 
DPP-4
dipeptidyl peptidase 4 
eCRF
electronic case report form
eDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMEA
European Medicines Agency
FDA
Food and Drug Administration
FPG
fasting plasma glucose
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP-1
glucagon-like peptide-1
GTED
global trial end date
HbA1c
hemoglobin A1c
HDL-C
high-density lipoprotein cholesterol
HOMA
homeostasis model assessment
HR
hazard ratio
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS/IWRS
interactive voice response system/interactive web response system
LCT
Leydig cell tumor
LDL-C
low-density lipoprotein cholesterol
LOCF
last-observation-carried-forward
MACE
major adverse cardiovascular events
MDRD
Modification of Diet in Renal Disease
MI
myocardial infarction
mITT
modified intent-to-treat
MRU
Medical Resource Utilization
MSRC
Medical Safety Review Committee
NAG
N-acetyl glucosaminidase
NYHA
New York Heart Association
PG
plasma glucose
PP
per-protocol
PQC
Product Quality Complaint
SAP
statistical analysis plan
SGLT1/SGLT2
sodium-glucose co-transporter 1/sodium-glucose co-transporter 2
SMBG
self-monitored blood glucose
SU
sulphonylurea
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
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UGE
urinary glucose excretion
ULN
upper limit of normal
US
United States
UVA/UVB
ultraviolet A/ultraviolet B
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1. INTRODUCTION 
Over the past decades, the incidence of type 2 diabetes mellitus (T2DM) has been rapidly 
rising worldwide, driven primarily by an increasing incidence of obesity and sedentary 
lifestyles. Patients with T2DM can develop severe microvascular complications, related 
to persistently elevated glucose concentrations, including blindness, renal failure, or 
nerve damage, and have a higher incidence of atherosclerotic vascular disease with 
complications such as myocardial infarction (MI), stroke, and amputations due to 
vascular insufficiency. Improved glucose control reduces the incidence of microvascular 
complications in patients with both type 1 diabetes mellitus (T1DM) and T2DM. The 
impact of improved glycemic control on macrovascular events is less well-established.
Despite the availability of a range of therapeutic options, many patients with T2DM do 
not achieve or maintain glycemic control. Many of these treatments are associated with 
safety or tolerability issues, including hypoglycemia, edema, or gastrointestinal adverse 
experiences which can limit dose and hence therapeutic benefit. Further, some of the 
current antihyperglycemic agents (AHAs) are associated with weight gain, and only a 
few agents (eg, metformin and glucagon-like peptide-1 [GLP-1] analogues) lead to 
weight loss, an important advantage in a patient population that is often obese. Most 
patients with T2DM are initially managed with single-agent therapy, usually metformin. 
Over time, patients often require more intensive regimens, combinations of 2 or 3 agents, 
and eventually require insulin to maintain target glycemic control. Underlying this need 
for increasingly intensive treatment is a progressive loss of beta-cell mass and function, 
with consequent diminished insulin secretion. There remains a substantial unmet medical 
need for new medications to treat patients with T2DM that are well tolerated and 
efficacious, provide good durability, beneficially impact beta-cell function and insulin 
secretion, and are associated with weight loss.
In healthy individuals, glucose is freely filtered through the renal glomerulus and then 
reabsorbed in the proximal tubules. The renal threshold for glucose (RTG) is the glucose 
plasma concentration above which glucose reabsorption by the proximal renal tubules is 
incomplete and glucose is excreted into the urine. A typical RTG level in healthy 
individuals is approximately 180 mg/dL (10 mmol/L) (Ganong 2005; Rave 2006; 
Seifter 2005). Glucose reabsorption in the renal tubules, determining the renal threshold 
is largely due to 2 key glucose transporters: sodium glucose co-transporter 2 (SGLT2) 
and sodium glucose co-transporter 1 (SGLT1). Sodium glucose co-transporter 2 is a 
high-capacity and low-affinity glucose transporter exclusively expressed at the luminal 
membrane of the S1 and S2 segments of the proximal renal tubules. Sodium glucose 
co-transporter 2 is responsible for the majority of filtered glucose reabsorption from the 
lumen. Sodium-glucose co-transporter 1 expressed in the S3 segment, a low capacity and 
high-affinity transporter, is also involved in reabsorption of filtered glucose from the 
lumen (Wright 2001). Sodium-glucose co-transporter 1 is also highly expressed in the 
intestine and is responsible for intestinal glucose and galactose absorption.
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Pharmacologic inhibition of SGLT2 is a novel mechanism to decrease renal glucose 
reabsorption, as it lowers the RTG and leads to an increase in urinary glucose excretion 
(UGE), thereby directly lowering plasma glucose in individuals with elevated glucose 
concentrations. Canagliflozin is an orally active inhibitor of SGLT2. This agent has much 
higher potency for SGLT2 relative to SGLT1; at the plasma drug concentrations achieved 
with the doses in this study, canagliflozin would be expected to provide significant 
systemic inhibition of SGLT2 and not of SGLT1. In addition to lowering plasma glucose 
concentrations, the increased renal glucose excretion with SGLT2 inhibition also 
translates to a loss of calories, leading to a net negative energy balance and the potential 
for weight loss.
The canagliflozin clinical program was designed to assess the safety and efficacy of 
canagliflozin in subjects with T2DM. As of 01 May 2013, approximately 1,840 subjects 
(including healthy subjects, non-diabetic subjects with specific diseases [eg, renal or 
hepatic disease], and subjects with T2DM), have completed studies in the Phase 1 
program conducted by the sponsor. In addition, 1,106 subjects in three Phase 2 studies 
and 10,961 subjects in 10 Phase 3 studies have completed or are participating in clinical 
studies conducted by the sponsor.
A Phase 3 development program provided evidence for the effectiveness of canagliflozin 
both as monotherapy and in combination with approved, commonly prescribed AHA 
therapies in T2DM. These 9 studies spanned a range of clinical uses (as monotherapy or 
as combination therapy) to treat T2DM. Three of the Phase 3 studies evaluated 
canagliflozin in special populations, including older adults with T2DM, subjects with 
T2DM who had moderate renal impairment, and subjects with T2DM who had or were at 
high risk for cardiovascular (CV) disease. Results of the extensive Phase 3 clinical 
development program indicate that canagliflozin has the potential to be a useful addition 
to currently available AHAs.  
Canagliflozin was approved as an adjunct to diet and exercise to improve glycemic 
control in adults with type 2 diabetes mellitus in the United State (29 March 2013), 
Australia (12 September 2013) and Mexico (23 October 2013). On 19 September 2013, 
the Committee for Medicinal Products for Human Use (CHMP) adopted a positive 
opinion, recommending the granting of a marketing authorization for canagliflozin. 
An ongoing clinical program designed to continue research on the effects of the agent on 
renal and CV outcomes is underway. The goal of this study is to assess the effects of 
canagliflozin compared to placebo on CV events.
The term “sponsor” used throughout this document refers to the entities listed in the Contact Information 
page(s), which will be provided as a separate document.
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1.1.
Background
For more detailed and current information regarding the preclinical characterization of 
canagliflozin pharmacokinetics (PK) (ie, absorption, distribution, metabolism and 
excretion) and toxicology, and clinical study results, refer to the current version of the 
Investigator's Brochure for canagliflozin (IB JNJ-28431754).
1.1.1.
Brief Overview of Nonclinical Studies
For a complete review of the findings and discussions regarding implications for human 
risk, please refer to the current version of the canagliflozin Investigator's Brochure.
1.1.2.
Clinical Studies
Pharmacokinetics
Canagliflozin exhibits similar PK in healthy subjects and subjects with T2DM. The mean 
absolute oral bioavailability of canagliflozin was 65% following single-dose 
administration of the canagliflozin 300 mg tablet in healthy subjects. In healthy subjects 
(25 to 1,600 mg once-daily [QD]) and subjects with T2DM (50 mg to 300 mg QD and 
300 mg twice-daily [BID]), after oral administration of single and multiple doses, mean 
canagliflozin AUC0-% increased in an approximately dose-proportional manner whereas 
mean maximum plasma concentration
(Cmax) increased in an approximately 
dose-proportional manner up to 1,200 mg. Following oral administration of canagliflozin, 
the median time to reach maximum plasma concentration (tmax) was approximately 1 to 
2 hours. The mean terminal plasma elimination half-life (t1/2) of canagliflozin was 10 and 
13 hours with canagliflozin doses of 100 and 300 mg, respectively. The tmax was 
independent of dose. After repeated dosing with 50 to 300 mg canagliflozin, steady state 
was reached by 4 to 5 days. Minimal accumulation of canagliflozin was observed at 
steady-state across 50, 100, and 300 mg doses with mean accumulation ratios ranging 
from 1.3 to 1.4 in subjects with T2DM. Bioavailability of canagliflozin was not affected 
after co-administration of canagliflozin 300 mg with food in healthy subjects indicating 
that the canagliflozin tablet formulation may be taken without regard to meals.
O-glucuronidation is the major metabolic elimination pathway for canagliflozin in 
humans. In human plasma, 2 non-pharmacologically active O-glucuronide conjugates of 
unchanged drug, M5 (formed by UGT2B4) and M7 (formed by UGT1A9), were present. 
Co-administration with rifampin, a nonselective inducer of several UGT enzymes, 
decreased canagliflozin area under the curve (AUC) by 51%, which may decrease 
efficacy. There was an increase in the AUC and Cmax of digoxin when co-administered 
with canagliflozin 300 mg. Subjects taking concomitant digoxin should be monitored 
appropriately. The Cmax of canagliflozin was not meaningfully altered by renal
impairment.
Based on in vitro data and the clinical drug-drug interaction studies conducted to date, the 
potential for clinically significant CYP450 based PK interactions appears to be low. 
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Pharmacodynamics
In subjects with T2DM following single and multiple oral doses (30 to 600 mg QD and 
300 mg BID), canagliflozin treatment dose dependently increased UGE0-24h, with mean 
UGE0-24h of approximately 100 g/day typically observed with doses of 100 mg/day or 
higher. 
In subjects with T2DM, canagliflozin treatment with 100 mg and 300 mg once daily 
lowered RTG to approximately 70 to 90 mg/dL (3.9 to 5.0 mmol/L), respectively. 
Because RTG remains above PG levels associated with hypoglycemia and because very 
little UGE occurs whenever plasma glucose (PG) is below the RTG, canagliflozin, itself,
is not expected to pose a risk for hypoglycemia.
Efficacy
In the Phase 3 studies, canagliflozin has been assessed as monotherapy, as add-on therapy 
with metformin, sulphonylurea (SU), metformin and SU, metformin and a peroxisome 
proliferator-activated receptor (PPARγ) agonist (pioglitazone), and as add-on therapy 
with insulin (with or without other AHAs). The Phase 3 program also includes studies in 
special populations of patients with T2DM: subjects with renal impairment (estimated 
glomerular filtration rate [eGFR] !30 to <50 mL/min/1.73 m2); subjects with or at high 
risk for CV complications; and older subjects. The latter 2 studies also included subjects 
on incretin-based therapies, including dipeptidyl peptidase 4 (DPP-4) inhibitors and 
GLP-1 agonists. 
Glycemic Efficacy
Results of the Phase 3 studies demonstrated the efficacy of canagliflozin in reducing 
hemoglobin A1c (HbA1c) in a broad range of subjects with T2DM, both with recent onset 
as well as long-standing diabetes and on a range of different background AHAs. A 
clinically meaningful improvement in glycemic control was seen when canagliflozin was 
given as monotherapy and when given in dual combinations (add-on to metformin or to 
SU agents), in triple oral AHA combinations (add-on to metformin plus an SU agent or 
metformin plus pioglitazone), in combination with insulin (alone or in combination with 
other agents), or as an add-on to existing diabetes therapy (any approved oral or 
parenteral therapy). In the monotherapy study, HbA1c reductions of -0.91% and -1.16% 
relative to placebo for canagliflozin 100 mg and 300 mg, respectively, were observed. In 
the studies examining specific add-on combination uses, the efficacy of canagliflozin in 
lowering HbA1c, relative to placebo, was generally consistent ranging from -0.62% 
to -0.74% with the 100 mg dose and from -0.73% to -0.92% with the 300 mg dose. 
Across all studies, the 300 mg dose consistently provided greater HbA1c lowering relative 
to the 100 mg dose; since reduction in diabetic microvascular complications is continuous 
with improvements in glycemic control, the additional glucose-lowering efficacy with the 
300 mg dose is considered likely to be clinically relevant (UKPDS 1998, DCCT 1993). 
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Results of subgroup analyses performed in a pooled population of the placebo-controlled 
Phase 3 studies found no important differences when comparing the effect of 
canagliflozin in change from baseline in HbA1c based on baseline demographic 
characteristics (age, sex, race, ethnicity), body mass index (BMI), or geographic region. 
Greater reductions in HbA1c relative to placebo were observed with canagliflozin among 
subjects with higher baseline HbA1c and higher eGFR values compared with subjects 
with lower baseline values. In subjects with moderate renal impairment (ie, baseline 
eGFR’s between 30 to 60 mL/min/1.73m2), the mean, placebo-subtracted reduction in 
HbA1c was 0.38% and 0.47% on canagliflozin 100 mg and 300 mg respectively. A total 
of 24% and 32% of subjects achieved a target HbA1c <7% at the end-of-treatment on 
canagliflozin 100 mg and 300 mg respectively compared to 17% of subjects on placebo. 
With regard to other glycemic endpoints, canagliflozin provided improvements in fasting 
plasma glucose (FPG) as well as in the post-prandial glucose (PPG) excursion. 
Canagliflozin also provided improvements in beta-cell function and a reduction in 
beta-cell stress as reflected by a decrease in the proinsulin/C-peptide ratio. The 
improvement in beta-cell function and reduction in beta-cell stress is consistent with the 
sustained effect of canagliflozin on both HbA1c and FPG observed in the 52-week 
studies.
Weight and Blood Pressure Effects 
In addition to the observed glycemic improvements, treatment with canagliflozin resulted 
in consistent, statistically significant reductions in total body weight relative to placebo. 
Weight loss with canagliflozin appeared dose-related (with -1.4% to -2.7% reductions 
with 100 mg and -1.8% to -3.7% reductions with 300 mg, relative to placebo). Results of 
specialized body composition investigations using dual energy X-ray absorptiometry 
(DXA) in 2 of the Phase 3 studies showed that the body weight reduction with 
canagliflozin was attributable to a greater decrease in body fat mass relative to lean body 
mass. 
Reductions in SBP were observed with canagliflozin in Phase 3 studies (ranging 
from -2.2 to -5.7 mm Hg of SBP with canagliflozin 100 mg dose, and -1.6 to -7.9 mm Hg 
with the 300 mg dose, relative to placebo, in placebo-controlled 26-week studies), and 
were generally statistically significantly greater for both doses relative to placebo, and 
also greater relative to comparator agents (glimepiride and sitagliptin). 
Safety
For a complete review of the adverse drug reactions (ADRs) and laboratory findings 
associated with canagliflozin, please refer to the current version of the canagliflozin 
Investigator’s Brochure (IB JNJ-28431754).
The safety and tolerability profile that emerges from the development program for 
canagliflozin shows a medication that is overall well tolerated. The incidence of 
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discontinuations due to adverse events was slightly higher than seen in the control group, 
though generally low. The small increase in discontinuations due to adverse events were 
generally related to specific ADRs, described below, with each particular ADR 
infrequently leading to discontinuations; there was no increase in serious adverse events 
or deaths in the canagliflozin treatment groups relative to control groups. 
Adverse drug reactions associated with canagliflozin include genital mycotic infections, 
urinary tract infections, adverse events related to osmotic diuresis, and adverse events 
related to reduced intravascular volume, as well as constipation, and a low incidence of 
rash or urticaria.
In men, the genital mycotic infections (including balanitis and balanoposthitis) occurred 
predominantly in uncircumcised individuals and in those with a past history of genital 
mycotic infections, generally did not lead to discontinuation from the study. 
Circumcision was performed in 17/3569 (0.5%) and 3/1924 (0.2%) of men treated with 
canagliflozin and control, respectively. In women, genital mycotic infections (including 
candidal vulvovaginitis) occurred more commonly in women with a prior history of 
genital mycotic infections and did not generally lead to discontinuation. A modest 
increase in the incidence of adverse events of urinary tract infection (mostly lower tract 
infections) was observed with canagliflozin relative to control, without an increase in 
serious adverse events of urinary tract infection.
Adverse drug reactions were observed that relate to the osmotic diuretic effect of 
canagliflozin, with increases in UGE leading to a diuretic action; this included ADRs of 
pollakiuria (increased urinary frequency), polyuria (increased urinary volume), and thirst. 
Adverse drug reactions related to reduced intravascular volume were observed including 
postural dizziness, orthostatic hypotension, and hypotension. Risk factors for 
volume-related adverse events on canagliflozin treatment were !75 years of age, eGFR of 
30 to 60 ml/min/1.73m2 and use of loop diuretics. These adverse events were generally 
considered as mild or moderate in intensity, and infrequently led to discontinuation. No 
increase in serious adverse events related to reduced intravascular volume were seen with 
canagliflozin treatment. The reduction in intravascular volume also led to reversible 
reductions in eGFR that generally attenuated with continued treatment. 
Based on the observations from the 2-year rat carcinogenicity study (findings of renal 
tubular cell cancers, Leydig cell tumors [LCTs], and pheochromocytomas), an extensive 
preclinical toxicology program was conducted that demonstrated that these tumors related 
to effects of canagliflozin in rats, not seen in humans (including rises in luteinizing 
hormone [LH] associated with LCT, and carbohydrate malabsorption leading to 
associated metabolic effects, including marked hypercalciuria, inducing renal tubular 
tumors and pheochromocytomas). In the clinical program, there were no reports of LCT 
or pheochromocytoma and there was a low incidence across treatment groups of renal 
cell cancers without imbalance. 
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In preclinical studies in rats, hyperostosis (increased trabecular bone) was observed; 
mechanistic toxicology studies demonstrated that hyperostosis, like the tumors discussed 
above, related to carbohydrate malabsorption in rats treated with canagliflozin, with 
consequent marked hypercalciuria (which is not seen in human). A detailed analysis of 
bone safety was conducted in the Phase 3 program, including an assessment using DXA 
in a dedicated Phase 3 study (a study conducted in older subjects [ages !55 and 
#80 years] with T2DM) and a cross-program assessment of fracture incidence. Bone 
mineral density (BMD) was examined at 4 sites: at the lumbar spine, total hip, distal 
radius, and femoral neck. Minimal changes in BMD from baseline to Week 104 were 
seen in the lumbar spine (a cancellous bone region), femoral neck (a mixed cancellous 
and cortical bone region), and distal forearm. A decrease in BMD from baseline to 
Week 104 in the total hip, a site comprised of mixed cortical and cancellous bone (like 
the femoral neck), was observed for both canagliflozin treatment groups (0.9% and 1.2% 
in the canagliflozin 100 mg and 300 mg groups, respectively, placebo adjusted). In a 
cardiovascular study of 4,327 subjects with known or at high risk for cardiovascular 
disease (Study DIA3008), the incidence rates of bone fracture were 1.6, 1.6, and 1.1 per 
100 subject-years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and 
placebo, respectively, with the fracture imbalance initially occurring within the first 
26 weeks of therapy. In other T2DM studies with canagliflozin, which enrolled a general 
diabetes population of approximately 5,800 subjects, no difference in fracture risk was 
observed relative to control (Investigator's Brochure).
Increases in low-density lipoprotein
cholesterol (LDL-C) were observed with 
canagliflozin: in a pooled analysis of placebo-controlled 26-week studies, increases in 
LDL-C relative to placebo were 4.4 mg/dL (0.11 mmol/L) and 8.2 mg/dL (0.21 mmol/L) 
at the 100 mg and 300 mg doses, respectively. Relative increases in Apo B, non-HDL-C, 
and LDL particle number were approximately half as large as the rise in LDL-C. The 
changes in the CV risk profile with canagliflozin include reductions in SBP and increases 
in LDL-C, both established CV risk factors, and validated as surrogate endpoints. 
Improvements in other endpoints associated with CV risk, but not established as 
surrogate endpoints for CV benefit, such as body weight, glycemic control, HDL-C, and 
TG were also observed with canagliflozin. The cross-program CV meta-analysis 
(including results from the dedicated CV safety study) observed a hazard ratio (HR) of 
0.91 for a pre-specified composite endpoint of CV death, non-fatal MI, non-fatal stroke, 
and hospitalized unstable angina (95% confidence interval [CI]: 0.68, 1.22), showing no 
signal for an increase in the CV risk. 
As of 11 May 2015, in the T2DM clinical development program, incidence rates of 
unblinded serious adverse events of DKA, ketoacidosis, metabolic acidosis, and acidosis 
were 0.0522 (0.07%, 4/5337), 0.0763 (0.11%, 6/5350), and 0.0238 (0.03%, 2/6909) per 
100 subject-years with canagliflozin 100 mg, canagliflozin 300 mg, and comparator, 
respectively. Of the 12 subjects with serious adverse events of DKA, ketoacidosis, 
metabolic acidosis, or acidosis (all of whom were hospitalized), 6 subjects on
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canagliflozin (3 on canagliflozin 100 mg and 3 on canagliflozin 300 mg), and none on 
comparator were reported to have autoimmune diabetes (latent autoimmune diabetes of 
adulthood [LADA] or type 1 diabetes) or tested positive for GAD65 antibodies after 
being diagnosed with a serious DKA-related event. Eight of the 10 subjects on 
canagliflozin were receiving insulin therapy. The blood glucose values around the time of 
admission in 9 of 10 subjects on canagliflozin ranged from 347 to 571 mg/dL (9.3 to 
31.7 mmol/L). The remaining subject had blood glucose values ranging from 148 to 
320 mg/dL (8.2 to 17.8 mmol/L). Diabetic ketoacidosis has also been reported during 
post-marketing surveillance and has occurred in patients with blood glucose values less 
than 250 mg/dL (13.9 mmol/L). As a result, DKA is considered a rare adverse drug 
reaction.
During a routine review of unblinded interim data from the ongoing CANVAS study, the 
Independent Data Monitoring Committee observed a non-dose-dependent increase in the 
incidence of non-traumatic, lower-extremity amputations (mostly of the toes) in the 
canagliflozin 100 mg and 300 mg groups  compared to placebo. With a mean duration of 
follow-up in CANVAS of approximately 4.5 years, the annualized incidence of lower-
extremity amputation was 0.73, 0.54, and 0.30 events per 100 patient-years in the 
canagliflozin 100 mg, canagliflozin 300 mg, and placebo groups, respectively. Overall, 
treatment with canagliflozin was associated with an approximately 2-fold increase in 
amputation event rates (relative risk [RR] 2.15; 95% CI: 1.3-
3.5).
The 
CANVAS/CANVAS-R IDMC, which has access to unblinded CV outcomes data, 
notified the sponsor that “after consideration of all outcomes, the IDMC feels the study 
should continue.”
Infections were the events most commonly associated with 
amputations, and most amputations were of the toe. The factors associated with the 
greatest risk for amputation included prior amputation, peripheral vascular disease, and 
neuropathy.
1.2.
Overall Rationale and Goals for the Study
Patients with T2DM have an increased risk of both microvascular and macrovascular
complications which lead to morbidity and mortality. New therapies are needed that can 
provide improved glycemic control—which has been shown to reduce microvascular 
complications—and lower the risk of macrovascular complications.
Prior clinical studies of canagliflozin in patients with T2DM have demonstrated 
improvements in glycemic control (with reductions in HbA1c and FPG), reduction in 
body weight, and trends towards improvements in other CV disease risk factors 
(including increases in HDL-C, decreases in triglyceride levels, and decreases in blood 
pressure, especially at the 300-mg dose), with generally good tolerance and appropriate 
safety to support continued clinical development of this medication. With improved 
glycemic control, which itself may provide a benefit in CV risk (Ray 2009), and the 
trends towards benefit on other CV risk factors including body weight, the potential for a 
benefit of long-term treatment with canagliflozin on CV disease is raised. 
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The present study was intended to determine if treatment of subjects with T2DM with 
canagliflozin reduces CV risk for major adverse cardiovascular events (MACE, including 
CV death, nonfatal MI, and nonfatal stroke) and also was intended to achieve a number 
of other important goals. These include the assessment of overall safety and tolerability, 
glycemic efficacy (in the overall study population and in subjects on specific AHAs), 
long-term effects on beta-cell function, and long-term effects on renal function with 
canagliflozin treatment. This study also provides key support for a cross-canagliflozin 
program assessment of CV safety, examining a composite endpoint of MACE plus 
hospitalized unstable angina (pre-approval CV safety assessment) and MACE 
(post-approval CV safety assessment). Subsequent to the initial plan it was necessary to 
modify the design of the study.
To evaluate the effect of canagliflozin on CV risk, this study was to recruit up to 
18,500 subjects with T2DM who are at increased risk for CV events, in 2 separate 
cohorts, including an initial cohort of 4,500 subjects and a subsequent cohort of 
14,000 subjects (recruited after an interim analysis of results from the initial cohort). The 
study will now continue with the initial 4,330 randomized subjects.
The study was modified (as of amendment INT-5) because the cross-program 
meta-analysis of the pre-approval CV safety endpoint was unblinded to the sponsor to 
prepare regulatory submissions (originally this was to be unblinded to the study IDMC 
only); this was done based upon a decision by the sponsor, so that the impact of the small 
dose-related increase in LDL-C observed with canagliflozin treatment in Phase 3 
program on the CV HR could be evaluated. Due to the unblinding of these CV endpoint 
results, the study Steering Committee noted that the addition to the CANVAS study of 
the planned second cohort of subjects would not provide a robust assessment of the 
primary CV protection hypothesis.
As part of the safety and tolerability objective, the study was originally designed to be 
able to show, within 4 years of marketing approval in the US, that the upper bound of the 
CV HR for MACE plus unstable angina events was <1.3. Upon approval of canagliflozin 
for marketing, the US FDA required that the 1.3 requirement be met with MACE events 
(ie, CV death, nonfatal MI, and nonfatal stroke, and excluding hospitalized unstable 
angina), and that additional subjects with high CV risk be recruited to explore events 
occurring within the first 30 days after initiation of therapy. Accordingly, it was not 
possible to fulfill these requirements solely with the ongoing CANVAS study within the 
4 year post-approval timeframe required by FDA, and therefore another large-scale study 
of the effects of canagliflozin compared to placebo (CANVAS-R; 28431754DIA4003) 
with 5,700 subjects is being initiated to meet the FDA CV safety requirement.
The primary objective of the CANVAS-R study is to evaluate the effects of canagliflozin 
relative to placebo on albuminuria progression. The CANVAS and CANVAS-R studies 
will share similar inclusion and exclusion criteria and will enroll similar patient 
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populations. Both studies will require a standardized collection and evaluation of MACE 
endpoint events by the same Endpoint Adjudication Committee (see Section 9.3.5).
The original CANVAS cohort of 4,330 subjects who were randomly assigned to 
treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) or placebo, in a 1:1:1 ratio 
will continue to be followed. The data from CANVAS will be combined with the data 
from CANVAS-R in a pre-specified meta-analysis of CV safety outcomes to satisfy US 
FDA post-marketing requirements for canagliflozin. The details of the meta-analysis are 
described in a separate statistical analysis plan (SAP).
The study’s last subject last visit is targeted to occur when at least 688 MACE events 
(ie, CV death, nonfatal myocardial infarction, nonfatal stroke) are accumulated between 
the CANVAS and CANVAS-R studies, which is projected to occur prior to April 2017. 
In both studies, the effects of canagliflozin are being evaluated against a background of 
standard of care for the treatment of hyperglycemia and CV risk factors with study 
investigators counseled to assure appropriate management according to applicable 
national guidelines for the care of patients with T2DM with treatment individualized as 
clinically appropriate.
Assessment of glycemic efficacy of canagliflozin – overall and in key subgroups
The present study is also intended to provide important information on the glycemic 
efficacy of this medication. To achieve this goal, subjects will enter an 18-week AHA 
regimen stable period to provide an opportunity to characterize the glycemic efficacy of 
canagliflozin relative to placebo in this high CV risk population, and support important 
analyses aimed at understanding the response to this medication in patient subgroups 
defined by key demographic and anthropometric components, disease characteristics, and 
concomitant AHA treatments. After this 18-week AHA regimen stable period, and for the 
remainder of the double-blind treatment phase, investigators will adjust the subject’s 
AHA regimen with the goal of achieving individualized, target glycemic control. 
Embedded within this study are 3 substudies which will compare the glycemic efficacy 
and assess the safety of canagliflozin relative to placebo in subjects receiving regimens 
with (1) insulin as monotherapy or in combination therapy, (2) sulfonylurea 
monotherapy, or (3) pioglitazone and metformin combination therapy. These substudies 
are being conducted to better characterize the safety, tolerability, and efficacy profile of 
canagliflozin when used in conjunction with these specific glucose-lowering therapies. 
Assessment of long-term effects of canagliflozin on beta-cell function and renal function
Patients with T2DM usually have a progressive deterioration in glycemic control, with 
the need for stepwise added therapies. Underlying this progressively worse glucose 
control is a progressive deterioration in beta-cell function. Canagliflozin, by increasing 
UGE and possibly improving insulin sensitivity through weight loss, may “unload” the 
beta-cells, lowering secretory demand and potentially improving function over time, and 
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potentially providing good durability. In addition, improved glycemic control itself, 
through reversal of so-called “glucotoxicity,” may also improve beta-cell function. 
Analysis of results from a Phase 1 study in subjects with T2DM did show an 
improvement in a model-based assessment of beta-cell function, and HOMA-B, a 
measure of fasting beta-cell insulin secretion, was improved in the Phase 2b study of 
subjects with T2DM. To assess the effect on beta-cell function over time in the present 
study, standard fasting measures of beta-cell function (HOMA-B, proinsulin/insulin ratio) 
will be evaluated.
Another key issue in patients with T2DM is the potential for hyperglycemia to lead to 
progressive damage to the kidney. Early on, this damage is reflected by 
micro-albuminuria that may progress to macro-albuminuria and eventually loss of renal 
function. By virtue of its improvement in glycemic control, which has been shown to 
reduce micro-albuminuria progression in prior studies (ADVANCE 2008), and possible 
effects to reduce blood pressure (if confirmed in larger studies), canagliflozin may slow 
the progression of diabetic nephropathy. Additionally, proximal tubule inhibition of 
SGLT2 by canagliflozin is predicted to increase the distal delivery of sodium which 
could, via the macula densa, lead to a reduction in intraglomerular pressure and a 
decrease in glomerular damage (Vallon 1999). For these reasons, the study will also 
examine the potential benefit of canagliflozin on albuminuria.
2. OBJECTIVES AND HYPOTHESES
2.1.
Objectives
2.1.1.
Primary Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history or high risk 
of CV disease:
∃
to assess the effect of canagliflozin plus standard of care relative to placebo plus 
standard of care on CV risk as measured by the HR for a composite endpoint (MACE 
including CV death, nonfatal MI, and nonfatal stroke)
∃
to assess the safety and tolerability of canagliflozin plus standard of care relative to 
placebo plus standard of care
The data from this study will be combined with the data from CANVAS-R in a 
pre-specified meta-analysis of CV safety outcomes to satisfy US FDA post-marketing 
requirements for canagliflozin.
2.1.2.
Secondary Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history or high risk 
of CV disease:
∃
to assess the effect of canagliflozin plus standard of care relative to placebo plus 
standard of care on:
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–
fasting measures of beta-cell function (HOMA-B and the proinsulin/insulin ratio) 
(note: this assessment will be conducted in a subset of subjects at sites that elect 
to participate, including only subjects who are not receiving insulin at 
randomization) 
–
the proportion of subjects with progression of albuminuria (progression defined as 
!1 step increase, ie, no albuminuria to micro- or macro-albuminuria or from 
micro-albuminuria to macro-albuminuria)
–
the urinary albumin/creatinine ratio
–
renal function (as measured by the change from baseline in eGFR)
∃
to assess the effect of canagliflozin relative to placebo after 18 weeks and at the end 
of the treatment period on:
–
glycemic efficacy (HbA1c and FPG)
–
body weight 
–
blood pressure (systolic and diastolic)
–
fasting plasma lipids (triglycerides, HDL-C, low-density lipoprotein cholesterol 
[LDL-C], total cholesterol, and the ratio of LDL-C to HDL-C)
2.2.
Hypotheses
2.2.1.
Primary Hypothesis
In subjects with T2DM, with inadequate glycemic control, who have a history of or a 
high risk of CV disease, relative to placebo plus standard of care, canagliflozin plus 
standard of care reduces CV risk (as measured by the HR for a composite endpoint 
including CV death, nonfatal MI, and nonfatal stroke).
2.2.2.
Secondary Hypotheses
In subjects with T2DM, with inadequate glycemic control, who have a history of or a 
high risk of CV disease, relative to placebo plus standard of care, canagliflozin plus 
standard of care at the end of the treatment period:
∃
improves beta-cell function (change from baseline in HOMA-B)
∃
reduces progression of albuminuria (ie, proportion of subjects with a !1-step 
progression of albuminuria measured by the urine albumin/creatinine ratio)
2.3.
Substudies: Objectives and Hypotheses 
The three 18-week substudies will be conducted and are intended to assess the safety and 
tolerability and efficacy of canagliflozin in subjects with T2DM, with inadequate 
glycemic control in each of the 3 specific subgroups of subjects receiving (1) insulin 
!20 units/day monotherapy or in combination with other AHA(s), (2) sulfonylurea 
monotherapy at protocol-specified doses (Attachment 1), or (3) pioglitazone !30 mg/day
plus metformin !2,000 mg/day (or at least 1,500 mg/day for subjects who have a history 
of not being able to tolerate higher metformin doses) and no other AHA. The following 
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objectives and hypotheses will apply to each of these substudies. These are separate and 
distinct from the main study hypothesis testing.
Primary Substudy Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history of or a 
high risk of CV disease:
∃
to assess the HbA1c-lowering efficacy (change from baseline in HbA1c) of 
canagliflozin relative to placebo after 18 weeks of treatment
∃
to assess the safety and tolerability of canagliflozin 
Primary Substudy Hypothesis 
In subjects with T2DM, with inadequate glycemic control, who have a history of or a 
high risk of CV disease, after 18 weeks of treatment, canagliflozin provides a greater 
improvement in HbA1c relative to placebo (change from baseline in HbA1c).
Secondary Substudy Objectives and Hypotheses
Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history of or a 
high risk of CV disease:
∃
to assess the effect of canagliflozin relative to placebo after 18 weeks on:
-
body weight
-
FPG-lowering efficacy 
-
proportion of subjects reaching HbA1c <7.0%
-
systolic and diastolic blood pressure
-
fasting plasma lipids (triglycerides, HDL-C, LDL-C, total cholesterol, and the 
ratio of LDL-C to HDL-C)
∃
to assess the effect of canagliflozin relative to placebo after 52 weeks on:
-
glycemic efficacy (HbA1c and FPG)
-
body weight
-
systolic and diastolic blood pressure
-
fasting plasma lipids (triglycerides, HDL-C, LDL-C, total cholesterol, and the 
ratio of LDL-C to HDL-C)
Hypotheses
After 18 weeks, in subjects with T2DM, with inadequate glycemic control, who have a 
history or high risk of CV disease, relative to placebo, canagliflozin:
∃
reduces body weight 
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∃
reduces FPG 
∃
leads to a greater proportion of subjects achieving HbA1c <7%
∃
reduces systolic blood pressure 
∃
increases HDL-C concentrations
∃
lowers triglyceride concentrations
2.4.
Medical Resource Utilization Objective
To collect medical resource utilization (MRU) data that may be used in future economic 
modeling (the construction and reporting of the economic model will be conducted 
separately from this protocol).
3. OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, 3 parallel-group, multicenter 
study to evaluate the safety, tolerability, and CV risk with canagliflozin plus standard of 
care compared with placebo plus standard of care in subjects with T2DM, on a wide 
range of antihyperglycemic therapies, who have either a history or high risk of CV 
disease. Although the effects of canagliflozin on several CV risk factors (eg, glycemic 
control, body weight, blood pressure) appear favorable in short-term studies, the 
longer-term benefits on CV risk factors are currently unknown; in addition, Phase 3 
results demonstrated a small increase in LDL-C, without a change in the LDL-C to 
HDL-C ratio. 
Note that results from this study, integrated with cross-Phase 3 program results, were 
included in a pre-approval meta-analysis to evaluate CV safety (as required by the US 
FDA Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New 
Antidiabetic Therapies to Treat Type 2 Diabetes) by examining the composite of 
MACE-plus hospitalized unstable angina (referred to as the pre-approval CV safety 
endpoint). This CV meta-analysis was conducted in 2012 (addressing the US FDA filing 
requirement that the upper bound of the 2-sided 95% CI around the CV HR is <1.8); this 
meta-analysis confirmed the requirement, showing the upper bound was <1.8.
This study was originally designed to include 2 sequential cohorts, with up to 
18,500 subjects and a study duration for individual subjects of up to approximately 
8 years. The study will now recruit only the initial 4,330 subjects who were randomly 
assigned to treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) or placebo, in a 
1:1:1 ratio. 
The study’s last subject last visit will occur when at least 688 MACE events (ie, CV 
death, nonfatal myocardial infarction, nonfatal stroke) are accumulated between the 
CANVAS and CANVAS-R studies, which is projected to occur prior to April 2017. 
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The study was modified because the cross-program meta-analysis of the pre-approval CV 
safety endpoint was unblinded to the sponsor to prepare regulatory submissions 
(originally this was to be unblinded to the study IDMC only); this was done based upon a 
decision by the sponsor, so that the impact of the small dose-related increase in LDL-C 
observed with canagliflozin treatment in the Phase 3 program on the CV HR could be 
evaluated. Due to the unblinding of these CV endpoint results, the study Steering 
Committee noted that the addition to the CANVAS trial of the planned second cohort of 
subjects would not provide a robust assessment of the primary CV protection hypothesis.
The CANVAS study has additional objectives including the assessment of overall safety 
and tolerability of canagliflozin.
The study also includes several substudies intended to provide additional information 
about the efficacy and safety of canagliflozin compared to placebo in combination with 
specific AHAs. 
In this study, investigators will be counseled to assure appropriate management of
CV risk factors (eg, blood pressure and lipids) according to standard guidelines (eg, the 
American Diabetes Association [ADA] or other local diabetes guidelines) for the care of 
patients with T2DM. In addition, after a relatively brief period during which the subject’s 
antihyperglycemic regimen is to be kept stable (described in the section below), 
investigators will attempt to achieve good glycemic control, consistent with standard 
diabetes guidelines, individualized as considered clinically appropriate, with up-titration 
or stepwise addition of AHA therapies. Thus, this study will examine the impact on CV 
risk, and the safety and tolerability of treatment with canagliflozin along with standard of 
care for CV risk factor and glycemic management relative to placebo with standard of 
care management.
3.1.
Study Design
The following section provides an overview of subject management including screening, 
run-in, and double-blind treatment. 
Screening/Run-in Period Management
Subjects will undergo a screening visit for a preliminary determination of eligibility. Men 
or women with T2DM who have inadequate glycemic control (HbA1c !7.0 and #10.5%), 
not on an AHA or on an AHA in monotherapy or combination therapy, and who have 
known CV disease or who have 2 or more risk factors for CV events are eligible (refer to 
Section 4.2, Inclusion Criteria). 
A subject meeting initial enrollment criteria at the screening visit will return to the 
investigational site at Week -2 (single-blind run-in start visit) to complete the evaluation 
of enrollment criteria. At this visit, subjects continuing to be eligible will enter a 2-week 
single-blind placebo, diet/exercise, and CV risk factor (eg, blood pressure and lipids) 
management optimization period. All subjects will receive diet/exercise counseling at 
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entry into the 2-week single-blind run-in period, be counseled on hypoglycemia 
recognition and management, be dispensed single-blind placebo capsules, and be given a 
monitor and materials for self-monitored blood glucose (SMBG) measurements. If 
additional time in run-in is required for adjustment/optimization of lipid-altering or blood 
pressure-lowering medications (so as to avoid the need for adjustment of these 
medications after randomization), the 2-week placebo run-in may be extended by having 
the subject continue single-blind placebo up to 2 additional weeks.
Subjects meeting all inclusion and none of the exclusion criteria, and successfully 
completing the 2-week run-in period, will be randomized to treatment with canagliflozin 
100 mg, 300 mg, or matching placebo administered once daily (in a 1:1:1 ratio). 
Approximately 4,500 subjects will be randomized. Subjects will remain on a stable 
regimen (medications and doses) of their current AHA regimen (if on AHA) from 
screening entry until the Week 18 visit of the double-blind treatment phase 
(see “Double-blind Treatment Phase Management” below for details). 
An overview of the study design is illustrated in Figure 1.
Figure 1:  Study Design Outline
AHA=antihyperglycemic agent; CV=cardiovascular; R = randomization; SU=sulfonylurea; T2DM= type 2 
diabetes mellitus
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Double-blind Treatment Phase Management
Subjects will remain on a stable regimen (medications and doses) of their current AHA 
regimen through Week 18 of the double-blind treatment phase, unless down-titration is 
required to manage or avoid hypoglycemia, or unless glycemic rescue criteria are met 
(refer to Section 6.2.2, Glycemic Rescue Therapy Through Week 18: Criteria and 
Implementation). After the AHA regimen stable period is completed at Week 18, the 
investigator should adjust the subject’s AHA regimen so as to achieve target glycemic 
control, per standard diabetes care guidances, individualized as considered appropriate by 
the investigator. Adjustments in the AHA regimen should be carefully implemented 
throughout the study to avoid events of hypoglycemia.
Planned Meta-analyses (CANVAS and Other Canagliflozin Studies)
As described in Section 11.8, Meta-analyses to Support Regulatory Requirements, during 
the conduct of this study, data from CANVAS will be exported and integrated with data 
from other large, well-controlled, double-blind, randomized studies of canagliflozin to 
support meta-analysis to assess the rate of important CV events in a prespecified 
composite endpoint. 
Study Duration 
Subjects are expected to be followed for a maximum of approximately 7.25 years with 
the last visit for the last subject targeted to occur when at least 688 MACE events are 
accumulated between the CANVAS and CANVAS-R studies. All sites will be notified of 
the projected global trial end date (GTED) which is projected to occur prior to 
April 2017. The GTED is the stopping date of the study (ie, targeted date when the last 
subject completes last study visit), which will be announced to investigators at a time 
point when the actual accrual of events approaches the number of events required for the 
analysis; the announcement of the GTED may occur approximately 3 months prior to the 
GTED. Immediately after the projected GTED notification is sent, for subjects who 
remain on double-blind study drug, sites will be required to schedule the last on treatment 
visits and the 30-day off drug follow-up visits as per the Time and Events Schedule; for 
subjects who prematurely discontinue study drug, sites will be required to make a final 
contact (eg, schedule the last follow-up visit) or vital status check as soon as possible 
after announcement of GTED.
All visits (including the 30-day off drug follow-up visit) will need to be completed prior 
to the GTED. 
Figure 2 shows the intended follow-up of randomized subjects with respect to the GTED.
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Figure 2: Follow-up of Randomized Subjects With Respect to the GTED
Collection of Study Endpoints and Safety Measures
Events in the CV composite endpoint: Investigators will be counseled to report any 
event that they assess as potentially to be a component of the study CV composite 
endpoint (refer to Section 9.2, Reporting/Adjudication of Events in the CV Composite 
Endpoint and Other Events for Adjudication).
Collection of Information After Early Withdrawal: Early withdrawal (for subjects 
prematurely discontinued)/end-of-treatment (for subjects completing the study) 
evaluation will be performed at the time the subject discontinues double-blind study drug 
or when the study ends (refer to Sections 9.1.4, End-of-Treatment/Early Withdrawal, and 
9.1.5, Posttreatment Phase [Follow-Up] for collection of information on CV events and 
other assessments). In subjects that prematurely discontinue study drug, events in the CV 
composite endpoint, all deaths, serious adverse events and adverse events of fractures 
should continue to be collected until study completion.
Safety Evaluations and Adverse Events Requiring Collection of Additional 
Information: See Section 3.2, Safety Evaluations, for details around safety assessments 
and adverse events requiring collection of additional information.  Investigators may also 
be asked to provide additional information on other adverse events, based upon review by 
the Medical Safety Review Committee (MSRC) or the study IDMC (refer to 
Sections 9.3.3, Medical Safety Review Committee, and 9.3.4, Independent Data 
Monitoring Committee). 
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Pharmacogenomic Blood Sample: A pharmacogenomic blood sample should be 
collected on Day 1 (or at a subsequent visit if not collected on Day 1) from subjects who 
consent separately to the pharmacogenomic component of the study to allow for 
pharmacogenomic research, as necessary (where local regulations permit). Subject 
participation in pharmacogenomic research is optional. Refusal to consent for this 
component does not exclude a subject from participation in the clinical study. 
Substudies – Add-on Use with Specific AHAs
Randomized subjects on specific concomitant AHAs, listed below, will be included in 
3 substudies. These substudies will assess the glycemic efficacy and safety of 
canagliflozin in subjects on one of the following concomitant AHAs: insulin 
!20 units per day as monotherapy or in combination with other AHA(s); sulfonylurea 
monotherapy (at doses specified in Attachment 1); or pioglitazone !30 mg plus 
metformin !2,000 mg/day (or at least 1,500 mg/day for subjects who have a history of 
not being able to tolerate higher metformin doses) and no other AHAs. These subjects 
will follow the same procedures and assessments as described for the overall study (refer 
to the Time and Events Schedule that follows the Synopsis); no additional procedures or 
assessments are required for subjects in these substudies. Results from subjects in these 
substudies will be analyzed based upon prespecified objectives and hypotheses (refer to 
Section 2.4, Substudies: Objectives and Hypotheses).
Section 9.3, Study Management: Committees, provides details regarding the committees 
commissioned to provide oversight for the management of this study.
3.2.
Study Design Rationale
Overall Design, Blinding, Control, Study Phases/Periods, Treatment Groups
This study was designed in general accordance with the FDA and European Medicines 
Agency (EMEA) guidances on the development of medications and clinical 
investigations for the treatment and prevention of diabetes mellitus (FDA 2008; 
EMEA 2002, 2008), and will contribute CV events (for a prespecified meta-analysis) to 
meet the requirements of the FDA guidance for industry on evaluating CV risk in new 
AHAs to treat type 2 diabetes issued in December 2008 (Guidance for Industry: Diabetes 
Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 
Diabetes). 
The study was to have 2 sequential cohorts, with the decision to recruit further subjects 
(ie, re-open enrollment) based upon a protocol-specified interim analysis of results from 
the initial cohort planned approximately 4 years after study initiation, around the time of 
US regulatory agency approval. However, the study will now only recruit the initial
4,330 subjects randomized for the reason discussed in Section 3. Randomization and 
blinding will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic 
and baseline characteristics) are evenly balanced across treatment groups. Blinded 
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treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints. A placebo control will be used to establish the frequency and 
magnitude of changes in clinical endpoints that may occur in the absence of the active 
treatment.
The 2-week single-blind placebo period before randomization allows sufficient time for 
investigators to assess whether subjects demonstrate compliance with study procedures, 
and to study medication, and provides an opportunity to adjust treatment for other 
CV risk factors, by titration or addition of background medications at the investigator's 
discretion, before randomization. 
The stable AHA regimen period of 18 weeks was chosen because it is sufficiently long to 
evaluate the effect of canagliflozin on HbA1c. Maintaining stable background AHAs, 
permits an assessment of the effect of canagliflozin not confounded by changes in other 
agents, and hence supports the determination of glycemic efficacy of this potentially 
valuable medication across the entire study population as well as in the substudies. 
Study Population 
The study population includes subjects on a variety of different AHAs, with a range of 
baseline glycemic control-from mildly elevated to more moderately elevated HbA1c
values-and at higher risk of or having documented CV disease. This population was 
selected to provide a broad experience with canagliflozin so as to enhance the 
characterization of this new medications efficacy, safety, and tolerability profile, and to 
support assessment of the effect of treatment with this agent on CV risk. The substudy 
populations were selected to provide information on concurrent use of canagliflozin with 
important AHAs that are not being assessed in separate Phase 3 studies.
Dosage Selection, Route of Administration, Dose Interval, Treatment Period
The once daily oral therapy is an acceptable dosage regimen given the half-life of 
canagliflozin. 
Based on findings from the Phase 2b diabetes study, 100 mg once daily is deemed to be 
the lowest dose providing clearly sufficient efficacy in terms of HbA1c-lowering for 
approval as an AHA and 300 mg once daily is deemed to provide an incremental 
improvement in glycemic efficacy and possibly weight loss and blood pressure lowering,
greater than that achieved with the 100 mg once daily regimen. The safety and 
tolerability profile of these 2 doses appeared to be generally similar. In Phase 1 studies of 
canagliflozin, at doses above 200 mg, a decrease in incremental glucose and an increase 
in the time to peak glucose were observed after a meal challenge when study drug was 
administered before the meal. The mechanism of this reduction in post-meal glucose is 
not known, but could relate to inhibition of SGLT1 gut glucose transport based upon 
transiently high gut concentrations of canagliflozin after dose administration. If this effect 
on post-meal glucose is established, it may provide an additional mechanism of 
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glucose-lowering benefit. In the present study, double-blind study drug is to be taken 
before the first meal of the day so as to obtain this potential benefit of canagliflozin. 
Additional studies in the canagliflozin program will evaluate this effect on post-meal 
glucose.
Both the 100 and 300 mg doses of canagliflozin are being evaluated in this study. 
Collection of Additional Information for Selected Adverse Events 
The safety profile of canagliflozin has been well-established in the Phase 3 program, 
which included approximately 10,000 subjects from randomized, controlled clinical 
trials. As a condition of approval certain health authorities (eg, US FDA) are requesting 
enhanced pharmacovigilance on selected adverse events of interest (see Section 9.4, 
Safety Evaluations, for additional details).
Choice of Cardiovascular Outcome Composite Endpoint
To evaluate the study’s primary hypothesis of CV benefit (ie, a reduction in CV risk), the 
endpoint of MACE (CV death, nonfatal MI, nonfatal stroke) will be used. This has 
become the standard composite endpoint utilized for this purpose, and hence was selected 
for use in the current study. The effect of canagliflozin relative to placebo on the HR of 
the individual components of these endpoints will also be characterized. To support the 
planned meta-analysis of integrated results from this and other large, well-controlled, 
double-blind, randomized studies of canagliflozin), the pre-approval composite endpoint
included MACE and hospitalized unstable angina. This endpoint was utilized to support 
the pre-approval CV safety of canagliflozin, evaluating the hypothesis (in the separate 
meta-analysis SAP) of no unacceptable increase in CV risk (ie, rule out an upper bound 
of 1.8 or greater). The event of hospitalized unstable angina was included in this 
composite to cast a wider net, given the importance of such events, and their close 
relationship to, and prediction of, progression of coronary artery disease. 
Choice of Renal Efficacy Measures
The onset and progression of nephropathy is a major morbidity outcome in diabetic 
patients. Hyperglycemia, possibly through production of advanced glycation endproducts 
(Diabetes Control and Complications Trial [DCCT], Brownlee 2001), systemic 
hypertension (DCCT), and increases in intraglomerular pressure (Anderson 1986; 
ADA 2004) are known to be risk factors for the onset and progression of diabetic 
nephropathy. 
In the Phase 2b diabetes study, canagliflozin improved glycemic control, with a trend 
towards reduced blood pressure in the 300 mg once daily group. By virtue of its 
mechanism, canagliflozin will reduce the increased glucose flux across the proximal 
tubule and through the interstitium to be reabsorbed into the bloodstream. The reduced 
glucose flux within the kidney could lead to a reduction in renal advanced glycation 
endproduct accumulation resulting in a delay in the onset and/or progression of diabetic 
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nephropathy. Because SGLT2 in the proximal tubule cotransports both sodium and 
glucose, SGLT2 inhibition by canagliflozin will increase the distal delivery of sodium, 
which could lead to a reduction in intraglomerular pressure via the macula densa and a 
decrease in glomerular damage (Vallon 1999).
The development and progression of renal disease in people with diabetes follows a 
clearly 
defined 
pathway 
starting 
with 
micro-albuminuria, 
progressing 
to 
macro-albuminuria, then to reduced renal function (lower glomerular filtration rate), and 
finally to renal failure with the need for dialysis or transplantation. To assess the effects 
of canagliflozin on the progression of diabetic nephropathy, the proportion of subjects 
with categorical progression of albuminuria based upon the albumin/creatinine ratio in 
the first morning void was selected as a key secondary endpoint and will be assessed
according to the categorizations defined in the National Kidney Foundation Kidney 
Disease Outcomes Quality Initiative Guideline #1 (KDOQI 2007): the definition of 
micro-albuminuria is albumin/creatinine ratio of 30 to 300 mg/g, and the definition of 
macro-albuminuria is albumin/creatinine ratio greater than 300 mg/g.
In diabetes, the onset of urinary albumin excretion is a strong signal for progression of 
diabetic nephropathy (ADA 2004), and is associated with an increase in CV events 
(de Zeeuw 2004). In the present study, first morning void urine collections are being 
used. These collections have been shown to be more accurate than spot urine collections 
(Witte 2009) because they are less influenced by urinary albumin changes associated with 
physical activity.
Choice of Beta-cell Function Measures
Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by the 
progressive loss of beta-cell function and insulin secretory capacity (UKPDS 1998). In 
large clinical trials, HOMA-B is a well-accepted means of assessing fasting beta-cell 
function (Wallace 2004). Homeostasis model assessment (HOMA)-B is calculated using 
fasting insulin or C-peptide and glucose levels (Wallace 2004). Because C-peptide is not,
but insulin is, extracted by the liver, the use of C-peptide to calculate HOMA-B is not 
confounded by increased hepatic extraction such as that which can occur in conditions of 
improved hepatic insulin sensitivity. Given that canagliflozin is predicted to cause weight 
loss, which could lead to improved hepatic insulin sensitivity, C-peptide was chosen to be 
used for HOMA-B calculations, which will be assessed in a subset of subjects who are 
not receiving insulin at baseline; if a subject starts insulin therapy after baseline, no 
further assessments of these analytes will be made for that subject. Approximately 
1,200 subjects (400 per treatment group) will be studied in this subset, at sites that elect 
to participate.
In this subset of subjects, fasting proinsulin and insulin will also be measured to assess 
beta-cell function. Elevated proinsulin/insulin ratios reflect increasing degrees of 
impairment in beta-cell function in T2DM (Roder 1998).
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DNA Collection
It is recognized that genetic variation can be an important contributory factor to 
interindividual differences in drug distribution and response and can also serve as a 
marker for disease susceptibility and prognosis. Pharmacogenomic research may help to 
explain interindividual variability in clinical outcomes and may help to identify 
population subgroups that respond differently to a drug. The goal of the 
pharmacogenomic component is to collect DNA to allow the identification of genetic 
factors that may influence glucose and lipid metabolism, and supporting interpretation of 
dynamic effects measured in the study or to characterize genes potentially affecting drug 
absorption, distribution, metabolism, or excretion of canagliflozin. DNA samples may be 
used to help address emerging issues and to enable the development of safer, more 
effective, and ultimately individualized therapies in the future. Details are provided in 
Section 9.6, Pharmacogenomic Evaluations.
Archive Samples for Exploratory Research and Specimens for Biomarker 
Assessment
Numerous biomarkers have been studied as potentially important surrogate measures of 
CV and overall health in subjects with T2DM (Ridker 2004). Fasting plasma, serum, and 
urine archive samples will be collected (where local regulations permit) to allow for the 
analysis of important biomarkers (not prespecified) that could help to further explain and 
examine the efficacy and safety findings in this study. See Attachment 4 for details of 
specimen collection.
Medical Resource Utilization
Should canagliflozin reduce the risk of CV events, the risk of onset and progression of 
nephropathy and improve beta-cell function, the utilization of medical resources such as 
physician visits (outside of protocol-specified), hospitalizations, and medication 
requirements may be lower in the canagliflozin group than in the standard care group. To 
assess this, information will be collected in order to characterize differences in the need 
for additional medical interactions (eg, physician visits, hospitalizations).
4. STUDY POPULATION
4.1.
General Considerations
The study will include subjects with a diagnosis of T2DM and a history or high risk of 
CV disease. Approximately 4,500 subjects will be randomized.
Subjects must have inadequate glycemic control (as defined by HbA1c !7.0 to #10.5% at 
screening) and be either (1) not currently on AHA therapy or (2) on AHA monotherapy 
or combination therapy with any approved agent: eg, sulfonylurea, metformin, 
pioglitazone, alpha-glucosidase inhibitor, GLP-1 analogue, DPP-4 inhibitor, or insulin. 
Subjects receiving AHA therapy must be on a stable dose of that therapy for at least 
8 weeks before the screening visit. Subjects taking rosiglitazone within 8 weeks before 
the prescreening or screening visit may not enter the study. Subjects taking rosiglitazone 
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who are already in screening are not eligible for randomization. Subjects who have been 
randomized before implementation of Protocol 28431754DIA3008 Amendment INT-3 
and are taking rosiglitazone should be evaluated in a timely manner to determine how to 
modify their rosiglitazone-containing antihyperglycemic regimen, if clinically 
appropriate and in accordance with local regulatory requirements.
As noted, subjects must also either have a prior history of documented CV disease or be 
at high risk of CV disease (on the basis of 2 or more specific CV risk factors). For details, 
refer to Section 4.2, Inclusion Criteria, below.
Subjects will be recruited from centers in Asia-Pacific, North America, Latin America, 
Europe, and possibly other regions for this study. 
The inclusion and exclusion criteria for enrolling subjects in this study are described in 
the following sections. If there is a question about the inclusion or exclusion criteria 
below, the investigator should consult with the appropriate sponsor representative before 
enrolling the subject in the study. 
4.2.
Inclusion Criteria
Potential subjects must satisfy all of the following criteria to be enrolled in the study:
Inclusion Criteria at Screening Visit
∃
Man or woman with a diagnosis of T2DM with HbA1c level !7.0% to #10.5% at 
screening and be either (1) not currently on AHA therapy or (2) on AHA 
monotherapy or combination therapy with any approved agent: eg, sulfonylurea, 
metformin, pioglitazone, alpha-glucosidase inhibitor, GLP-1 analogue, DPP-4 
inhibitor, or insulin. 
∃
History or high risk of CV disease defined on the basis of either:
–
Age !30 years with documented symptomatic atherosclerotic CV disease: 
including stroke; MI; hospital admission for unstable angina; coronary artery 
bypass graft; percutaneous coronary intervention (with or without stenting); 
peripheral revascularization (angioplasty or surgery); symptomatic with 
documented hemodynamically-significant carotid or peripheral vascular disease; 
or amputation secondary to vascular disease
–
Age !50 years with 2 or more of the following risk factors determined at the 
screening visit: duration of T2DM of 10 years or more, systolic blood pressure 
>140 mmHg (average of 3 readings) recorded at the Screening Visit, while the 
subject is on at least one blood pressure-lowering treatment, current daily 
cigarette smoker, documented micro- or macro-albuminuria (see Section 3.2, 
Study Design Rationale, for definition), or documented HDL-C of <1 mmol/L 
(<39 mg/dL). 
Note: An overall 70%:30% target ratio for CV history (first category): risk 
factors (second category) will be implemented (with a maximum of approximately 
40% in the second category). This ratio is intended to be a global ratio and may 
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vary by region. The proportion of subjects in these categories will be monitored 
centrally.
∃
Women must be: 
–
postmenopausal, defined as 
&
>45 years of age with amenorrhea for at least 18 months, or
&
>45 years of age with amenorrhea for at least 6 months and less than 
18 months and a serum follicle stimulating hormone (FSH) level >40 IU/L, or
–
surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal 
ligation), or otherwise be incapable of pregnancy, or
–
heterosexually active and practicing a highly effective method of birth control, 
including hormonal prescription oral contraceptives, contraceptive injections, 
contraceptive patch, intrauterine device, double-barrier method (eg, condoms,
diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner 
sterilization, consistent with local regulations regarding use of birth control 
methods for subjects participating in clinical trials, for the duration of their 
participation in the study, or
–
not heterosexually active.
Note: subjects who are not heterosexually active at screening must agree to utilize a 
highly effective method of birth control if they become heterosexually active during 
their participation in the study.
∃
Women of childbearing potential must have a negative urine ∋-human chorionic 
gonadotropin (∋-hCG) pregnancy test at screening and baseline (predose, Day 1).
∃
Willing and able to adhere to the prohibitions and restrictions specified in this 
protocol.
∃
Subjects must have signed an informed consent document indicating that they 
understand the purpose of and procedures required for the study and are willing to 
participate in the study.
∃
To participate in the optional pharmacogenomic component of this study, subjects 
must have signed the informed consent form for pharmacogenomic research 
indicating willingness to participate in the pharmacogenomic component of the study 
(where local regulations permit). Refusal to give consent for this component does not 
exclude a subject from participation in the clinical study.
Inclusion Criterion for Randomization
∃
Subjects must have taken !80% of their single-blind placebo capsules during the 
2-week run-in period at Day 1 to be eligible for randomization.
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4.3.
Exclusion Criteria
Potential subjects who meet any of the following criteria will be excluded from 
participating in the study:
Diabetes-Related/Metabolic
∃
History of DKA, T1DM, pancreas or beta-cell transplantation, or diabetes secondary 
to pancreatitis or pancreatectomy
∃
On an AHA and not on a stable regimen (ie, agents and doses) for at least 8 weeks 
before the screening visit and through the screening/run-in period
Note: a stable dose of insulin is defined as no change in the insulin regimen 
(ie, type[s] of insulin) and #15% change in the total daily dose of insulin (averaged
over 1 week to account for day to day variability).
∃
Fasting fingerstick glucose at home or at investigational site >270 mg/dL 
(>15 mmol/L) at Baseline/Day 1 
∃
For patients on a sulfonylurea agent or on insulin: fasting fingerstick glucose at 
home or at investigational site <110 mg/dL (<6 mmol/L) at Baseline/Day 1
Note: at the investigator’s discretion, based upon an assessment of recent SMBG 
values, subjects meeting either of these fingerstick glucose exclusion criteria may 
continue the single-blind placebo and return to the investigational site within 14 days 
and may be randomized if the repeat fasting fingerstick value no longer meets the 
exclusion criterion. Subjects with fingerstick glucose >270 mg/dL (>15 mmol/L) may 
have their AHA regimen adjusted, and be rescreened once on a stable regimen for at 
least 8 weeks.
∃
History of one or more severe hypoglycemic episode within 6 months before 
screening 
Note: a severe hypoglycemic episode is defined as an event that requires the help of 
another person. Refer to Attachment 2, Hypoglycemia: Definitions, Symptoms, and 
Treatment, for a definition of severe hypoglycemia.
∃
History of hereditary glucose-galactose malabsorption or primary renal glucosuria
∃
Ongoing, inadequately controlled thyroid disorder
Note: subjects on thyroid hormone replacement therapy must be on a stable dose for 
at least 6 weeks before Day 1.
Renal/Cardiovascular
∃
Renal disease that required treatment with immunosuppressive therapy or a history of 
chronic dialysis or renal transplant. Note: subjects with a history of treated childhood 
renal disease, without sequelae, may participate.
∃
Myocardial 
infarction, 
unstable 
angina, 
revascularization 
procedure, 
or 
cerebrovascular accident within 3 months before screening, or a planned 
revascularization procedure, or history of New York Heart Association (NYHA) 
Class IV cardiac disease; refer to Attachment 3, New York Heart Association 
Classification of Cardiac Disease, for a description of the classes
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∃
Findings on 12-lead ECG that would require urgent diagnostic evaluation or 
intervention (eg, new clinically important arrhythmia or conduction disturbance)
Gastrointestinal
∃
History of hepatitis B surface antigen or hepatitis C antibody positive (unless 
associated 
with 
documented 
persistently 
stable/normal 
range 
aspartate 
aminotransferase [AST] and ALT levels), or other clinically active liver disease
∃
Any history of or planned bariatric surgery
Laboratory
∃
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 at screening 
(provided by the central laboratory) 
∃
For subjects taking metformin: at screening, serum creatinine !1.4 mg/dL 
(124 ∀mol/L) for men or !1.3 mg/dL (115 ∀mol/L) for women; no contraindication to 
the use of metformin (including eGFR) based on the label of the country of 
investigational site
∃
ALT levels >2.0 times the ULN or total bilirubin >1.5 times the ULN at screening, 
unless in the opinion of the investigator and as agreed upon by the sponsor’s medical 
officer, the findings are consistent with Gilbert’s disease
Other conditions
∃
History of malignancy within 5 years before screening (exceptions: squamous and 
basal cell carcinomas of the skin and carcinoma of the cervix in situ, or a malignancy 
that in the opinion of the investigator, with concurrence with the sponsor’s medical 
monitor, is considered cured with minimal risk of recurrence)
∃
History of human immunodeficiency virus (HIV) antibody positive
∃
Subject has a current clinically important hematological disorder (eg, symptomatic 
anemia, proliferative bone marrow disorder, thrombocytopenia)
∃
Investigator’s assessment that the subject’s life expectancy is less than 1 year, or any 
condition that in the opinion of the investigator would make participation not in the 
best interest of the subject, or could prevent, limit, or confound the protocol-specified 
safety or efficacy assessments
∃
Major surgery (ie, requiring general anesthesia) within 3 months of the screening visit 
or any surgery planned during the subject’s expected participation in the study 
(except minor surgery, ie, outpatient surgery under local anesthesia)
∃
Any condition that, in the opinion of the investigator, would compromise the well 
being of the subject or prevent the subject from meeting or performing study 
requirements
Medications/Therapies
∃
Current use of other SGLT2 inhibitor; use of rosiglitazone within 8 weeks of 
screening. (Note: subjects taking rosiglitazone who are already in screening are not 
eligible for randomization.)
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∃
Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients 
(refer to Section 14.1, Physical Description of Study Drug[s])
∃
Current use of a corticosteroid medication or immunosuppressive agent, or likely to 
require treatment with a corticosteroid medication (for longer than 2 weeks in 
duration) or an immunosuppressive agent. Note: subjects using inhaled, intranasal, 
intra-articular, or topical corticosteroids, or corticosteroids in therapeutic replacement 
doses may participate
∃
Received an active investigational drug (including vaccines) or used an 
investigational medical device within 3 months before Day 1/baseline or received at 
least one dose of canagliflozin in a prior study
General
∃
History of drug or alcohol abuse within 3 years before screening
∃
Pregnant or breast-feeding or planning to become pregnant or breast-feed during the 
study
∃
Employees of the investigator or study center, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study 
center, as well as family members of the employees or the investigator
Note: Investigators should assure that all study enrollment criteria have been met and 
determine that the subject has not had any interval change in clinical status since 
screening. Before randomization, subjects whose status changes after screening, such that 
they now meet an exclusion criterion, should be excluded from participation.
4.4.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
∃
Women of childbearing potential who are heterosexually active must use a highly 
effective method of birth control throughout their participation in the study (refer to 
Section 4.2, Inclusion Criteria)(refer to Section 12.2.3, Pregnancy, for instructions in 
cases of a positive pregnancy test) 
∃
Prohibited medications include other SGLT2 inhibitors; subjects must not take any 
other investigational agents during the study (if a subject prematurely discontinues 
from the study medication but continues in the posttreatment follow-up phase, 
entering another investigational trial is discouraged but is not prohibited; however, 
entering another canagliflozin trial is prohibited)
∃
Strenuous exercise may affect urine protein excretion and other safety laboratory 
results; for this reason, strenuous exercise should be avoided within 72 hours before 
planned study visits
∃
Subjects should not collect first morning void during acute illness with fever. The 
collection and respective visit should be postponed until the subject is recovered from 
the acute illness.
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4.5.
Rescreening
Subjects who do not meet all inclusion criteria or who meet an exclusion criterion may, at 
the discretion of the investigator, be rescreened one time if the reason for non-eligibility 
relates to duration (eg, time from an MI, or duration on a stable dose of thyroid hormone, 
or duration on a stable AHA regimen), or appropriate clinical management leads to study 
eligibility (eg, HbA1c >10.5% that prompts adjustment of the subject’s AHA regimen, or 
subject is on a medication not allowed per local prescribing information [eg, on 
metformin with eGFR below level permitted per label], and the subject’s treatment 
regimen is being adjusted as clinically appropriate to be consistent with local prescribing 
information).
Rescreening for an abnormal laboratory value is only allowed as indicated for the specific 
laboratory exclusion criterion. Typically, rescreening will require that all screening 
and/or run-in parameters be repeated. However, with the concurrence of the sponsor’s 
Medical Monitor, a non-qualifying laboratory test may be repeated one time, without 
completely rescreening the subject, in situations where there is a clinical reason to do so.
5. TREATMENT ALLOCATION
To ensure sufficient experience in subjects with documented, pre-existing CV 
disease(the highest risk group(approximately 70% (minimum of 60%) of subjects 
(globally) are targeted to be in this group. 
Stratification for Substudies 
Subjects will have within-subgroup balanced (1:1:1) randomization to each of the 
3 treatment groups within the following 6 predefined strata, which are based upon AHA 
medication(s) that the subject is receiving at the run-in visit and will be continuing at 
entry into the double-blind treatment phase: 
∃
Stratum 1: insulin monotherapy !20 units per day, on stable doses at least 10 weeks 
before the run-in visit
∃
Stratum 2: insulin !20 units per day plus metformin, on stable doses at least 10 weeks 
before the run-in visit, and no other background AHA therapy
∃
Stratum 3: insulin !20 units per day plus any other AHA(s) on stable dose(s) for at 
least 10 weeks before the run-in visit
∃
Stratum 4: sulfonylurea monotherapy (at doses specified in Attachment 1), on stable 
doses at least 10 weeks before the run-in visit
∃
Stratum 5: pioglitazone !30 mg/day plus metformin !2,000 mg/day (or at least 
1,500 mg/day for subjects who have a history of not being able to tolerate higher 
metformin doses) and no other background AHA therapy, on stable doses at least 
10 weeks before the run-in visit
∃
Stratum 6: subjects not in one of the above AHA subgroups
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Note: a stable dose of insulin is defined as no change in the insulin regimen (ie, type[s] of 
insulin) and #15% change in the average total daily dose of insulin (as averaged over one 
week).
The stratification process will be handled via queries in the Interactive Voice Response 
System (IVRS) or after logging on to the Interactive Web Response System (IWRS) 
being used for the study, described below.
Randomization and Blinding Procedures
Central randomization will be implemented in this study. Subjects will be randomly 
assigned to 1 of 3 treatment groups based on a computer-generated randomization 
schedule prepared by or under the supervision of the sponsor before the study. The 
randomization will be balanced by using randomly permuted blocks and will be stratified 
based on the use of specific concomitant antihyperglycemic medications at baseline (as 
noted above). Based on this randomization schedule, the study drug will be packaged and 
labeled. Medication numbers will be preprinted on the study drug labels and assigned as 
subjects qualify for the study and are assigned to double-blind treatment.
At baseline (Day 1), the randomization number and medication numbers, the treatment 
code, which is linked to the randomization schedule, will be assigned after telephoning 
into the IVRS or after logging on to the IWRS designated by the sponsor. The requestor 
must use his/her own user identification (ID) and personal identification number (PIN) 
when contacting the IVRS/IWRS, and will then give the relevant subject details to 
uniquely identify the subject. Based on this information, the IVRS/IWRS will assign a 
unique treatment code, which will dictate the treatment assignment and study drug kit for 
the subject. As subjects are randomly assigned to treatment, the IVRS/IWRS will assign a 
study drug kit to be dispensed at that visit. New medication numbers will be assigned 
each time the IVRS/IWRS is contacted for dispensing additional study drug. The 
randomization (or initial subject allocation) number at baseline will be the identifying 
number linking all subsequent kits to the individual subject.
The study drugs will be identical in appearance and will be packaged in identical 
containers.
The randomization code that links the randomization number assigned to the subject with 
a treatment group assignment will be maintained within the IVRS/IWRS. This 
randomization code will not be provided to the investigator unless required, as described 
below, for unblinding in emergency situations. 
The treatment blind should be broken to provide unblinded information to the site only if 
specific emergency treatment/course of action would be dictated by knowing the 
treatment status of the subject. In such cases, the investigator may in an emergency 
determine the identity of the treatment through the IVRS or IWRS. It is recommended 
that the investigator contact the sponsor or its designee if possible to discuss the 
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particular situation, before breaking the blind. The reason for unblinding is not captured 
through IVRS. Telephone contact with the sponsor or its designee will be available 
24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be 
informed as soon as possible. The date and reason for the unblinding must be 
documented in the appropriate section of the eCRF and in the source documents. The 
documentation received from the IVRS indicating the code break must be retained with 
the subject's source documents in a secure manner (eg, sealed envelope) so as not to 
unblind the treatment assignment to the study site or sponsor personnel. The investigator 
is also advised not to reveal the study treatment assignment to the study site or sponsor 
personnel. 
Subjects who have had their treatment assignment unblinded by the investigator will be 
discontinued (refer to Section 10.2, Withdrawal from the Study).
Randomization codes will be released based upon protocol-specified interim or 
meta-analyses, and after completion of the study. At the time of these analyses, the 
translation of randomization codes into treatment and control groups will be disclosed 
only to those authorized and only for those subjects included in the interim analysis (refer 
to Section 11.7, Interim Analyses of CANVAS and Section 11.8, Meta-analysis to Meet 
Regulatory Requirements). 
To maintain the treatment blind, the FPG and HbA1c values after baseline and before 
Week 18 will be masked to the study sites unless: (1) the FPG meets specific glycemic 
criteria for the initiation of rescue therapy (as described in Section 6.2.2, Glycemic 
Rescue Therapy Through Week 18: Criteria and Implementation), or (2) glycemic rescue 
therapy has been initiated.
Urine glucose measurements will not be performed on first morning void urine 
specimens, or on urinalyses during the study, as an additional step to ensure the 
maintenance of the treatment blind. Unless required by urgent subject management, 
investigators should obtain all urinalyses through the central laboratory and not by a local 
laboratory so as to avoid potential for unblinding related to urine glucose results (which 
will not be reported by the central laboratory). If a urinalysis must be performed locally 
for appropriate subject management (eg, to evaluate a potential infection), investigators 
should request microscopic rather than dipstick urinalysis (if microscopic evaluation is 
considered clinically sufficient).
6. DOSAGE AND ADMINISTRATION
6.1.
Study Drugs
Run-in Period Single-Blind Placebo
Upon successful completion of screening, all potentially eligible individuals will enter a 
2-week run-in period, during which they will receive single-blind placebo capsules (one 
capsule to be administered once daily). 
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Double-Blind Study Medication
Subjects will be randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups: 
canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. 
Subjects will be counseled to take their dose of canagliflozin or matching placebo, one 
capsule once daily, before the first meal of the day for the duration of the study or until 
early discontinuation. Subjects will take the first dose of study drug at the study center on 
Day 1. 
On the days of study visits when fasting blood samples are collected (refer to the Time 
and Events Schedule that follows the Synopsis), subjects will be instructed to refrain 
from taking the study drug before the clinic visit. The subject will be instructed to take 
the dose of study drug before the subject’s next meal. 
The study drug must be swallowed whole with liquid and not chewed, divided, dissolved, 
or crushed. If the subject does not take the study drug within 12 hours after the first meal 
of the day, the dose of study drug should be skipped for that day and the subject should 
be instructed to take the study drug on the following day before the first meal of the day.
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol.
Study drug treatment may be interrupted (eg, for safety and/or tolerability reasons such as 
hospitalizations for major surgical procedure or serious medical illness). Study drug 
treatment interruptions, occurring for any reason and lasting 7 days or longer, will be 
documented in source documents at the site. Study drug may be reinstituted at the 
investigator's discretion once the subject has recovered and the safety and/or tolerability 
concern is no longer present (provided the subject has not been off study drug for 
>90 days).  
For subjects who develop conditions that are associated with amputations, such as a 
lower-extremity infection, skin ulcer, osteomyelitis, gangrene, or critical limb ischemia, 
study drug should be interrupted until the condition has resolved in the opinion of the 
investigator. In the event of an amputation, restarting of dosing with canagliflozin should 
only be done after careful consideration of the individual risk:benefit and following 
discussion with the sponsor.
6.2.
Concomitant Antihyperglycemic and Other Therapies
6.2.1.
Management of Glycemic Control and CV Risk Factors
Run-in Period Management
Subjects will receive diet/exercise counseling at entry into the 2-week run-in period and 
will remain on a stable regimen (medications and doses) of their current AHA regimen (if 
on an AHA[s]), except as described below. During the run-in period, investigators will 
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counsel subjects to perform regular fasting SMBG determinations, in general at least 
2 measurements per week, with additional measurements as considered clinically 
appropriate by the investigator.
Double-blind Treatment Phase Glycemic Management 
Subjects should remain on a stable AHA regimen (doses and medications) from screening 
to Week 18, unless a down-titration is considered necessary to manage or avoid 
hypoglycemia, or if glycemic rescue criteria are met (refer to Section 6.2.2, Glycemic 
Rescue Therapy Through Week 18: Criteria and Implementation). From Week 18, the 
AHA regimen should be adjusted to achieve glycemic goals, using standard guidances, 
and as considered appropriate by the investigator for the individual subject. Adjustment to 
the AHA regimen (from Week 18) should be carefully implemented so as to avoid events 
of hypoglycemia.
Adjustment of AHA therapy will be performed by the investigator, consistent with 
standard diabetes guidances: no specific AHA treatment algorithm is utilized in this 
study. Treatment may include reinforcement of lifestyle counseling, up-titration to 
maximum labeled doses of current AHAs, the addition of oral AHAs, addition of GLP-1 
analogue, or the initiation and up-titration of insulin (intermediate or long-acting insulin 
and subsequent short-acting, pre-meal insulin, if needed). Investigators should make all 
reasonable efforts to achieve and maintain the subject’s individualized target glycemic 
control, and may add unscheduled visits, if clinically appropriate, to monitor glycemic 
control, and adjust the subject’s regimen. All adjustments to the AHA regimen should be 
documented in the appropriate eCRF. 
Use of AHAs and adjustments to the AHA regimen (dose or agents) should be consistent 
with the labeled use of the AHA within the country of the investigational site.
During the double-blind treatment period, investigators will counsel subjects to perform 
regular fasting SMBG determinations; in general, the guidance should be for subjects to 
perform at least 2 measurements per week, with additional measurements as considered 
clinically appropriate by the investigator, although it is recognized that subjects may not 
always be compliant with this guidance for various reasons.
Therapeutic Management of CV Risk Factors
Before randomization and throughout the study, investigators will be expected to manage 
the subject’s diet/exercise and medication regimens so as to achieve goals for CV risk 
factors (eg, lipid levels, blood pressure) based upon standard guidances for the care of 
patients with T2DM. 
During the 2-week single-blind placebo run-in period, investigators should adjust the 
subject’s regimen as needed to optimize the subject’s CV risk factors and thereby to 
reduce the need for adjustments of medications after randomization. If additional time in 
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run-in is required for adjustment/optimization of lipid-altering or blood pressure-lowering 
medications (so as to avoid the need for adjustment of these medications after 
randomization), the 2-week placebo run-in may be extended by having the subject 
continue single-blind placebo up to 2 additional weeks.
6.2.2.
Glycemic Rescue Therapy Through Week 18 Criteria and 
Implementation
So as to avoid poorer glycemic control during the 18-week AHA dose-stable period, 
glycemic rescue criteria will be applied. After Week 18, investigators will determine 
subject’s glycemic goals and the need for adjustments in the AHA regimen.
From Day 1 to Week 18, the criteria for starting glycemic rescue therapy are based on an 
FPG value exceeding the glucose cutpoints shown in the table below. Subjects should be 
counseled to contact the site if their SMBG consistently exceeds these values and an FPG 
measurement (ie, venous blood collection) to determine eligibility for initiation of 
glycemic rescue therapy should be obtained. 
Rescue Criteria Through Week 18
Time point
Glucose
After Day 1 through Week 6
>270 mg/dL (15 mmol/L)
After Week 6 through Week 12
>240 mg/dL (13.3 mmol/L)
After Week 12 through Week 18
>200 mg/dL (11.1 mmol/L)
Glycemic rescue therapy should be as determined to be clinically appropriate by the 
investigator: either up-titration of current AHA medications or the stepwise addition of 
non-insulin antihyperglycemic agent(s) and then insulin therapies. After initiation of 
rescue therapy, the glycemic goals will be based upon standard diabetes guidances, 
individualized for the subject, as considered appropriate by the investigator.
Investigators must complete the appropriate eCRF page (documenting initiation of 
therapy) for subjects starting on rescue medication. From Week 18, adjustment of the 
subject’s diabetes treatment regimen is permitted per protocol, and hence such 
adjustments are not considered as rescue (and therefore the eCRF for rescue therapy does 
not need to be completed).
Double-blind study drug is to be continued after initiation of rescue therapy.
7. TREATMENT COMPLIANCE
The investigator or designated study research staff will maintain a log of all drug 
dispensed and returned (including a count of capsules dispensed and returned). Drug 
supplies for each subject will be inventoried and accounted for throughout the study. 
Subjects who are poorly compliant with taking the study drug (based on capsule counts) 
should receive counseling on the importance of dosing compliance and may continue in 
the study, at the investigator’s discretion.
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Subjects will receive clear instructions on compliance with study procedures at the 
screening visit. During the course of the study, the investigator or designated study 
research staff will be responsible for providing additional instructions to reeducate any 
subject who is not compliant with taking the study drug or with completing the diary, as 
required.
8. PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapy includes any therapy used before the first dose of double-blind study 
medication. Concomitant therapy is any therapy used after the first dose of double-blind 
study drug. 
Prestudy therapies administered up to 30 days before screening (and up to 12 months 
before screening for AHA) and up to the time of the first dose of double-blind study drug 
must be recorded.
Concomitant therapies must be recorded throughout the study beginning with start of the 
first dose of study drug to 30 days after the last dose of study drug.
All therapies (prescriptions or over-the-counter medications, including vitamins and 
herbal supplements; nonpharmacologic therapies such as electrical stimulation, 
acupuncture, special diets, exercise regimens) different from the study drug must be 
recorded as prestudy therapy (before the first dose of double-blind study drug) or as 
concomitant therapy (after the first dose of double-blind study drug) on the eCRF.
Concomitant therapies will not be provided or reimbursed by the sponsor. 
Disallowed Therapies
Other SGLT2 inhibitors may not be used concurrently, and subjects should not take any 
other investigational agents during the study (however, please note the guidance for 
subjects in posttreatment follow-up in Section 4.4).
The sponsor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered.
9. STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule that follows the Synopsis summarizes the frequency and 
timing of efficacy, safety, and other measurements applicable to this study. 
Visit Schedules and Visit Windows
A screening visit should occur 1 to 2 weeks before the run-in start visit. The single-blind 
placebo run-in period should be 2 weeks in length (with a recommended visit window of 
)4 days). If additional time in run-in is required for adjustment/optimization of 
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lipid-altering or blood pressure-lowering medications (so as to avoid the need for 
adjustment of these medications after randomization), the 2-week placebo run-in may be 
extended by having the subject continue single-blind placebo up to 2 additional weeks.
Subsequent scheduled study visits during the first year of the study should occur at Day 1 
(baseline, the day of randomization), Weeks 6, 12, 18, 26, 39, and 52. After the first year, 
scheduled (in-clinic) study visits may occur at 13-week or 26-week intervals (at the 
option of the investigator). If in-clinic visits are changed to an every 26-week frequency, 
a telephone contact should occur in between the 26-week interval in-clinic visits such that 
there will be contact with the subject every 13 weeks (in-clinic visits alternating with 
telephone contacts) (see the Time and Events Schedule). For each post-baseline visit up 
through Week 26, the recommended visit window is )7 days. After Week 26, the 
recommended visit window is )14 days. After Week 65, on those occasions when the 
26- and/or 52-week-interval visits overlap, the visit with the more comprehensive 
procedures (as outlined in the Time and Events Schedule that follows the Synopsis) will 
be followed.
Telephone contacts, or optional site visits, should be conducted at Weeks 2, 4, and 9. 
Refer to the Time and Events Schedule that follows the Synopsis for further details. If a 
telephone contact or study visit is not possible, follow-up information may be collected 
via email or other electronic or non-electronic means.
For study visits that are unable to be held within the protocol-recommended visit 
windows, the visit should be conducted as closely as possible to the protocol-specified 
study visit timing. All subsequent visits should be scheduled based on the date of 
randomization, not the date of the rescheduled visit. The study visits at Week 52, and 
annual visits, should occur as closely as possible to this scheduled time. 
Pregnancy Testing
Serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any 
time during the study (refer to the Time and Events Schedule that follows the Synopsis 
for further details regarding urine pregnancy testing).
Subject Diary: Collection of Self-Monitoring of Blood Glucose (SMBG), Possible 
Hypoglycemic Event Information, Medical Resource Utilization Information
A standard, protocol-specified diary will be provided to each subject. Routine SMBG 
measurements may be recorded in the diary, and all events of possible hypoglycemia that 
are serious adverse events or that lead to study drug discontinuation should be 
documented as well as associated fingerstick glucose measurements, if available.
The diary may also be used to keep track of medications and/or medication changes at the 
investigator’s discretion. In addition, the diary should be used for the subject to record 
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health-care provider visits (other than protocol-specified study visits), emergency care, 
and hospital visits (refer to Section 9.8, Medical Resource Utilization). 
The diary should be reviewed by study research staff at each scheduled visit.
Collection of Other Endpoints: Optional Specimens for Exploratory Research
A set of fasting plasma, serum, and urine samples will be collected at the time points 
specified in the Time and Events Schedule from subjects who consent to this component 
of the study to allow for exploratory research related to canagliflozin and biomarker 
analyses that may provide further understanding regarding the diagnosis and treatment of 
T2DM or obesity (where local regulations permit). Subject participation in this 
component of the study is optional. Refusal to consent for this component does not 
exclude a subject from participation in the clinical study. Refer to Section 9.7, 
Exploratory Evaluations, for further details. Refer to Attachment 4, Optional Specimens 
for Exploratory Research - Sample Collection and Handling, for further information 
regarding the collection and handling of exploratory blood and urine samples.
Pharmacogenomic Testing
A blood sample will be collected on Day 1 (or any time after Day 1 if the specimen is 
inadvertently missed on Day 1) from subjects who have consented to participate in the 
pharmacogenomic component of the study. Refer to Attachment 5, Pharmacogenomic 
Sample Collection and Shipment Procedures, for details on collecting and handling blood 
samples for pharmacogenomic research. In the event of DNA extraction failure, a 
replacement pharmacogenomic blood sample may be requested from the subject. Signed 
informed consent will be required to obtain a replacement sample.
9.1.2.
Pretreatment Phase
Screening Visit (Week -3)
Potential subjects will be seen at a screening visit, approximately 3 weeks before 
scheduled randomization, at which informed consent will be obtained and an initial 
assessment of eligibility will be performed. 
At the screening visit, a focused medical history and initial screening assessment of 
inclusion/exclusion criteria will be performed and key laboratory studies (including 
serum chemistry and HbA1c, and fasting lipids [if subject is fasting at the screening visit]) 
will be obtained. 
Run-in Visit (Week -2)
At the Week –2 run-in visit, a complete medical history will be obtained and a physical 
examination and additional laboratory evaluations (including hematology, urinalysis, 
FPG, fasting lipids [if not obtained at screening visit]), and an ECG will be performed, 
per the Time and Events Schedule that follows the Synopsis. 
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At this visit, subjects who continue to meet enrollment criteria may then be dispensed 
single-blind placebo capsules (through IVRS or IWRS, refer to Section 5, Treatment 
Allocation) and enter the 2-week single-blind placebo run-in period. An assessment of 
the subjects’ adherence to protocol procedures during the run-in will be made at the end 
of the period, before randomization, and will provide investigators with an opportunity to 
assess subjects’ compliance with taking the single-blind study drug (by counting
capsules), and having a stable diet and exercise regimen. 
Subjects who do not meet all inclusion criteria or meet a study exclusion criterion based 
upon the results of the screening or run-in visit laboratory studies should be excluded 
from the study, and discontinue single-blind placebo. 
At the run-in visit and during the 2-week run-in period (ie, at additional visits as 
considered appropriate), investigators should evaluate CV risk factors (eg, blood 
pressure, and fasting lipid levels) and adjust therapies, if necessary (refer to Section 6.2.1, 
Management of Glycemic Control and CV Risk Factors). At the run-in visit (Week -2), 
subjects who continue to be eligible will be provided with a glucose meter and testing 
supplies and instructed on the performance of SMBG. In addition, a standard, 
protocol-specified diary will be provided to each subject. Subjects will also receive 
counseling regarding diet and exercise consistent with standard diabetes guidance 
recommendations (eg, ADA), and will be counseled regarding recognition and 
management of hypoglycemia, including recording of possible hypoglycemic events on 
the subject diary along with concurrent fingerstick glucose measurements. Subjects 
should be counseled by the study research personnel regarding the importance of good 
compliance with all study procedures throughout the study. 
9.1.3.
Double-Blind Treatment Phase 
Day 1/Day of Randomization
Potential subjects who return for the Day 1 (baseline), who have taken !80% of the 
scheduled single-blind placebo capsules during the run-in period, and who meet the 
enrollment criteria will be randomly assigned in a 1:1:1 ratio to once daily treatment with 
canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. Subjects will continue 
treatment until the study completes or the subject is prematurely withdrawn from 
double-blind study medication (refer to Section 10.2, Withdrawal From the Study, for 
reasons for withdrawal). 
In addition, pharmacogenomic informed consent will be obtained (only from those 
subjects who agree to participate in this component).
Visits Following Randomization
Subjects will be seen in the clinic at visits or contacted by telephone as described in 
Section 9.1.1, Overview, and in the Time and Events Schedule. Procedures and clinical 
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laboratory assessments for each visit or contact are outlined in the Time and Events 
Schedule.
Subjects who experience nonfatal events in the CV composite endpoint (ie, nonfatal MI, 
nonfatal stroke) during the double-blind treatment phase will continue in the study, 
continuing to receive double-blind study drug and complete all assessments at all 
scheduled visits, as appropriate.
9.1.4.
End-of-Treatment/Early Withdrawal
The end-of-treatment/early withdrawal evaluation
will be performed when the 
double-blind treatment phase of the study is ended or at the time the subject is withdrawn 
from the study. The evaluation should be performed as soon as possible after stopping the 
study drug. 
Refer to the Time and Events Schedule that follows the Synopsis for procedures at the 
End-of-Treatment/Early Withdrawal evaluation.
Subjects who prematurely discontinue double-blind treatment will have follow-up contact 
as described in Section 9.1.5, Posttreatment Phase (Follow-Up) and in the Posttreatment 
Time and Events Schedule. If it becomes no longer possible for a subject to continue to 
make site visits for posttreatment measurement of vital signs and laboratory specimen 
collection, the investigator may revert to telephone contacts (with the subject or, as a last 
resort, with relatives or a family physician) or other available medical records to assess 
and collect information regarding serious adverse events, CV events, and fractures on the 
timelines described in the Time and Events Schedule, and forego the clinic visits.
Alternately, at the investigator’s discretion, less frequent in-clinic visits may be 
interspersed with other forms of contact, including telephone, email, letters, social media 
sources, fax, or other electronic or non-electronic means.
9.1.5.
Posttreatment Phase (Follow-Up)
All subjects should have a follow-up telephone contact (or optional study visit, at the 
discretion of the investigator) (if a telephone contact or study visit is not possible, 
follow-up information may be collected via email or other electronic or non-electronic
means) approximately 30 days (but no more than 42 days) after the last dose of study 
drug to collect: 
–
Nonfatal CV events in the primary composite endpoint (nonfatal MI, nonfatal 
stroke) 
–
Death from any cause
–
Nonfatal serious adverse events
–
Adverse events of fracture
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Subjects who discontinue treatment early for any reason (other than withdrawal of 
consent for follow-up contacts) will be contacted according to the Posttreatment Time 
and Events Schedule (or more frequently if necessary based on the investigator’s 
knowledge of the subject) until completion of the overall study, with the goal of 
collecting any CV outcome events (ie, nonfatal events in the CV composite endpoint), 
deaths from any cause, adverse events of fracture, and any serious adverse events. 
Subjects who discontinue treatment less than 26 weeks before the completion of the study 
will be contacted by telephone at the end of the study to collect any of the events in the 
list above.
9.2.
Reporting/Adjudication of Events in the CV Composite Endpoint and 
Other Events for Adjudication
Investigators will be counseled to report any event that they assess as potentially being a 
component of the study CV composite endpoints: CV death, nonfatal MI, and nonfatal 
stroke. In addition, all deaths (to determine cause of death) as well as events of 
hospitalized heart failure, will be submitted for adjudication.
For events of hospitalized unstable angina, adjudication
will conclude with 
implementation of amendment INT-6. However, investigators will continue to report 
such events that are serious or that lead to study drug discontinuation on the eCRF.  
Investigators will complete a separate eCRF for potential events in the CV composite 
endpoints and must provide a specific package of information to be submitted for 
adjudication evaluation that will be provided in a procedural manual. An independent 
Endpoint Adjudication Committee will assess all events that could potentially contribute 
to the specified CV endpoints and only those events that the committee, using 
methodology defined in the committee’s charter, determines are prespecified endpoint 
events will be included in the analysis. The Endpoint Adjudication Committee will 
classify the outcome events while blinded to treatment assignment. The same Endpoint 
Adjudication Committee will adjudicate events from all of the studies that will contribute 
to the meta-analysis of the pooled large, well-controlled, randomized studies of 
canagliflozin (including CANVAS).
Note that events assessed by the investigator as an event in the CV composite endpoint, 
with the exception of CV death, should not be reported as adverse events/serious adverse 
events (refer to Section 12, Adverse Event Reporting). If the event is adjudicated by the 
Endpoint Adjudication Committee as not meeting the event definition, then the event 
should be reported as an adverse event/serious adverse event (with reporting timelines 
starting at the time of notification of this by the Endpoint Adjudication Committee).
With the implementation of INT-6, hospitalized unstable angina events should now be 
reported as adverse events/serious adverse events (see Section 9.4, Safety Evaluations).
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9.3.
Study Management: Committees 
9.3.1.
Academic Research Organization
An Academic Research Organization (ARO) will provide scientific and academic 
oversight of the study. The ARO will also have a role in site monitoring for a portion of 
the sites.
9.3.2.
Steering Committee
A Steering Committee, made up of external scientific experts will provide scientific 
advice regarding the study design, conduct, and data collection. The Steering Committee 
is responsible for providing input on study design, academic leadership to study sites, 
reviewing study progress, and reviewing study results before publication. Details of the 
composition, roles, and responsibilities will be documented in its charter. 
9.3.3.
Medical Safety Review Committee
An MSRC will be established to ensure that the safety of subjects participating in the 
study is not compromised. The MSRC will include, but will not be limited to, at least one 
medical expert and at least one statistician. The MSRC will include members from the 
sponsor organization and may include ARO representatives. The MSRC will monitor the 
progress of the study by reviewing blinded data on a regular basis and will refer safety 
concerns to the IDMC.
Details of the composition, roles, and responsibilities will be documented in its charter.
9.3.4.
Independent Data Monitoring Committee
An IDMC will be commissioned for this study to review accumulated, unblinded safety 
information during the study. Details of the composition, roles, and responsibilities will 
be documented in its charter. 
The IDMC will also have responsibility for review of the primary CV endpoints for this 
study as well as across the canagliflozin clinical development program. 
9.3.5.
Endpoint Adjudication Committee
An independent Endpoint Adjudication Committee composed of external specialists, 
blinded to treatment assignment, will be commissioned to review case information on 
potential MACE events. The operations, processes, and endpoint definitions to be 
employed by the committee will be defined in its charter.
9.4.
Safety Evaluations
Only serious adverse events, non-serious adverse events resulting in study drug 
discontinuation, and adverse events of interest (see below) will be recorded on eCRFs.
Safety and tolerability will include an evaluation of serious adverse events, adverse 
events of interest, discontinuation due to adverse events, clinical laboratory tests, vital 
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signs (pulse, blood pressure), and body weight. Cardiovascular safety will be assessed as 
part of the meta-analysis of CANVAS and CANVAS-R.
Refer to Section 9.2, Reporting/Adjudication of Events in the CV Composite Endpoint 
and Other Events for Adjudication, for reporting and adjudication of events in the CV 
composite endpoint.
Adverse Events of Interest
Adverse 
events 
of 
interest 
include: 
all 
malignancies, 
fatal 
pancreatitis, 
hemorrhagic/necrotizing pancreatitis, severe hypersensitivity reactions (eg, angioedema, 
anaphylaxis, Stevens-Johnson syndrome), photosensitivity reactions, serious adverse 
events of hepatic injury, nephrotoxicity/acute kidney injury, venous thromboembolic 
events, fractures, male genital infections (balanitis, phimosis, events leading to 
circumcision), and pregnancy. Information on these events will be recorded on 
supplemental eCRFs or other designated forms for any event that is serious or that leads 
to study drug discontinuation. In addition, non-serious adverse events of malignancies, 
photosensitivity reactions, fractures, venous thromboembolic events, male genital 
infections (balanitis, phimosis, events leading to circumcision), and amputations for 
which information on non-serious adverse events will also be recorded on the 
supplemental CRF pages or other designated forms (in addition to the information 
collected on serious AEs and AEs leading to study drug discontinuation). Diabetic 
ketoacidosis has been designated as an adverse event of special interest and therefore 
adverse events related to DKA, ketoacidosis, metabolic acidosis or acidosis need to be 
reported to the sponsor within 24 hours of becoming aware of the event, which is the 
same timeframe for reporting of serious adverse events. These adverse events must be 
reported using a supplemental DKA Reporting form, to complement standard information 
collected on the eCRF AE/SAE page. Amputation has also been designated as an adverse 
event of special interest and therefore amputations need to be reported to the sponsor
within 24 hours of becoming aware of the event. If adverse events of interest are 
identified in the future, guidance concerning the reporting of those events may be 
provided to investigators via appropriately-documented study communications. (see 
Table 1)
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Table 1:  Adverse Event Collection Requirements
Collect all (serious or non-serious):
Collect if serious or if adverse event causes 
discontinuation:
∃
Malignancies (especially renal cell 
cancer, pheochromocytoma, Leydig 
cell tumor)
∃
Photosensitivity 
∃
Venous thromboembolic events
∃
Fractures
∃
Male genital infections (balanitis 
phimosis, 
events 
leading 
to 
circumcision)
∃
Amputations
∃
Diabetic ketoacidosis
∃
Any pregnancy
∃
Fatal 
pancreatitis 
and 
hemorrhagic/necrotizing pancreatitis
∃
Severe 
hypersensitivity 
reactions 
(eg, 
angioedema, anaphylaxis, Stevens-Johnson 
syndrome)
∃
Serious adverse events of hepatic injury
∃
Nephrotoxicity/acute kidney injury
∃
Any other event
Detailed collection of information on serious adverse events of hypoglycemia or adverse 
events of hypoglycema that lead to study drug discontinuation will be performed on 
supplemental eCRFs. For selected specific adverse events (ie, vulvovaginal adverse 
events, superficial genital adverse events in men, and adverse events of urinary tract 
infection), investigators will be asked to provide additional information, on separate 
eCRFs, so as to support more detailed analyses for events that are serious or that lead to 
study drug discontinuation.  
All deaths will undergo adjudication by the Endpoint Adjudication Committee to 
determine cause of death and whether CV disease was a proximate or underlying cause.
Events with characteristics of DKA will be adjudicated by an ad hoc adjudication 
committee, to verify whether or not the event meets a specified definition of DKA. Other 
categories of events (eg, renal) may undergo adjudication as necessary based on 
regulatory agency requests or to supplement data analyses.
Adverse Events
Adverse events as noted above will be reported by the subject (or, when appropriate, by a 
caregiver, surrogate, or the subject’s legally-acceptable representative) for the duration of 
the study, beginning when the informed consent is signed. Adverse events will be 
followed by the investigator as specified in Section 12, Adverse Event Reporting. 
For purposes of reporting serious adverse events for this study, the components of 
the CV composite endpoints (with the exception of CV death) will not be considered 
adverse events or serious adverse events. Events in the CV composite endpoints will 
not be considered as unexpected but as disease-related, and as such will not be 
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unblinded. Refer to Section 12, Adverse Event Reporting, for details regarding the 
handling of components of the CV composite endpoints (note: hospitalized unstable 
angina, previously considered a component of the CV composite endpoint, will now be 
considered as a serious adverse event and should be recorded on the adverse 
event/serious adverse event eCRF page).  
Information for all adverse events will be collected in source documents (eg, progress 
notes) retained at the investigative sites. 
Follow-Up Collection of Safety Information
Any clinically significant abnormalities persisting at the time of end-of-treatment or early 
withdrawal will be followed by the investigator until resolution or until a clinically stable 
endpoint is reached, or until further follow-up is no longer considered by the investigator 
to be clinically meaningful. For details on the end-of-treatment or early withdrawal
evaluations, and posttreatment follow-up collection of information, see Section 9.1.4, 
End-of-Treatment/Early 
Withdrawal, 
and 
Section 9.1.5, 
Posttreatment 
Phase 
(Follow-Up).
Clinical Safety Laboratory Tests 
Subjects will be monitored with safety laboratory measurements (hematology, chemistry, 
and urinalysis [with urine glucose not measured to avoid unblinding]) as described in 
Attachment 6. 
In subjects with elevations in ALT !3-fold ULN, subjects will be monitored and 
managed using the algorithm in Attachment 7.
Alerts will be provided to investigators by the central laboratory identifying important 
laboratory changes or key out-of-range values, so the investigator can follow up as 
necessary. For creatine phosphokinase (CPK) elevations, the investigator should 
determine if follow-up evaluation is clinically appropriate to exclude a potential cardiac 
event. The review of such alerts should be documented by the investigator as soon as 
possible after receipt of the results.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the 
eCRF.
Urine samples from first morning void on day of designated visits will be collected for 
urine albumin and creatinine determinations. If the subject does not provide the morning 
void collection on the day of the visit, the subject may bring a first morning void 
specimen to the investigational site during the subsequent week. For subjects working a 
night shift, or who otherwise have atypical sleep patterns, the collection should be made 
at the end of the subject’s usual sleep period.
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The urine collections for exploratory analysis, as well as the routine urinalyses, should be 
obtained from a spot urine specimen in the clinic. 
Urine glucose will not be measured in the first morning void urine specimens or 
urinalyses. 
For SMBG monitoring during the study, see Section 6.2.1, Management of Glycemic 
Control and CV Risk Factors.
Vital Signs (pulse, blood pressure)
Vital signs will consist of pulse and blood pressure measurements and will be obtained 
after the subject has been in the sitting position for 5 minutes and before blood sample 
collection for laboratory tests. Pulse rate will be measured once at each clinic visit. Blood 
pressure will be assessed manually with a mercury sphygmomanometer, or a properly 
calibrated automated blood pressure monitor; if neither of these is available, a 
high-quality aneroid sphygmomanometer calibrated according to manufacturer 
specifications will be acceptable. Three consecutive blood pressure readings will be taken 
and recorded, at intervals of at least 1 minute apart, as specified in the Time and Events 
Schedule.
In addition, blood pressure will be measured 3 times in both arms at the screening visit; if 
there is a difference between arms of >10 mmHg in either the mean systolic or diastolic 
pressure, the arm with the higher pressure should be used to measure blood pressure and
should be used for all subsequent blood pressure measurements during the study. If 
possible, if blood pressure is measured manually, it should be measured by the same 
individual, using the same equipment, at each clinic visit to reduce variability.
Body Weight
Body weight will be measured using the same calibrated scale at each visit. The study 
center will be responsible for calibrating the scale before the first subject enrolled in the 
study at the site is weighed and then at approximately 12-week intervals during the study. 
Calibration must be documented in a calibration log. Subjects should be weighed at 
approximately the same time of day on the same scale, wearing underwear and a gown 
and without shoes (note: if disrobing for weighing is logistically impossible, the subject 
must be dressed as lightly as possible, with consistency from visit to visit); subjects will 
be asked to urinate before being weighed.
Urine Pregnancy Testing 
Serum or urine pregnancy tests may be performed in women (unless they are surgically 
sterile or unless there is a documented history of their postmenopausal status), as 
determined necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the study (refer to Section 12.2.3, Pregnancy, for 
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instructions in cases of a positive pregnancy test). Supplies for urine and serum 
pregnancy testing will be provided by the central laboratory, where possible.
9.5.
Measures of Efficacy/Efficacy Endpoints
The primary measure of efficacy is the HR of the composite endpoint of MACE (CV 
death, nonfatal MI, nonfatal stroke). Secondary measures of efficacy include beta-cell 
function (HOMA-B; in subjects who are not receiving insulin) and progression of 
albuminuria (based upon categories determined by urinary albumin/creatinine ratio).
The primary efficacy endpoint, the hypothesis of CV benefit for canagliflozin, will be 
evaluated based upon the events in the CV composite endpoint of MACE (CV death, 
nonfatal MI, nonfatal stroke). As previously described, an independent Endpoint 
Adjudication Committee will assess all events that could potentially be in the specified 
CV endpoint and only those events where the committee, using methodology and 
definitions defined in the committee’s charter, determines a specified endpoint has 
occurred will be included in the analysis. The independent Endpoint Adjudication 
Committee (refer to Section 9.3.5) will apply the endpoint definitions contained in its 
charter and classify the outcome events while blinded to treatment assignment.
The secondary efficacy endpoint of change in HOMA-B will be assessed in a subset of 
subjects (approximately 1,200 subjects at sites that elect to participate) who are not 
receiving insulin at baseline. Homeostasis model assessment-B will be assessed based 
upon C-peptide and fasting glucose; for subjects who initiate therapy with insulin during 
the study, data from the last proinsulin, insulin, and C-peptide measurement before 
initiation of insulin will be utilized for beta-cell function analyses. 
The categorical secondary efficacy endpoint of the proportion of subjects with 
progression of albuminuria (defined as !1 step increase in category [as defined below] of 
albuminuria [ie, none to micro- or macro-, or micro- to macroalbuminuria]) will be 
assessed from first morning void urine collections according to the categorizations 
defined in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
Guideline #1 (KDOQI 2007). The definition of micro-albuminuria is albumin/creatinine 
ratio of 30 to 300 mg/g and the definition of macro-albuminuria is albumin/creatinine 
ratio greater than 300 mg/g. 
Additional efficacy endpoints of interest will include the following: changes from 
baseline to end-of-treatment in the proinsulin/insulin ratio (in a subset of subjects), 
urinary albumin/creatinine ratio, and eGFR; changes from baseline to Week 18 in HbA1c, 
FPG, systolic and diastolic blood pressure, and body weight; and percent change from 
baseline to Week 18 in fasting plasma lipids (triglycerides, HDL-C, LDL-C, total 
cholesterol, and the ratio of LDL-C to HDL-C). The eGFR will be calculated using the 
Modification of Diet in Renal Disease [MDRD] equation (Levey 2006).
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Refer to Section 11.5, CV Outcomes and Efficacy Analyses, for the evaluation of 
efficacy criteria.
9.6.
Pharmacogenomic Evaluations 
There are 2 parts to the pharmacogenomic component of this study.
Analysis Related to the Study (Part 1)
Part 1 of pharmacogenomic research allows for the analysis of genes that may be relevant 
to help to better understand canagliflozin, or T2DM or obesity. Candidate genes will only 
be genotyped, if it is hypothesized that this may help resolve issues with the clinical data. 
Analyses may involve the analysis of known candidate genes or the analysis of genetic 
variants throughout the genome (genome-wide association analysis), both in relation to 
canagliflozin, or T2DM or obesity (provided in Attachment 8). Genotyping of any of 
these candidate genes would be performed on identifiable samples.
Additional genes may be analyzed on identifiable samples if these genes are hypothesized 
to be relevant to canagliflozin, or T2DM or obesity between the time that the clinical 
protocol has been issued and the samples have been made nonidentifiable.
DNA Storage for Future Research (Part 2)
Part 2 of the pharmacogenomic research allows for the storage of DNA samples for 
future genetic research related to canagliflozin or the indication(s) for which it is 
developed. Stored DNA samples and relevant clinical data will be made nonidentifiable 
after the Clinical Study Report has been issued. This involves removing personal 
identifiers and replacing the study subject identifier with a new number to limit the 
possibility of linking genetic data to a subject’s identity. 
Subjects will be given the option to participate in Part 1 only, Part 2 only, both parts, or 
neither part of the pharmacogenomic component of this study (where local regulations 
permit).
9.7.
Exploratory Evaluations
A set of fasting plasma, serum, and urine samples will be collected (where local 
regulations permit) at the time points specified in the Time and Events Schedule for the 
following:
∃
exploratory analysis that may be done to provide insight into the actions of 
canagliflozin or assist in understanding of adverse events possibly associated with the 
compound. Samples may also be used for future exploratory research to improve 
understanding of the pathophysiology of T2DM or obesity or to assess other 
pharmacodynamic effects of canagliflozin, and
∃
to develop biomarkers that may provide further understanding regarding the risk of 
development of diabetes-related complications. 
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This exploratory evaluation is optional and will only be performed in subjects who give 
informed consent for this specific component of the study.
9.8.
Medical Resource Utilization
Subjects will be requested to collect information in a protocol-specified diary on 
information related to their utilization of medical resources (see Attachment 9). This 
MRU data from the subject diaries will then be documented in the eCRF by the 
investigator and study research staff for all subjects at each visit throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses.
No cost data will be collected in this study.
10.SUBJECT COMPLETION/WITHDRAWAL
10.1. Completion
A subject will be considered to have completed the study if he or she has experienced a 
clinical endpoint that precludes further study (eg, early mortality due to CV event) or 
when the study ends. Note that occurrence of a nonfatal event in the CV composite 
endpoint (ie, nonfatal MI, nonfatal stroke) is not a study withdrawal criteria. Subjects 
with these events should be continued in the study, on study drug, unless they meet a 
study withdrawal criterion (see Section 10.2, Withdrawal From the Study). Subjects who 
prematurely discontinue study treatment for any reason before completion of the 
double-blind treatment phase will not be considered to have completed the study.
10.2. Withdrawal From Study Drug
A subject will be withdrawn from the study drug for any of the following reasons:
∃
Lost to follow-up 
∃
Withdrawal of consent (subject withdrew consent for treatment and refuses any 
further follow-up)
∃
Subject is persistently in poor compliance with study treatment or procedures
∃
The investigator believes that for safety or tolerability reasons (eg, an adverse event) 
it is in the best interest of the subject to stop treatment
∃
The subject becomes pregnant (study therapy should be immediately discontinued 
based upon a positive urinary hCG, and permanently discontinued if confirmed by a 
serum ∋-hCG test)
∃
The subject’s eGFR is <15 mL/min/1.73m2 (as reported by the central laboratory). 
Note: the central laboratory will alert the investigator for eGFR values 
<15 mL/min/1.73m2. A repeat determination should be performed within 2 weeks,
and study treatment discontinued if the repeat eGFR is <15 mL/min/1.73m2 (unless a 
reversible cause is identified [eg, short-term illness or transient volume depletion] in 
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which case an additional repeat determination can be performed after resolution of the 
short-term illness). 
∃
Subject requires dialysis or renal transplantation
∃
Subject has liver function test abnormalities meeting criteria for permanent 
discontinuation of study drug as outlined in Attachment 7
∃
The investigator formally unblinds the subject’s treatment allocation
∃
Subject initiates disallowed therapy (refer to Section 8, Prestudy and Concomitant 
Therapy)
∃
The subject experiences a serious adverse event of biochemically-confirmed (eg, pH, 
serum ketones, anion gap) DKA.
The end-of-treatment evaluations should be performed as soon as possible after stopping 
the study drug (see Section 9.1.4, End-of-Treatment/Early Withdrawal, and the Time and 
Events Schedule that follows the Synopsis for procedures to be performed). For 
posttreatment follow-up contacts, refer to Section 9.1.5, Posttreatment Phase (Follow-up).
Subjects who decide to withdraw from double-blind study drug must be interviewed by 
the investigator so as to determine if a specific reason for withdrawal can be identified. If 
the subject elects to withdraw due to an adverse event, the event should be recorded as 
the reason for withdrawal, even if the investigator’s assessment is that the adverse event 
would not require study drug withdrawal.
When a subject withdraws from double-blind study drug before completing the study, the 
reason for withdrawal is to be documented in the eCRF and in the source documentation. 
Study drug assigned to the withdrawn subject may not be assigned to another subject. 
Subjects who withdraw will not be replaced.
A subject who elects to withdraw consent for the biomarker specimen collections will not 
have further collections made after withdrawing consent, and has the following options:
∃
to allow the previously collected specimens to remain for biomarker analysis, or
∃
to request that the previously collected specimens be destroyed.
A subject who withdraws from the main part of the study will have the following options 
regarding pharmacogenomic research:
∃
The DNA extracted from the subject's blood will be retained and used in accordance 
with the subject's original pharmacogenomic informed consent.
∃
The subject may withdraw consent for pharmacogenomic research, in which case the 
DNA sample will be destroyed and no further testing will take place. To initiate the 
sample destruction process, the investigator must notify the sponsor site contact to 
request sample destruction. The sponsor site contact will, in turn, contact the 
pharmacogenomics representative to execute sample destruction. If requested, the 
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investigator will receive written confirmation from the sponsor that the sample has 
been destroyed.
Withdrawal from Pharmacogenomic Research Only
The subject may withdraw consent for pharmacogenomic research while remaining in the 
clinical study. In such a case, any DNA extracted from the subject’s blood will be 
destroyed. The sample destruction process will proceed as described above. However, all 
samples will be made nonidentifiable after the Clinical Study Report is issued and 
thereafter cannot be identified for destruction. If the sample has already undergone 
conversion to the nonidentifiable format, the sponsor will notify the investigator in 
writing.
10.3. Reinstitution of Subjects Who Have Prematurely Discontinued 
Double-Blind Study Drug to Active Status
Subjects for whom study drug is interrupted as a result of an adverse event, a life event 
(eg, temporary relocation to care for an ill family member), or other unforeseen 
circumstance may return to active status (ie, re-start double-blind study drug) in the study 
at the discretion of the investigator, with concurrence from the sponsor’s medical 
monitor, even if previously withdrawn from the study or off study drug for up to 90 days. 
Subjects off study drug for more than 90 days, or subjects who meet the conditions that 
require withdrawal (eg, unblinding), should not be returned to active status. If the subject 
had previously withdrawn consent but decides to retract that withdrawal, the subject will 
be reconsented. The investigator will be responsible for making all required notifications 
to the IRB or Ethical Committee.
10.4. Measures to Re-establish Contact in Subjects Lost to Follow-up
If a subject is lost to follow-up, all possible efforts must be made by the study site 
personnel to contact the subject and to determine endpoint status and the reason for 
discontinuation/withdrawal. The measures taken to follow-up must be documented. 
The informed consent form will stipulate that even if a subject decides to discontinue 
double-blind study drug, he/she will agree to be contacted periodically by the investigator 
to assess his/her endpoint status (refer to the Posttreatment Time and Events Schedule for 
subjects that prematurely discontinue double-blind study drug). Furthermore, the subject 
will be asked to agree to grant permission for the investigator to consult family members, 
the subject’s physicians and medical records, or public records, including the use of 
locator agencies as permitted by local law, to determine the subject’s endpoint status, in 
the event the subject is not reachable by conventional means (eg, office visit, telephone, 
email, or certified mail). The subject is informed that if the site of the study doctor closes, 
and the study doctor cannot reach the subject to inform him/her, the contact information 
will be transferred to another site where a new study doctor will consult with family 
members, the subject’s physicians and medical records, or public records, including the 
use of locator agencies as permitted by local law, to determine the subject’s endpoint 
status.
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11.STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy and safety 
data is outlined below. Specific details will be provided in the SAP. 
11.1. Analysis Sets
The ITT analysis set includes all subjects who are randomly assigned to a treatment 
group. The assessment of the primary objective will be based upon this analysis set. The 
primary CV analysis will be based on the time to the first occurrence of any component 
of the CV composite endpoint.
The modified intent-to-treat (mITT) analysis set includes randomized subjects who 
receive at least one dose of study drug and their data occurring between first dose and last 
dose plus 30 days.  
The alignment of the analysis of the secondary endpoints with the ITT and mITT analysis 
sets will be detailed in the study SAP.
11.2. Handling of Dose in Analysis
The primary comparison, to assess CV risk reduction, will be between canagliflozin 
(100 and 300 mg groups combined) versus placebo. Additionally, the HR and its 2-sided 
95% CIs versus placebo will be assessed for each dose of canagliflozin. 
11.3. Sample Size Determination
The sample size for the recruitment of the initial 4,500 subjects was based upon having a 
sufficient number of participants to support, in concert with the other controlled clinical 
trials in the canagliflozin development program, a detailed pre-approval assessment of the 
safety and tolerability of canagliflozin. Data from this initial cohort were exported and 
integrated with data from other Phase 3 well-controlled studies to support a planned 
pre-approval meta-analysis to demonstrate that the upper bound of the 2-sided 95% CI 
for the CV HR of canagliflozin relative to control in composite endpoint events (MACE 
and hospitalized unstable angina) was <1.8; the current US regulatory requirements for 
filing. The FDA post-marketing requirements for canagliflozin demand a subsequent 
estimate of CV safety that will be performed on data from CANVAS and CANVAS-R, 
when sufficient events have occurred to demonstrate that the upper bound of  the 95% CI
HR is <1.3 based on MACE (excluding hospitalized unstable angina).
The assumed per annum event rate is 2.25% and the per annum dropout rate is 5%. With 
an enrollment period 1.5 years, 4,500 randomized subjects were projected to contribute 
sufficient CV events to support the pre-approval CV meta-analysis.
The original phased recruitment strategy allowed for an interim assessment of study 
feasibility to demonstrate the primary hypothesis of CV benefit using the results of the 
interim analysis. Results from the interim analysis (conducted after approximately 2 to
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4 years from study initiation, eg, at approximately the time of US regulatory approval) 
were planned to be evaluated by a CV risk factor evaluation committee to assess the 
effect of canagliflozin on CV risk factors (to predict the likely effect of canagliflozin on 
CV events) and determine the point estimate for the HR for MACE. The data on the 
observed point estimate for the CV HR for MACE were to have been reviewed by the 
IDMC only and would not have been made more broadly available. Re-opening of 
enrollment was to have proceeded if the effects on the intermediate outcomes (ie, CV risk 
factors) as determined by appropriate models (to be prespecified before the interim 
analysis) that canagliflozin compared to placebo would result in an HR of 0.85 or less 
(for MACE) and if the observed HR (for MACE) is 0.95 or less. If recruitment did 
proceed, an additional 14,000 subjects would have been enrolled into Cohort B.
However, for the reason outlined above (see Section 3), this second cohort will no longer 
be recruited.
Without the recruitment of the second cohort of 14,000 subjects, CANVAS study power 
is reduced from the originally planned 90% power to detect a HR of 0.85 or less. It is 
now projected that at the completion of the study there will be about 400 MACE events 
recorded within CANVAS, which will provide 33% power to detect a HR of 0.85 or less, 
55% power to detect a HR of 0.80 or less, and 76% power to detect a HR of 0.75 or less 
using a 2-sided test with 0.05 alpha.
11.4. Safety Analyses
The safety analysis will be based on the mITT analysis set. The mITT analysis set 
includes all subjects who are randomly assigned to a treatment group and have received 
at least one dose of study drug and their data occurring between first dose and last dose 
plus 30 days. There will be no imputation for missing values for clinical laboratory test 
results or vital sign measurements in the analyses.
Safety and tolerability will be evaluated by summarizing and comparing the incidence of 
serious adverse events and adverse events of interest, discontinuation rate due to adverse 
events, clinically important changes in clinical laboratory tests, vital signs (pulse, blood 
pressure), and body weight between randomized groups. There will be no imputation for 
missing values for clinical laboratory test results or vital sign measurements in the 
analyses.
Adverse Events
The verbatim terms used in the eCRFs by investigators to identify adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported 
serious adverse events, adverse events resulting in study drug discontinuation, and 
adverse events of interest with onset during the treatment phase (ie, treatment-emergent 
adverse events) will be included in the analysis. For each adverse event, the percentage of 
subjects who experienced at least one occurrence of the given event will be summarized 
by treatment group. An adverse event will be considered to be a treatment-emergent 
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event if it occurs within 30 days of the last date of blinded study medication. The 
percentage of subjects with specific treatment-emergent adverse events will be 
summarized by severity and relationship to study drug, as classified by the investigators, 
for each treatment group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for 
those subjects who die, who discontinue treatment due to an adverse event, who 
experience a serious adverse event, or who experience an adverse event of interest.
Further analyses, described in the SAP for this study, will be conducted on the 
prespecified adverse events for which additional information is collected from the 
investigators (refer to Section 9.4, Safety Evaluations).
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Normal reference ranges 
will be provided. Criteria for markedly abnormal laboratory values will be prespecified in 
the SAP. The percentage of subjects with markedly abnormal results will be summarized
for each laboratory analyte. Descriptive statistics will be reported for each laboratory 
analyte at baseline and at each scheduled time point and for change from baseline.
Vital Signs
Descriptive statistics for pulse and sitting blood pressure (systolic and diastolic) values 
and changes from baseline will be summarized at each scheduled time point. The 
percentage of subjects with values beyond clinically important limits will be summarized.
11.5. CV Outcomes and Efficacy Analyses 
11.5.1.
CV Outcomes (Primary Efficacy Endpoint)
The primary endpoint for CV benefit will be time to MACE, which is calculated as the 
time from randomization to the first occurrence of MACE. The statistical hypothesis will 
be: 
H0(1.0): the HR =1.0, versus H1(1.0): the HR ≠1.0.
The primary analysis will be based on the ITT analysis set and the MACE events
determined by the EAC to meet prespecified criteria. The primary comparison of 
canagliflozin to placebo will be based on the HR estimate derived from Cox proportional 
hazards model with terms for treatment, history of a previous CV event as fixed effects.
The assumption of the proportional HR will be examined. In case the assumption is 
deemed not reasonable, sensitivity analyses that do not rely on the constant HR 
assumption will be conducted to verify the results of the primary analysis. 
Additionally, the HR and its 2-sided 95% CIs versus placebo will be assessed for each 
dose of canagliflozin. For individual components of the composite CV endpoint, the HR 
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and its 2-sided 95% CIs of canagliflozin combined doses relative to placebo will also be 
assessed.
Sensitivity analyses including CV endpoint events that occur within 30 days of the last 
dose of blinded study medication will be done.
The effects of different baseline demographic variables (eg, age, race, sex) as well as 
other important baseline disease characteristics (eg, history of prior CV disease, key 
concomitant therapy use, and region) on the primary endpoint will be explored; a detailed 
discussion of subgroup analyses will be provided in a SAP for this study, which will be 
finalized before the first interim analysis.
11.5.2.
Major Secondary Efficacy Endpoints
The continuous secondary efficacy endpoint, change from baseline in HOMA-B will be 
analyzed using an analysis of covariance (ANCOVA) model with treatment
(canagliflozin 100 mg, canagliflozin 300 mg or placebo) and stratification factors as fixed 
effects and the corresponding baseline value as a covariate. The treatment difference 
(each dose of canagliflozin minus placebo) in the least-squares means and the 2-sided 
95% CI will be estimated based on this model. The analyses for beta-cell function will be 
conducted on subjects not receiving insulin at randomization and, for subjects who are 
started on insulin during the study, the last data point before the initiation of insulin will 
be included for these analyses. 
The categorical secondary efficacy endpoint is the proportion of subjects with 
progression of albuminuria (defined as !1 step increase, ie, no albuminuria to micro- or 
macro-albuminuria or from micro-albuminuria to macro-albuminuria). The proportion of 
subjects with progression of albuminuria will be analyzed using the logistic model with 
treatment (canagliflozin 100 mg, canagliflozin 300 mg or placebo), and stratification 
factors as a fixed effect. Albuminuria will be assessed according to the categorizations 
defined in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
Guideline #1 (KDOQI 2007): the definition of micro-albuminuria is albumin/creatinine 
ratio of 30 to 300 mg/g, and the definition of macro-albuminuria is albumin/creatinine 
ratio greater than 300 mg/g. 
For the secondary endpoints of HOMA-B and proportion of subjects with progression of 
albuminuria, the analyses will compare the dose groups, combined and individually,
relative to placebo.
11.5.3.
Multiplicity Adjustment
To ensure the family-wise Type I error rate (alpha level) in this study is at most 5%, a 
gatekeeping procedure will be applied in testing the primary and secondary hypotheses. 
The superiority of the canagliflozin combined doses over placebo in time to MACE will 
be tested first. If statistically significant, the procedure will proceed to test the secondary 
endpoints of the proportion of subjects with progression of albuminuria and HOMA-B for 
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each canagliflozin dose versus placebo. Details of the gatekeeping procedure will be 
contained in the SAP.
11.5.4.
Additional Secondary Efficacy Endpoints
Additional efficacy endpoints of interest will include the following: 
∃
changes from baseline to end-of-treatment in the proinsulin/insulin ratio (in a subset 
of subjects), urinary albumin/creatinine ratio, and eGFR 
∃
changes from baseline to Week 18 in HbA1c, FPG, systolic and diastolic blood 
pressure, and body weight
∃
percent change from baseline to Week 18 in fasting plasma lipids (triglycerides, 
HDL-C, LDL-C, total cholesterol, and the ratio of LDL-C to HDL-C)
The continuous secondary efficacy endpoints, changes from baseline in the 
proinsulin/insulin ratio, HbA1c, FPG, body weight, blood pressure, albuminuria, and 
eGFR and percent change in fasting lipids will be analyzed in the same manner as the 
secondary efficacy endpoint, change from baseline in HOMA-B.
For the assessment of change from baseline in HbA1c at Week 18, subgroup analyses 
(described in detail in the SAP for this study) will be conducted to enhance understanding 
of factors that might impact glycemic response to canagliflozin.
11.6. Medical Resource Utilization Analyses
Medical Resource Utilization data analyses will be descriptively summarized by primary 
outcome variable (ie, those with a CV event versus those without) regardless of treatment 
group. These data may be used in future economic modeling to be done outside of the 
protocol.
11.7. Interim Analyses of CANVAS
11.7.1.
Interim Analyses for Health Authority Submissions
Interim analyses of CANVAS will be done to prepare: (1) an interim safety report in 
support of the initial health authority filing, (2) the 18-week substudy reports, and (3) the 
CV safety meta-analyses (based on adjudicated data). The interim data from the 
CANVAS study will primarily supplement the safety and tolerability data generated from 
other studies in the canagliflozin development program.
11.8. Meta-Analysis to Support Regulatory Requirements
11.8.1.
Meta-Analysis Pre-Regulatory Approval 
To support submissions for marketing approval, the CV event data and other safety and 
efficacy results in this study will be exported and integrated with the data from other 
large, well-controlled, double-blind, randomized studies in the canagliflozin clinical 
development program. A meta-analysis of the integrated CV data will be conducted to 
compare canagliflozin with active or placebo control (eg, current FDA guidance requires 
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exclusion of the upper bound of the 2-sided 95% CI around the HR of 1.8 or greater). It is 
projected that the meta-analysis to support regulatory approval would be conducted when 
an approximate range of 140 to 160 composite events of MACE (CV death, nonfatal MI, 
nonfatal stroke) and hospitalized unstable angina are observed across the canagliflozin 
clinical development program (including CANVAS). In no case would a meta-analysis to 
support regulatory approval occur with fewer than 80 events. Note that the primary 
composite endpoint to show CV risk reduction in the present study includes MACE, 
while the pre-approval meta-analysis to rule out harm utilizes a composite endpoint that 
includes MACE plus hospitalized unstable angina.
If the meta-analysis occurs with 140 to 160 events, 30 to 40 are expected to be observed 
in the other large, well-controlled, double-blind, randomized studies that will be included 
in the meta-analysis and 110 to 120 observed from the CANVAS study. 
Sponsor personnel will be unblinded to the data during the submission of data from this 
analysis; however, blinding to the subject’s treatment allocation will be maintained for 
the 
subjects, 
investigators, 
Endpoint 
Adjudication 
Committee, 
and 
sponsor 
site-monitoring personnel throughout the study. In order to maintain data integrity with 
respect to endpoint adjudication, individuals within the sponsor responsible for 
submitting events to the Endpoint Adjudication Committee will handle the review and 
submission of adjudication packages in a completely blinded fashion.
The meta-analysis will be the subject of a separate SAP in which the objectives, 
hypotheses, and analytic strategy are described.
11.8.2.
Meta-Analysis Post-Regulatory Approval
To meet US regulatory requirements post-approval (refer to Section 1.2, Overall 
Rationale and Goals for the Study), results from this study will be exported and 
integrated with results from CANVAS-R to demonstrate that the upper bound of the 95% 
CI around the HR for important CV events (MACE) is <1.3. The primary objective of the 
CANVAS-R study is to evaluate the effects of canagliflozin relative to placebo on 
albuminuria progression. The CANVAS and CANVAS-R studies will share similar 
inclusion and exclusion criteria and will enroll similar patient populations. Both studies 
will require a standardized collection and evaluation of MACE endpoint events by the 
same Endpoint Adjudication Committee (see Section 9.3.5). 
A CV meta-analysis was conducted with 201 MACE plus events. The pre-approval 
condition was met by demonstrating that the upper bound of the 2-sided 95% CI for the 
HR was <1.8. The post-approval condition for the exclusion of HR of 1.3 was then tested 
with 0.001 alpha, and was not met.
As part of the post-approval CV safety requirement, a meta-analysis based on the data 
from this study and the data from another large-scale study, CANVAS-R, will be
conducted when at least 688 MACE events are accumulated in the 2 studies, which is 
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projected to occur prior to April 2017. With at least 688 MACE events, the power to 
show the HR <1.3 is about 90% with a 2-sided significance level of 0.05.
The ‘Statistical Analysis Plan for the Post-Marketing Requirement for the CV Risk 
Assessment of Canagliflozin (CANVAS and CANVAS-R)’ was finalized and submitted 
to FDA.  
11.9. Glycemic Efficacy Substudies 
11.9.1.
Analysis Sets
The mITT analysis set includes all subjects who are randomly assigned to a treatment 
group and received at least one dose of study medication. The per-protocol (PP) analysis 
set will consist of all mITT subjects who completed 18 weeks of treatment, and have no 
protocol deviations that may affect the interpretation of the primary efficacy endpoint (to 
be defined in the SAP before database lock and unblinding of the treatment groups) and 
have not received glycemic rescue therapy. The primary efficacy analysis will be based 
on the mITT set. The efficacy data measured after the initiation of rescue therapy will be 
treated as missing. Analysis based on the PP set will also be conducted as a sensitivity 
analysis.
Efficacy data will be analyzed according to the randomization assignment, regardless of 
actual treatment received. Safety data will be analyzed according to actual treatment 
received. The approaches to handle study treatment deviations will be detailed in the 
SAP.
11.9.2.
Sample Size Determination
The primary objectives of the substudies are to compare the HbA1c-lowering efficacy of 
canagliflozin with placebo after 18 weeks of treatment, in subjects on specific AHAs.
With the exception of the sulfonylurea substudy, assuming a group difference of 0.50% 
and a common SD of 1.0% with respect to change in HbA1c, and using a 2-sample, 
2-sided t-test with Type I error rate of 0.05, it is estimated that 258 randomized subjects 
(86 subjects in each of the 3 treatment groups) would provide 90% power.
Recently published literature with another SGLT2 inhibitor (Strojek 2010) suggest that 
the observed standard deviation with respect to HbA1c change from baseline in subjects 
taking sulfonylureas is less than originally anticipated in the protocol (ie, SD was 
reported to be 0.75% instead of 1.0%). These new data would allow for an assessment of 
the primary substudy endpoint (ie, change in HbA1c from baseline) in the sulfonylurea 
substudy using a smaller sample size in this substudy, ie, 150 randomized subjects 
(50 subjects in each of the 3 treatment groups) would provide 90% power. 
11.9.3.
Efficacy Analyses
For each substudy, except the sulfonylurea substudy as noted above, the primary efficacy 
analysis will only be performed when sufficient subjects (!258) in the subpopulation are 
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randomized in each of the 3 treatment groups (!86 per group). The analysis will be 
conducted when the sponsor prepares for the regulatory submissions. For the sulfonylurea 
substudy, the primary efficacy analysis will only be performed when sufficient subjects 
(!150) in the subpopulation are randomized in each of the 3 treatment groups (!50 per 
group).
The primary efficacy endpoint will be the change in HbA1c from baseline through 
Week 18. The LOCF method will be applied when the Week 18 values are missing. In 
subjects receiving rescue therapy, their measurements made before rescue will be used as 
the last observation. An ANCOVA model with treatment as a fixed effect and the
corresponding baseline value as covariate will be used. The treatment difference (each 
dose of canagliflozin minus placebo) in the least-squares means and the 2-sided 95% CI 
will be estimated based on this model. 
As a supportive analysis, change from baseline in HbA1c will be analyzed using a 
restricted maximum likelihood (REML) based on repeated measures approach. The 
analysis will be based on observed data and will include the fixed, categorical effects of 
treatment, visit, and treatment-by-visit interaction, as well as the continuous, fixed 
covariates of baseline and baseline-by-visit interaction. An unstructured covariance will 
be used to model the within-subject errors. The treatment comparisons will be made 
between each dose of canagliflozin and placebo at Week 18 and significance tests will be 
based on the difference of the least-squares means.
The secondary efficacy evaluations of change in body weight, FPG, and systolic and 
diastolic blood pressure, and percent change in fasting plasma lipids will be analyzed 
using an ANCOVA model similar to that used in the primary efficacy analysis. The 
percentage of subjects with HbA1c <7% at Week 18 will be assessed by means of a 
logistic model with treatment and stratification factors as fixed effects and baseline 
HbA1c as a covariate.
11.9.4.
Multiplicity Adjustment
To ensure the family-wise Type I error rate (alpha level) in each substudy is at most 5%, 
a gatekeeping procedure will be applied in testing the hypotheses in the substudy. The 
superiority over placebo in HbA1c reduction will be tested sequentially for the descending 
doses of canagliflozin. After the superiority of the 2 doses on HbA1c is concluded, the 
hypothesis of the secondary endpoints will be tested via 2 testing sequences as illustrated 
in Figure 3. The alpha level will be split evenly for the 2 sequences.
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Figure 3:  Testing Sequences for Substudy Secondary Efficacy Endpoints
300 mg superiority vs. placebo
in HbA1c reduction
100 mg superiority vs. placebo
in HbA1c reduction
300 mg superiority vs. placebo
in body weight reduction
100 mg superiority vs. placebo
in body weight reduction
300 mg superiority vs. placebo
in FPG reduction
100 mg superiority vs. placebo
in FPG reduction
300 mg superiority vs. placebo
in proportion (HbA1c <7%)
100 mg superiority vs. placebo
in proportion (HbA1c <7%)
300 mg superiority vs. placebo
in systolic blood pressure
100 mg superiority vs. placebo
in systolic blood pressure
300 mg superiority vs. placebo
in HDL-C and triglycerides
100 mg superiority vs. placebo
in HDL-C and triglycerides
Testing in each sequence stops as soon as any hypothesis in the sequence is failed to be 
rejected. The Hochberg procedure will be applied for the 2 lipid parameters at the end of 
the testing sequence. Note that the alpha level in the main study and the alpha level in 
each substudy are separately controlled.
11.9.5.
Safety Analyses
The safety analysis for the substudies will follow the methodology as outlined in 
Section 11.4, Safety Analyses.
12.ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of subjects, investigators, and the sponsor, and are 
mandated by regulatory agencies worldwide. The sponsor has established Standard 
Operating Procedures (SOPs) in conformity with regulatory requirements worldwide to 
ensure appropriate reporting of safety information; all clinical studies conducted by the 
sponsor or its affiliates will be conducted in accordance with those procedures.
All deaths and events that are assessed by the investigator as being one of the 
components of the CV composite endpoints* (ie, CV deaths, nonfatal MI, nonfatal 
stroke) should be handled as follows:
∃
Events in the CV composite endpoints will be captured on an eCRF page specifically 
designed to record endpoint events (note: hospitalized unstable angina events which 
were previously recorded on the CV eCRF page will now be recorded on the AE/SAE 
eCRF page) (note: with the implementation of INT-6, hospitalized unstable angina is 
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no longer part of the CV safety composite endpoint and should now be recorded on 
the adverse event/serious adverse event eCRF page. This type of event will no longer 
undergo adjudication as discussed in Section 9.2, Reporting/Adjudication of Events in 
the CV Composite Endpoint and Other Events for Adjudication).   
∃
Because these events in the CV composite endpoint are not unexpected in this high 
CV risk population (and are considered part of the natural history of the disease), 
these events, with the exception of CV deaths (and hospitalized unstable angina), will 
not be reported (or recorded) as adverse events (ie, not recorded in the adverse event 
or serious adverse event eCRF page). 
∃
All deaths, including CV deaths, will be reported as serious adverse events, and 
submitted for adjudication to the Endpoint Adjudication Committee. These events 
will be subject to expedited reporting to health authorities by the sponsor, but will not 
be subject to unblinding (unless it is determined by the Adjudication Committee that 
the death was non-CV related).
*Note that for the study primary hypothesis of CV benefit, the post-approval CV composite 
endpoint includes MACE (CV death, nonfatal MI, nonfatal stroke); the composite endpoint to 
assess pre-approval CV safety (as part of a meta-analysis of events from pooled large, 
well-controlled, randomized studies including CANVAS to assess CV safety) includes 
MACE plus hospitalized unstable angina (refer to Section 3.2, Study Design Rationale).
∃
Events that are initially reported by the investigator as a study endpoint event, but 
which are determined by the Endpoint Adjudication Committee as not meeting the 
definition of a study endpoint, will be reported as an adverse event or a serious 
adverse event upon the sponsor’s receipt of this determination by the Endpoint 
Adjudication Committee (with the sponsor reporting timeline starting from the time 
of notification by the Adjudication Committee). Such serious adverse events will be 
handled as per serious adverse event reporting guidelines, when the sponsor is 
notified by the Endpoint Adjudication Committee. The sponsor will notify the 
investigator to immediately report the event as a serious adverse event.
∃
Nonfatal CV events in the composite endpoint that, due to a reporting error or other 
reason, are initially classified as a serious adverse event, but which are subsequently 
determined by the Endpoint Adjudication Committee as meeting the definition of a 
study endpoint, will be reviewed on an individual basis by the sponsor regarding 
whether the case should be recorded only on the specific endpoint eCRF page and
removed from the database as an adverse event or serious adverse event; clear and 
appropriate documentation of any changes will be maintained.
Deaths or events with an outcome of death will be reported as outcome events if within 
the composite (ie, if considered a CV death) and the cause of death will also be reported 
as a serious adverse event (and hence managed per serious adverse event reporting 
guidelines).
Investigators may also be asked to provide additional information on other adverse 
events, based upon review by the MSRC or the study IDMC (refer to Sections 9.3.3, 
Medical Safety Review Committee, and 9.3.4, Independent Data Monitoring Committee). 
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Refer to Section 9.4, Safety Evaluations, for additional information on the adverse events
of interest.
12.1. Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse 
event does not necessarily have a causal relationship with the treatment. An adverse event 
can therefore be any unfavorable and unintended sign (including an abnormal finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational or 
non-investigational) product, whether or not related to that medicinal (investigational or 
non-investigational) product. (Definition per International Conference on Harmonisation 
[ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities.
Note: The sponsor collects adverse events starting with the signing of the informed 
consent form (refer to Section 12.2.1, All Adverse Events, for time of last adverse event 
recording).
Change in Adverse Event Collection with the Implementation of INT-6
Only serious adverse events, adverse events resulting in study drug discontinuation, and 
adverse events of interest will be recorded on eCRFs. Details regarding adverse event 
collections are provided in Section 9.4, Safety Evaluations.
Serious Adverse Event
See above for handling of components of the composite CV endpoint other than CV 
deaths.
A serious adverse event as defined by ICH is any untoward medical occurrence that at 
any dose meets any of the following conditions:
∃
Results in death
∃
Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe).
∃
Requires inpatient hospitalization or prolongation of existing hospitalization
∃
Results in persistent or significant disability/incapacity, or
∃
Is a congenital anomaly/birth defect
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Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in situations other than those listed above. For example, 
important medical events may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent one 
of the outcomes listed in the definition above. Any adverse event is considered a serious 
adverse event if it is associated with clinical signs or symptoms judged by the 
investigator to have a significant clinical impact.
As described in the section above, nonfatal events in the CV composite endpoint 
(nonfatal MI and nonfatal stroke) will not be considered or reported as adverse events, 
but collected as study endpoints, subjected to adjudication, and only reported as adverse 
events if the Endpoint Adjudication Committee determines that the event does not meet 
the prespecified criteria for an endpoint event.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An unlisted adverse event is one for which the nature or severity of which is not 
consistent with the applicable product reference safety information. For an investigational 
product, the expectedness of an adverse event will be determined by whether or not it is 
listed in the Investigator's Brochure. For a comparator product or baseline therapy with a
marketing authorization, the expectedness of an adverse event will be determined by 
whether or not it is listed in the approved label for the product.
Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is 
possible, probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant 
drug(s), concomitant disease(s), or the relationship in time suggests that a causal 
relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time 
is reasonable; therefore, the causal relationship cannot be excluded.
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Probable
An adverse event that might be due to the use of the drug. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant drug(s), concomitant disease(s).
Very likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). 
The relationship in time is very suggestive (eg, it is confirmed by dechallenge and 
rechallenge).
12.1.3.
Severity Criteria 
Mild: Awareness of symptoms that are easily tolerated causing minimal discomfort and 
not interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the intensity of events not 
directly experienced by the subject (eg, laboratory abnormalities).
12.2. Procedures
12.2.1.
All Adverse Events
All adverse events, whether serious or non-serious, will be collected in source documents 
from the time a signed and dated informed consent form is obtained until completion of 
the last study-related procedure (may include contact for follow-up of safety). 
Data will be collected on the eCRF for serious adverse events, adverse events that result 
in study drug discontinuation, and adverse events of interest described in Section 9.4, 
Safety Evaluations. 
Serious adverse events, including those spontaneously reported to the investigator within 
30 days (with the exception of those components of the clinical primary composite 
endpoints) after the last dose of study drug, must be reported using a Serious Adverse 
Event Form, which must be completed and signed by a member of the investigational 
staff, and transmitted to the sponsor within 24 hours. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol. 
Adverse events, as specified in Section 9.4, Safety Evaluations, must be recorded using 
medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology 
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(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
“upper respiratory infection”). Investigators must record in the eCRF their opinion 
concerning the relationship of the adverse event to study therapy. All measures required 
for adverse event management must be recorded in the source document and reported 
according to sponsor instructions.
Study research staff should make study subjects aware of potential signs and symptoms 
of DKA such as difficulty breathing, nausea, vomiting, abdominal pain, feeling confused, 
fruity-smelling breath, and unusual fatigue or sleepiness. Study subjects should be 
instructed to contact the site if they experience such symptoms. If the investigator 
suspects these symptoms may be related to DKA (even if the subject’s blood glucose 
levels are less than 250 mg/dL [13.9 mmol/L]), testing for urine or blood ketones should 
be considered.
Consistent with standard diabetes treatment guidelines, all study participants should be 
provided with routine preventative foot care and early intervention for foot problems. 
Specifically:
o
Provide or ensure that all subjects have had general foot self-care education. 
o
Perform a comprehensive foot evaluation at each visit to identify risk factors for 
ulcers and amputations.  The examination should include inspection of the skin, 
assessment of foot deformities, neurological assessment including pinprick or 
vibration testing or assessment of ankle reflexes, and vascular assessment 
including pulses in the legs and feet. 
o
Subjects who have a history of prior lower-extremity complications, loss of 
protective sensation, structural abnormalities, or peripheral arterial disease should 
be referred to foot care specialists for ongoing preventive care. 
For all study participants, there should be a clinical evaluation at every visit to assess the 
presence of any sign or symptom suggestive of volume depletion (eg, hypotension, 
postural dizziness, orthostatic hypotension, syncope, and dehydration), which if present 
should be adequately treated either by decreasing dose or eliminating use of diuretics or 
other antihypertensive medications or interrupting study drug until the condition resolves.
The sponsor assumes responsibility for appropriate reporting of adverse events to the 
regulatory authorities. The sponsor will also report to the investigator all serious adverse 
events that are unlisted (unexpected) and associated with the use of the drug, according to 
standard operating procedures and the requirements outlined in this protocol. These 
events will be reported blinded to the investigator when and where possible. The 
investigator (or sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the 
protocol unless otherwise required and documented by the IEC/IRB. Subjects (or their 
designees, if appropriate) must be provided with a “study card” indicating the name of 
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the investigational study drug, the study number, the investigator’s name, a 24-hour 
emergency contact number, and, if applicable, excluded concomitant medications.
12.2.2.
Serious Adverse Events
All serious adverse events occurring during clinical studies must be reported to the 
appropriate sponsor contact person by investigational staff within 24 hours of their 
knowledge of the event. For purposes of reporting serious adverse events for this study, 
the components of the clinical primary composite endpoints (with the exception of CV 
death, which, as with all deaths, will be reported as a serious adverse event; see 
Section 12, Adverse Event Reporting) will not be considered adverse events or serious 
adverse events and will not be considered as unexpected but as disease-related, and as 
such will not be unblinded. These events will be captured on the eCRF as endpoint events 
only and will not be unblinded or subject to expedited reporting.
Events that are adjudicated as non-endpoints by the Endpoint Adjudication Committee 
will be subject to standard reporting requirements, but the reporting time limit will start 
when the sponsor learns that the event is not an endpoint as per the Endpoint 
Adjudication Committee.
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject’s participation in the study, must be 
followed until any of the following occurs:
∃
The event resolves
∃
The event stabilizes
∃
The event returns to baseline, if a baseline value is available
∃
The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct
∃
It becomes unlikely that any additional information can be obtained (subject or 
health-care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as 
a serious adverse event.
The cause of death of a subject in a clinical study, whether or not the event is expected or 
associated with the investigational agent, is considered a serious adverse event. Any 
event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject’s participation in a clinical study must be reported as a serious adverse 
event, except hospitalizations for the following:
∃
Related to a component of the clinical primary composite endpoints
∃
Social reasons in absence of an adverse event
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∃
Surgery or procedure planned before entry into the study (must be documented in the 
eCRF)
12.2.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the investigational 
staff within 24 hours of their knowledge of the event using the appropriate pregnancy 
notification form. Abnormal pregnancy outcomes are considered serious adverse events 
and must be reported using the Serious Adverse Event Form. Any subject who becomes 
pregnant during the study must immediately discontinue further study treatment. 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.
12.3. Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding safety issues or questions regarding the study are listed on the 
Contact Information page(s), which will be provided as a separate document.
13.PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related 
to manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, 
quality, durability, reliability of a product, including its labeling or package integrity. 
PQCs may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from clinical studies are crucial 
for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established procedures in conformity 
with regulatory requirements worldwide to ensure appropriate reporting of PQC 
information; all clinical studies conducted by the sponsor or its affiliates will be 
conducted in accordance with those procedures.
13.1. Procedures
All initial PQCs must be reported to the sponsor by the investigational staff within 
24 hours after being made aware of the event.
If the defect is combined with a serious adverse event, the investigational staff must 
report the PQC to the sponsor according to the serious adverse event reporting timelines 
(refer to Section 12.2.2, Serious Adverse Events). A sample of the suspected product 
should be maintained for further investigation if requested by the sponsor.
13.2. Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed on the Contact Information page(s), 
which will be provided as a separate document.
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14.STUDY DRUG INFORMATION
14.1. Physical Description of Study Drug(s)
Canagliflozin will be supplied for this study as over encapsulated 100- or 300-mg tablets 
in a gray-colored, hard, gelatin capsule. The over encapsulated tablet will be backfilled 
with microcrystalline cellulose to prevent the tablet from rattling in the capsule shell.
Matching placebo capsules will consist of microcrystalline cellulose within a gray-colored, 
hard, gelatin capsule.
It will be manufactured and provided under the responsibility of the sponsor. Refer to the 
Investigator's Brochure for a list of excipients.
14.2. Packaging
The study drug will be packaged either as individual blister cards or individual bottles.
The study drug will be packaged according to good manufacturing practices and local 
regulations. The study supplies will be packaged according to the randomization code 
and each unit will be labeled with a medication ID number.
All study drug will be dispensed in child-resistant packaging.
14.3. Labeling
Study drug labels will contain information to meet the applicable regulatory 
requirements.
14.4. Preparation, Handling, and Storage 
All study drug must be stored at controlled temperatures ranging from 20°C to 25°C 
(68∗F to 77∗F) and kept out of reach of children. Where applicable, excursions from 
15∗C to 30∗C (59∗F to 86∗F) are allowed.
14.5. Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. The dispensing of study drug to the 
subject, and the return of study drug from the subject, must be documented on the drug 
accountability form. Subjects or their legally-acceptable representative where applicable, 
must be instructed to return all original containers, whether empty or containing study 
drug. The study drug administered to the subject must be documented on the drug 
accountability form. All study drug will be stored and disposed of according to the 
sponsor's instructions. Site staff must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label 
and must be stored at the study site in a limited access area or in a locked cabinet under 
appropriate environmental conditions. Unused study drug and partially used study drug 
returned by the subject (if applicable), must be available for verification by the sponsor’s 
or sponsor-delegated site monitor during on-site monitoring visits. The return to the 
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sponsor of unused study drug, or partially used study drug returned for destruction, will 
be documented on the drug return form. When the site is an authorized destruction unit 
and study drug supplies are destroyed on site, this must also be documented on the drug 
return form.
Study drug should be dispensed under the supervision of the investigator, a qualified 
member of the investigational staff, or by a hospital/clinic pharmacist. Study drug will be 
supplied only to subjects participating in the study. Returned study drug must not be 
dispensed again, even to the same subject. Study drug may not be relabeled or reassigned 
for use by other subjects. The investigator agrees neither to dispense the study drug from, 
nor store it at, any site other than the study sites agreed upon with the sponsor.
15.STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
∃
Recruitment and retention tools
∃
IVRS/IWRS manual and worksheets
∃
eCRF completion guidelines
∃
Study binder with all other necessary documentation (eg, protocol, IB, clinical trial 
agreement)
∃
Manual of instructions regarding endpoints, endpoint documentation required, and 
adjudication-related procedures
∃
Home blood glucose monitoring system, glucose strips, lancets, and calibration 
solution
∃
Diary card
∃
Materials to support diet and exercise counseling
∃
Standardized ECG recording devices and instruction manual
∃
Laboratory manual, requisition forms, sampling supplies, and equipment, if necessary
∃
Computer, if the study site is assessed to require a laptop computer to enter eCRF 
data for the study
16.ETHICAL ASPECTS
16.1. Study-Specific Design Considerations
The primary ethical concerns of this study are that the safety profile of canagliflozin has 
not been fully established so that subjects may be placing themselves at an increased risk 
of unexpected adverse events by participating in this study, and that subjects with T2DM 
who have not achieved optimal glycemic control at study entry could fail to achieve 
optimal glycemic control for a prolonged period. In this study, there is no requirement to 
discontinue prestudy medications. The investigator is asked not to change the 
antihyperglycemic regimen during the first 18 weeks of the study, but rescue criteria are 
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specified. The potential risks that are apparent in the present study include exposure to 
study drug, with the potential for side effects and the inherent risks associated with 
venipuncture and multiple blood sample collections. The study has been designed to 
mitigate these inherent risk factors.1
Based on data from clinical studies with canagliflozin and the theoretical possibilities 
associated with SGLT2 and intestinal SGLT1 inhibition, potential human adverse effects 
may occur, including osmotic diuresis due to increased UGE, alterations in serum or 
urine electrolytes, gastrointestinal intolerability, hypoglycemia, changes in bone 
formation and/or bone resorption and in the hormones controlling calcium homeostasis, 
abnormalities in renal function, photosensitivity, or vulvovaginal adverse events. Data 
from the Phase 1 studies as well as from Phase 2b studies involving over 1,200 subjects 
indicates that canagliflozin is generally well tolerated and serious adverse events are 
uncommon.
Results from the photosensitivity studies demonstrate that canagliflozin has no clinically 
relevant photosensitizing effect at the doses studied in the Phase 3 studies (100 mg or 
300 mg once daily), and support safe participation of subjects in these Phase 3 studies 
without specific photo-protection precautions.
As described in Section 1.1.2, Clinical Studies, women subjects may be at an increased 
risk for vulvovaginal adverse events. Also, because of the modest magnitude of the 
observed increase of serum CTx levels and the biologic variability associated with this 
marker as well as it not being associated with changes in other markers of bone turnover, 
the increase in serum CTx levels is of uncertain significance; nonetheless, this will be 
monitored in Phase 3 studies by careful collection of information on any fractures and 
additional assessments in selected Phase 3 studies. Renal glomerular and tubular integrity 
were assessed using several biomarkers in Phase 2b studies. A urinary NAG increase 
noted could be secondary to increased flow in the proximal tubule or to glucosuria. Based 
on the preclinical, theoretical, and clinical experience to date, appropriate safety measures 
have been included to help in the selection of subjects as defined in the inclusion and 
exclusion criteria in Sections 4.2 and 4.3, respectively.
This study will provide scientific guidance on using canagliflozin in a T2DM subject 
population requiring improved glycemic control, and it should answer important 
questions about canagliflozin. Subjects will be randomly assigned to either canagliflozin 
100 or 300 mg, both of which have shown glucose-lowering activity in Phase 1 and 
Phase 2b clinical studies, or placebo. The use of placebo as a comparator in this study 
does not represent an ethical compromise because subjects will be allowed to remain on a 
                                                
1 The study-specific design considerations are reflective of the available data at the time the protocol was 
originally designed. For updated information regarding canagliflozin, please refer to the current version 
of the Investigator’s Brochure.
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background of standard care for diabetes or to add other agents as the investigator 
considers necessary according to established treatment guidelines.
One of the objectives of this study is to demonstrate safety in subjects treated with the 
compound. Safety will be evaluated on a frequent and ongoing basis, and all adverse 
events will be treated according to standard medical practice. Hypoglycemia is 
considered to be a side effect of treatment in T2DM. It occurs most frequently with 
insulin therapy, but hypoglycemia can occur with the use of other agents as well. Because 
canagliflozin does not alter the regulation of glucose-dependent insulin secretion, 
hypoglycemia is not intrinsic to the mechanism of action of canagliflozin and should not 
be a frequent occurrence in subjects treated with this agent. 
Clinical and laboratory evaluations will be performed throughout the study (according to 
the Time and Events Schedule that follows the Synopsis) to monitor the safety of 
subjects. HbA1c will be measured approximately every 3 months. Subjects will be 
required to report episodes of hypoglycemia and encouraged to report any changes in 
their clinical condition to the investigator. 
Subjects will be followed after discontinuing study drug and early withdrawal from the 
study by a follow-up contact to evaluate adverse events and concomitant therapy use, and 
to document CV events. 
The investigator will be provided with detailed information about the study to ensure that 
the study research staff is fully informed. Potential subjects will be fully informed of the 
risks and requirements of the study and, during the study, subjects will be given any new 
information that may affect their decision to continue participation. They will be told that 
their consent to participate in the study is voluntary and may be withdrawn at any time 
with no reason given and without penalty or loss of benefits to which they would 
otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, 
and potential adverse events of the study, and provide their consent voluntarily will be 
enrolled.
Subjects will sign an informed consent form before any study-related procedure is 
performed.
The maximum blood volume that would be collected if a subject were to continue in the 
study for 7.25 years would be approximately 850 mL. The maximum amount that would be 
collected at a single visit would be approximately 80 mL. These volumes are considered to 
be well within the normal range for this subject population over this time frame according 
to blood donation standards (American Red Cross).
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16.2. Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current ICH guidelines on Good Clinical Practice (GCP), 
and applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, 
safety, and well being of study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki, and that the clinical study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB)
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by 
local regulations):
∃
Final protocol and, if applicable, amendments
∃
Sponsor-approved informed consent form (and any other written materials to be 
provided to the subjects)
∃
Investigator’s Brochure (or equivalent information) and amendments
∃
Sponsor-approved subject recruiting materials
∃
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable
∃
Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by IEC/IRB)
∃
Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects
∃
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the informed consent form, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a 
copy of this approval. This approval letter must be dated and must clearly identify the 
IEC/IRB and the documents being approved.
Approval for the pharmacogenomic research component of the clinical study and for the 
pharmacogenomic informed consent form must be obtained from the IEC/IRB. Approval 
for the protocol can be obtained independent of approval for pharmacogenomic research.
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During the study the investigator (or sponsor where required) will send the following 
documents and updates to the IEC/IRB for their review and approval, where appropriate:
∃
Protocol amendments
∃
Revision(s) to informed consent form and any other written materials to be provided 
to subjects
∃
If applicable, new or revised subject recruiting materials approved by the sponsor
∃
Revisions to compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable
∃
Investigator’s Brochure amendments or new edition(s)
∃
Summaries of the status of the study at intervals stipulated in guidelines of the 
IEC/IRB (at least annually)
∃
Reports of adverse events that are serious, unlisted, and associated with the 
investigational drug
∃
New information that may adversely affect the safety of the subjects or the conduct of 
the study
∃
Deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects
∃
Report of deaths of subjects under the investigator's care
∃
Notification if a new investigator is responsible for the study at the site
∃
Development Safety Update Report or Periodic Safety Update Report and Line 
Listings, where applicable
∃
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or trial conduct), the amendment and applicable informed 
consent form revisions must be submitted promptly to the IEC/IRB for review and 
approval before implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this clinical 
study. The reapproval should be documented in writing (excluding the ones that are 
purely administrative, with no consequences for subjects, data or trial conduct).
At the end of the study, the investigator (or sponsor where required) will notify the 
IEC/IRB about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of 
the study has been fully explained. The consent form must be signed before performance 
of any study-related activity. The consent form that is used must be approved by both the 
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sponsor and by the reviewing IEC/IRB. The informed consent should be in accordance 
with principles that originated in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the 
investigational staff must explain to potential subjects the aims, methods, reasonably 
anticipated benefits, and potential hazards of the study, and any discomfort participation 
in the study may entail. Subjects will be informed that their participation is voluntary and 
that they may withdraw consent to participate at any time. They will be informed that 
choosing not to participate will not affect the care the subject will receive for the 
treatment of his or her disease. Subjects will be told that alternative treatments are 
available if they refuse to take part and that such refusal will not prejudice future 
treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their 
records may be accessed by health authorities and authorized sponsor staff without 
violating the confidentiality of the subject, to the extent permitted by the applicable 
law(s) or regulations. By signing the informed consent form the subject is authorizing 
such access, and agrees to allow his or her study physician to recontact the subject for the 
purpose of obtaining consent for additional safety evaluations, if needed, or to obtain 
information about his or her survival status.
The subject will be given sufficient time to read the informed consent form and the 
opportunity to ask questions. After this explanation and before entry into the study, 
consent should be appropriately recorded by means of either the subject's personally 
dated signature. After having obtained the consent, a copy of the informed consent form 
must be given to the subject.
Subjects will be asked to consent to participate in a pharmacogenomic research 
component of the study where local regulations permit. After informed consent for the 
clinical study is appropriately obtained, the subject will be asked to sign and personally 
date a separate pharmacogenomic informed consent form indicating agreement to 
participate in optional pharmacogenomic research. A copy of the signed 
pharmacogenomic informed consent form will be given to the subject. Refusal to 
participate will not result in ineligibility for the clinical study.
If the subject is unable to read or write, an impartial witness should be present for the 
entire informed consent process (which includes reading and explaining all written 
information) and should personally date and sign the informed consent form after the oral 
consent of the subject is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the efficacy, safety, quality, and 
utility of the investigational study drug(s) used in this study.
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These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations. Appropriate technical and organizational measures to protect the personal 
data against unauthorized disclosures or access, accidental or unlawful destruction, or 
accidental loss or alteration must be put in place. Sponsor personnel whose 
responsibilities require access to personal data agree to keep the identity of study subjects 
confidential.
The informed consent obtained from the subject includes explicit consent for the 
processing of personal data and for the investigator to allow direct access to his or her 
original medical records for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal 
data and the right to request rectification of any data that are not correct or complete. 
Reasonable steps will be taken to respond to such a request, taking into consideration the 
nature of the request, the conditions of the study, and the applicable laws and regulations.
For those subjects who gave consent to store DNA samples for future genetic research 
(Part 2), samples and corresponding relevant clinical data will be made nonidentifiable by 
the removal of personal identifiers. Samples will be stored until completely used. Only 
research related to the drug or the indications for which the drug is developed will be 
done on stored samples. For data generated on identifiable samples (Part 1), the sponsor 
will provide the individual raw data, through the investigator, to subjects who submit a 
written request. The sponsor cannot make decisions as to the significance of any findings 
resulting from this pharmacogenomic research, and cannot, therefore, provide genetic 
counseling. Genotypic data generated on nonidentifiable samples (Part 2) cannot be 
returned to individual subjects.
16.2.5.
Country Selection
Unless explicitly addressed as a specific ethical consideration in Section 16.1, 
Study-Specific Design Considerations, this study will only be conducted in those 
countries where the intent is to help ensure access to the developed product, unless 
explicitly addressed as a specific ethical consideration in Section 16.1, Study-Specific 
Design Considerations.
17.ADMINISTRATIVE REQUIREMENTS
17.1. Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal 
amendment. All protocol amendments must be issued by the sponsor, and signed and 
dated by the investigator. Protocol amendments must not be implemented without prior 
IEC/IRB approval, or when the relevant competent authority has raised any grounds for 
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non-acceptance, except when necessary to eliminate immediate hazards to the subjects, in 
which case the amendment must be promptly submitted to the IEC/IRB and relevant 
competent authority. Documentation of amendment approval by the investigator and 
IEC/IRB must be provided to the sponsor or its designee. When the change(s) involves 
only logistic or administrative aspects of the study, the IRB (and IEC where required) 
only needs to be notified.
During the course of the study, in situations where a departure from the protocol is 
unavoidable, the investigator or other physician in attendance will contact the appropriate 
sponsor representative (refer to Contact Information pages provided separately). Except 
in emergency situations, this contact should be made before implementing any departure 
from the protocol. In all cases, contact with the sponsor must be made as soon as possible 
to discuss the situation and agree on an appropriate course of action. The data recorded in 
the eCRF and source documents will reflect any departure from the protocol, and the 
source documents will describe this departure and the circumstances requiring it.
17.2. Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory 
authorities in each respective country, if applicable. A study may not be initiated until all 
local regulatory requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug 
to the investigational site:
∃
Protocol and amendment(s), if any, signed and dated by the principal investigator
∃
A copy of the dated and signed written IEC/IRB approval of the protocol, 
amendments, informed consent form, any recruiting materials, and if applicable, 
subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.
∃
Name and address of the IEC/IRB including a current list of the IEC/IRB members 
and their function, with a statement that it is organized and operates according to 
GCP and the applicable laws and regulations. If accompanied by a letter of 
explanation, or equivalent, from the IEC/IRB, a general statement may be substituted 
for this list. If an investigator or a member of the investigational staff is a member of 
the IEC/IRB, documentation must be obtained to state that this person did not 
participate in the deliberations or in the vote/opinion of the study.
∃
Regulatory authority approval or notification, if applicable
∃
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
∃
Documentation of investigator qualifications (eg, curriculum vitae)
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∃
Completed investigator financial disclosure form from the principal investigator, 
where required
∃
Signed and dated clinical trial agreement, which includes the financial agreement
∃
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
subject:
∃
Completed investigator financial disclosure forms from all clinical subinvestigators
∃
Documentation of subinvestigator qualifications (eg, curriculum vitae)
∃
Name and address of any local laboratory conducting tests for the study, and a dated 
copy of current laboratory normal ranges for these tests, if applicable
∃
Local laboratory documentation demonstrating competence and test reliability 
(eg, accreditation/license), if applicable.
17.3. Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit 
easy identification of each subject during and after the study. This document will be 
reviewed by the sponsor site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be 
filed by the investigator in the study file. To ensure subject confidentiality, no copy will 
be made. All reports and communications relating to the study will identify subjects by 
subject identification and date of birth. In cases where the subject is not randomized into 
the study, the date seen and date of birth will be used.
The investigator must also complete a subject-screening log, which reports on all subjects 
who were seen to determine eligibility for inclusion in the study.
17.4. Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy 
parameters as required by the protocol; record of all adverse events; and follow-up of 
adverse events; concomitant medication; drug receipt/dispensing/return records; study 
drug administration information; and date of study completion, and reason for early 
discontinuation of study drug or withdrawal from the study, if applicable. 
It is recommended that the author of an entry in the source documents be identifiable.
At a minimum, the type and level of detail of source data available for a study subject 
should be consistent with that commonly recorded at the site as a basis for standard 
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medical care. Specific details required as source data for the study will be reviewed with 
the investigator before the study and will be described in the monitoring guidelines (or 
other equivalent document).
17.5. Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be 
transcribed by study personnel from the source documents onto an electronic eCRF, and 
transmitted in a secure manner to the sponsor within 3 working days of the subject’s visit. 
The electronic file will be considered to be the eCRF. Worksheets may be used for the 
capture of some data to facilitate completion of the eCRF. Any such worksheets will 
become part of the subjects’ source documentation. All data relating to the study must be 
recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in English.
Designated site personnel must complete eCRFs as soon as possible after a subject visit, 
and the forms should be available for review at the next scheduled monitoring visit.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool.
The investigator or study-site personnel must adjust the eCRF (if applicable) and 
complete the query. A query is generally to be answered within 5 days of generation of 
the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done 
in 3 different ways:
∃
Site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool)
∃
Site manager (SM) can generate a query (field data correction form [DCF]) for 
resolution by the investigational staff
∃
Clinical data manager (CDM) can generate a query for resolution by the 
investigational staff 
17.6. Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified investigators and appropriate study centers, review of protocol procedures with 
the investigator and associated personnel before the study, periodic monitoring visits by 
the sponsor, and transmission of clinical laboratory data from a central laboratory into the 
sponsor’s data base. Written instructions will be provided for collection, handling, 
storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study personnel 
before the start of the study.
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The sponsor will review eCRFs for accuracy and completeness during on-site monitoring 
visits and after transmission to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. After upload of the data into the clinical study 
database they will be verified for accuracy and consistency with the data sources.
17.7. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all 
eCRFs and all source documents that support the data collected from each subject, as 
well as all study documents as specified in ICH/GCP Section 8, Essential Documents for 
the Conduct of a Clinical Trial, and all study documents as specified by the applicable 
regulatory requirement(s). The investigator/institution will take measures to prevent 
accidental or premature destruction of these documents.
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor 
to inform the investigator/institution as to when these documents no longer need to be 
retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. The sponsor must be notified in writing of the name and 
address of the new custodian. Under no circumstance shall the investigator relocate or 
dispose of any study documents before having obtained written approval from the 
sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review 
any documentation relating to this study, the investigator must permit access to such 
reports.
17.8. Monitoring
The sponsor and ARO designated by the sponsor will perform on-site monitoring visits as 
frequently as necessary. The monitor will record dates of the visits in a study center visit 
log that will be kept at the site. The first post-initiation visit will be made as soon as 
possible after enrollment has begun. At these visits, the monitor will compare the data 
entered into the eCRFs with the hospital or clinic records (source documents). The nature 
and location of all source documents will be identified to ensure that all sources of 
original data required to complete the eCRF are known to the sponsor and investigational 
staff and are accessible for verification by the sponsor site contact. If electronic records 
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are maintained at the investigational site, the method of verification must be discussed 
with the investigational staff. 
Direct access to source documentation (medical records) must be allowed for the purpose 
of verifying that the data recorded in the eCRF are consistent with the original source 
data. Findings from this review of eCRFs and source documents will be discussed with 
the investigational staff. The sponsor expects that, during monitoring visits, the relevant 
investigational staff will be available, the source documentation will be accessible, and a 
suitable environment will be provided for review of study-related documents. The 
monitor will meet with the investigator on a regular basis during the study to provide 
feedback on the study conduct.
17.9. Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed (ie, GTED) with the last visit/contact of the last 
subject participating in the study. The final data from the investigational site will be sent 
to the sponsor (or designee) after completion of the final subject visit/contact at that site, 
3 days after the subject’s visit/contact (query generation and resolution excluded), or in 
the time frame specified in the clinical trial agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at 
any time for any reason at the sole discretion of the sponsor. Investigational sites will be 
closed upon study completion. An investigational site is considered closed when all 
required documents and study supplies have been collected and a site closure visit has 
been performed.
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of an investigational site by the sponsor or investigator may 
include but are not limited to:
∃
Failure of the investigator to comply with the protocol, the sponsor’s procedures, or 
GCP guidelines
∃
Inadequate recruitment of subjects by the investigator
∃
Discontinuation of further study drug development.
17.10. On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the site 
at any time during or after completion of the study to conduct an audit of the study in 
compliance with regulatory guidelines and company policy. These audits will require 
access to all study records, including source documents, for inspection and comparison 
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with the eCRFs. Subject privacy must, however, be respected. The investigator and staff 
are responsible for being present and available for consultation during routinely 
scheduled site audit visits conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, 
either as part of a national GCP compliance program or to review the results of this study 
in support of a regulatory submission. The investigator should immediately notify the 
sponsor if they have been contacted by a regulatory agency concerning an upcoming 
inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding canagliflozin or the 
sponsor’s operations (eg, patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, and any data, including pharmacogenomic 
research data, generated as a result of this study, are considered confidential and remain 
the sole property of the sponsor. The investigator agrees to maintain this information in 
confidence and use this information only to accomplish this study, and will not use it for 
other purposes without the sponsor’s prior written consent.
The investigator understands that the information developed in the clinical study will be 
used by the sponsor in connection with the continued development of canagliflozin, and 
thus may be disclosed as required to other clinical investigators or regulatory agencies. 
To permit the information derived from the clinical studies to be used, the investigator is 
obligated to provide the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the 
sponsor and will contain eCRF data from all investigational sites that participated in the 
study and clinical laboratory data from a central laboratory via direct transmission into 
the sponsor's data base. Recruitment performance or specific expertise related to the 
nature and the key assessment parameters of the study will be used to determine a 
coordinating investigator. Results of pharmacogenomic analyses performed after the 
Clinical Study Report has been issued will be reported in a separate report and will not 
require a revision of the Clinical Study Report. Study subject identifiers will not be used 
in publication of results. Any work created in connection with performance of the study 
and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor 
as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical 
Journal Editors guidelines, the sponsor shall have the right to publish such data and 
information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator 
wishes to publish information from the study, a copy of the manuscript must be provided 
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to the sponsor for review at least 60 days before submission for publication or 
presentation. Expedited reviews will be arranged for abstracts, poster presentations, or 
other materials. If requested by the sponsor in writing, the investigator will withhold such 
publication for up to an additional 60 days to allow for filing of a patent application. In 
the event that issues arise regarding scientific integrity or regulatory compliance, the 
sponsor will review these issues with the investigator. The sponsor will not mandate 
modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and substudy approaches, results may need to be published 
in a given sequence (eg, substudies) should not generally be published before the primary 
endpoints of a study have been published. Similarly, investigators will recognize the 
integrity of a multicenter study by not publishing data derived from the individual site 
until the combined results from the completed study have been published in full, within 
12 months after conclusion, abandonment, or termination of the study at all sites, or the 
sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such 
as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided 
critical review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical 
studies as required by law.
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REFERENCES
ADA 2004. American Diabetes Association. Nephropathy in Diabetes. Diabetes Care 2004;27(1):S79-83.
ADVANCE 2008. The ADVANCE collaborative Group. Intensive blood glucose control and vascular 
outcomes in patients with Type 2 Diabetes. N Engl J Med 2008;358:2560-72.
American 
Red 
Cross. 
American 
Red 
Cross 
Website. 
http://www.redcrossblood.org/donating-
blood/donation-faqs. Accessed March 3, 2011.
Anderson S (1986), Brenner B. The role of intraglomerular pressure in the initiation and progression of 
renal disease. J Hypertension Suppl. 1986;4(5):S236-8.
Brownlee M (2001). Biochemistry and molecular cell biology of diabetic complications. Nature 
2001;414:813-820.
DCCT (1993). The Diabetes Control and Complications Trial (DCCT) Research Group. The Effect of 
Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in 
Insulin-Dependent Diabetes Mellitus. N Engl J Med 1993; 329:977-86.
de Zeeuw D (2004), Remuzzi G, Parving H-H, et al. Albuminuria, a therapeutic target for cardiovascular 
protection in type 2 diabetic patients with nephropathy. Circulation. 2004;110:921-927.
EMEA 2002. The European Medicines Agency. Committee for Proprietary Medicinal Product (CPMP). 
Note For Guidance On Clinical Investigation Of Medicinal. Products In The Treatment Of Diabetes 
Mellitus (30 May 2002).
EMEA 2008. The European Medicines Agency. Committee for Proprietary Medicinal Product (CPMP). 
Concept 
Paper 
on 
the 
Need 
for 
Revision 
of 
the 
Note 
For 
Guidance 
on 
Clinical 
Investigation of Medicinal Products in the Treatment of Diabetes Mellitus (30 May 2008). 
http://www.emea.europa.eu/pdfs/human/ewp/17634808en.pdf
FDA 2008. U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for 
Industry Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 
2 Diabetes (December 2008).
Friedewald WT (1972), Levy RI, and Fredrickson DS. Estimation of the Concentration of Low-Density 
Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge. Clinical Chemistry 
1972;18;499-502.
Ganong W (2005) Review of Medical Physiology. McGraw-Hill Professional. 2005
IB
JNJ-28431754 Edition 12. Document ID No. EDMS-ERI-13482463. Johnson & Johnson 
Pharmaceutical Research and Development, L.L.C. Investigator’s Brochure (08 September 2014).
KDOQI 2007. National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). 
American Journal of Kidney Diseases 2007;49(2, Suppl 2):S1-S180.
Levey AS (2006), Coresh J, Greene T, Stevens LA, Zhang Y. Using Standardized Serum Creatinine Values 
in the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate. 
Ann Int Med 2006;145:247-55.
Rave K (2006), Nosek L, Posner J, Heise T, Roggen K, van Hoogdalem EJ. Renal glucose excretion as a 
function of blood glucose concentration in subjects with type 2 diabetes - results of a hyperglycaemic 
glucose clamp study. Nephrol Dial Transplant. 2006;21:2166-2171.
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Ray KK (2009), Seshasai SRK, Wijesuriya S, et al. Eff ect of intensive control of glucose on cardiovascular 
outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. 
Lancet 2009;373:1765–72.
Ridker PM (2004), Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma 
biomarkers in the prediction of first atherothrombotic events. Circulation 2004;109:Suppl 1:IV6-IV19.
Roder ME (1998), Porte D, Schwartz RS, Kahn SE. Disproportionately elevated proinsulin levels reflect 
the degree of impaired b cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J 
Endocrinol Metab 1998;83:604-8.
Seifter J (2005), Sloane D, Rather A: concepts in medical Physiology. Lippincott Williams & Wilkins, 
2005.
Strojek K (2010), Hruba V, Elze M, Langkilde A, Parikh S. Efficacy and safety of dapagliflozin in patients 
with type 2 diabetes mellitus and inadequate glycaemic control on glimepiride monotherapy. European 
Association for the Study of Diabetes Annual Meeting (Stockholm, Sweden). Presentation 870. Session A. 
PS 079 SGLT-2 inhibitors. September 2010.
UKPDS 1998. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with 
type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53.
Vallon V (1999), Richter K, Blantz RC, Thomson S, Osswald, H. Glomerular hyperfiltration in 
experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 
1999;10:2569-2576.
Wallace TM (2004), Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 
2004;27(6):1487-95.
Witte EC (2009), Lambers Heerspink HJ, de Zeeuw D, Bakker SJL, de Jong PE, Gansevoort R. First 
morning voids are more reliable than spot urine samples to assess microalbuminuria. J Amer Soc Nephr 
2009;20:436-443.
Wright EM (2001). Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 2001;280:F10-F18.
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Attachment 1:
Sulfonylurea Monotherapy Doses for Stratification Purposes
Monotherapy consisting of one of the following:
∃
glipizide !20 mg/day
∃
glipizide extended release !10 mg/day
∃
glyburide/glibenclamide !10 mg/day
∃
glimepiride !4 mg/day
∃
gliclazide !160 mg/day
∃
gliclazide modified release !60 mg/day
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Attachment 2:
Hypoglycemia: Definitions, Symptoms, and Treatment
Hypoglycemia is defined and classified as follows:
Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are 
accompanied by a measured plasma glucose (PG) concentration #70 mg/dL (3.9 mmol/L) 
Asymptomatic hypoglycemia is defined as an event not accompanied by typical symptoms of 
hypoglycemia but with a measured PG concentration #70 mg/dL (3.9 mmol/L) 
Probable symptomatic hypoglycemia is defined as an event during which symptoms of hypoglycemia are 
not accompanied by a PG determination. 
Severe hypoglycemia is defined as an event requiring the assistance of another person to actively 
administer a carbohydrate, glucagon, or other resuscitative actions. A subject is considered to "require 
assistance" if he/she is unable to help himself/herself. An act of kindness to assist a subject when it is not 
necessary does not qualify as "requiring assistance". These episodes may be associated with sufficient 
neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during 
such an event, but neurologic recovery attributable to the restoration of PG to normal is considered 
sufficient evidence that the event was induced by a low PG concentration. 
Symptoms
Subjects will receive information regarding the symptoms of and treatment for hypoglycemia. Signs and 
symptoms of hypoglycemia and other specific details should be captured in the subject diary, which should 
be returned to the study center for review by research study staff at each visit. The following list of 
symptoms is not meant to be exhaustive but represents the more common symptoms associated with 
hypoglycemia:
∃
Seizure
∃
Loss of consciousness
∃
Headache
∃
Tremor
∃
Hunger 
∃
Sweating 
∃
Nervousness
∃
Palpitations
∃
Light headedness
∃
Blurred vision 
∃
Disorientation
∃
Dizziness
∃
Feeling faint
Treatment
The treatment of hypoglycemia requires the ingestion of glucose- or carbohydrate-containing foods. The 
acute glycemic response correlates better with the glucose content than with the carbohydrate content of the 
food. Therefore, glucose (15 to 20 g) is the preferred treatment for hypoglycemia. Although pure glucose 
may be the preferred treatment, any form of carbohydrate that contains glucose will raise blood glucose and 
may be used. Adding protein to a carbohydrate does not affect the glycemic response and does not prevent 
subsequent hypoglycemia. However, adding fat may retard and then prolong the acute hypoglycemic 
response. Treatment effects should be apparent within 15 minutes although the effects may only be 
temporary. Therefore, PG should be retested in approximately 15 minutes, as additional treatment may be 
necessary.
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Attachment 3:
New York Heart Association Classification of Cardiac Disease
The following table represents the NYHA classification of cardiac disease:
Functional capacity
Objective assessment
Class I. Patients with cardiac disease but without resulting 
limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or anginal pain
A. No objective evidence of 
cardiovascular disease
Class II. Patients with cardiac disease resulting in slight limitation 
of physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain
B. Objective evidence of minimal 
cardiovascular disease
Class III. Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at rest. Less 
than ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.
C. Objective evidence of moderately 
severe cardiovascular disease.
Class IV. Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. Symptoms of 
heart failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is increased.
D. Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 
1994:253-256.
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Attachment 4:
Optional Specimens for Exploratory Research - Sample Collection and Handling
Materials and Labeling
∃
The central laboratory will provide the study site with blood collection tubes, storage tubes, preprinted 
Janssen Research and Development labels (or tubes labeled with preprinted labels), and related 
supplies for the collection and shipment of exploratory samples.
∃
The central laboratory will provide the study site with urine collection containers, storage tubes, and 
preprinted Janssen Research and Development labels (or tubes labeled with preprinted labels), for the 
collection and shipment of urine exploratory samples.
∃
Use of alternative materials will not result in a protocol amendment if preapproved by the Bioanalysis 
Scientist.
∃
Detailed information regarding the collection and storage containers will be provided in the laboratory 
manual from the central laboratory.
Preparation of Exploratory Plasma Samples
∃
Collect one full blood sample into the K2EDTA-containing collection tube (eg, Vacutainer+) provided 
(10 mL or 5 mL) at the appropriate time point.
∃
Immediately after draw, gently invert the plasma tube 8 times (up-down-up=1 inversion) to completely 
mix tube contents. Place tubes at room temperature, 15∗C to 25∗C, until processed.
∃
Record the exact date and time of sampling in the eCRF or laboratory requisition form, as appropriate.
∃
Centrifuge blood sample at room temperature within 1 hour of collection in a clinical centrifuge 
according to the specifications in the laboratory manual.
∃
The following steps should be done separately for each blood sample that was collected. Do not 
combine the plasma. Keep aliquots separate.
∃
Immediately after centrifugation, transfer all separated plasma with a clean disposable plastic pipette to 
a prelabeled storage tube. Gently mix the tube by inversion.
∃
Dispense the plasma (0.5 to 1.0 mL aliquots) into two prelabeled microfuge tubes or cryovials 
(1.5- to 2-mL size) and securely cap.
∃
Store the plasma samples in an upright position in a freezer at –70∗C or colder until transfer to the 
central laboratory. Record the exact time of storage in the eCRF or laboratory requisition form, as 
appropriate. Shipment on dry ice on the day of collection is acceptable if the site does not have a 
freezer at –70∗C or colder.
∃
The time between blood collection and freezing the plasma must not exceed 2 hours.
∃
Ship specimens on dry ice according to the instructions provided by the central laboratory.
∃
Questions regarding handling the exploratory plasma specimens should be addressed to the contact 
person for the sponsor.
∃
Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis 
Scientist.
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Attachment 4: (Continued)
Optional Specimens for Exploratory Research - Sample Collection and Handling 
Preparation of Exploratory Serum Samples
∃
Collect one 8.5 mL of blood into the appropriate plastic collection tube (Serum SST; SST with clot 
accelerator and gel barrier, also called Red & Black Tiger top) at the appropriate time point.
∃
Immediately after draw, gently invert the serum tube 5 times (up-down-up=1 inversion) to completely 
mix tube contents. Place tube at room temperature, 15°C to 25°C, for a minimum of 30 minutes or 
until processed.
∃
Record the exact date and time of sampling in the eCRF or laboratory requisition form, as appropriate.
∃
Centrifuge blood sample at room temperature within 45 min of collection in a clinical centrifuge 
according to the specifications in the laboratory manual.
The following steps should be done separately for each blood sample that was collected. Do not combine 
the serum. Keep aliquots separate.
∃
Immediately after centrifugation, transfer all separated serum with a clean disposable plastic pipette to 
a pre-labeled storage tube. Gently mix the tube once by inversion.
∃
Dispense the serum (0.5-1.0 mL aliquots) into two prelabelled microfuge tubes or cryovials (1.5 to 2 
mL size) and securely cap.
∃
Store serum samples in an upright position in a freezer at –70°C or colder until transfer to the central 
laboratory. Record the exact time of storage in the eCRF or laboratory requisition form, as appropriate.
∃
Shipment on dry ice on the day of collection is acceptable if the site does not have a freezer at –70°C 
or colder.
∃
The time between blood collection and freezing the serum must not exceed 2 hours.
∃
Ship specimens on dry ice according to the instructions provided by the central laboratory.
∃
Questions regarding handling the exploratory serum specimens should be addressed to the contact 
person for the sponsor.
Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis Scientist.
Preparation of Exploratory Urine Samples
∃
Collect voided urine in the appropriate urine collection container at the time designated in the protocol.
∃
Thoroughly mix the urine.
∃
Transfer one 3-mL aliquot into a labeled cryovial.
∃
Store the urine sample in an upright position in a freezer at –70∗C or colder until transfer to the central 
laboratory. Shipment on dry ice on the day of collection is acceptable if the site does not have a freezer 
at –70°C or colder.
∃
The time between urine collection and freezing should not exceed 1 hour.
∃
Ship specimen on dry ice according to the instructions provided by the central laboratory.
∃
Questions regarding handling the exploratory urine sample should be addressed to the contact person 
for the sponsor.
∃
Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis 
Scientist.
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Attachment 5:
Pharmacogenomic Sample Collection and Shipment Procedure 
Pharmacogenomic Sample Supplies and Labeling
The central laboratory will provide the investigational site with prelabeled 10 mL blood collection tubes 
containing potassium or sodium EDTA. Detailed information is provided in the laboratory manual from the 
central laboratory.
Preparation of Pharmacogenomic Samples
Pharmacogenomic samples should be prepared as follows:
∃
Invert the tube 10 to 15 times immediately after collection, to prevent coagulation.
∃
DO NOT centrifuge the sample.
∃
Freeze the samples at or below -20°C in an upright position immediately after collection
Pharmacogenomic Sample Shipment
Once collected, the blood samples must immediately be frozen at or below -20°C in an upright position. 
Samples must remain at this temperature until shipment to the central laboratory. All samples must then be 
shipped with sufficient dry ice to ensure samples remain frozen during shipment. Detailed information will 
be provided in the laboratory manual from the central laboratory.
The following guidelines should be adhered to:
∃
Shipment of the frozen pharmacogenomic blood samples should be arranged with other clinical study 
samples. If this is not possible, a separate shipment for these blood samples should be organized, using 
the courier recommended by the central laboratory.
∃
Notify the courier, at least 24 hours in advance of the planned shipment. Provide the courier with the 
appropriate account number to be used, if applicable.
∃
Package the samples in sufficient dry ice to ensure that the samples remain frozen during shipment.
∃
Label the package with the study number and all other information required by the central laboratory.
∃
Include a return address (that includes the investigator’s name) on the outside of each shipping 
container.
∃
Comply with all courier regulations for shipment of biological specimens (include all paperwork).
∃
Retain all documents indicating date, time, and signature(s) of person(s) making the shipment, in the 
study files.
∃
The blood samples should be shipped to the name and address indicated in the central laboratory 
manual.
NOTE: If there are changes regarding the courier or location to which samples are shipped during the 
course of the clinical study, written notification will be provided to the investigator; a protocol amendment 
will not be required.
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Attachment 6:
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be collected for 
the tests listed below. The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes (in the investigator’s judgment) occurring during the study in the adverse 
event section of the eCRF.
The following tests will be performed by the central laboratory (the use of local laboratory studies should 
be limited to situations in which immediate availability of laboratory study results are necessary for 
appropriate care of the subject):
Hematology Panel
Chemistry Panel
Urinalysis*
Hemoglobin
Sodium, potassium, chloride, 
Uric acid
Specific gravity
Hematocrit
bicarbonate
Calcium
pH
RBC count
Blood urea nitrogen (BUN) 
Phosphate
Protein
WBC with automated 
Serum creatinine
Albumin
Blood
differential
Glucose
Total protein
Ketones
Platelet count
Aspartate aminotransferase (AST)
Magnesium
Bilirubin/
Alanine aminotransferase (ALT)
Creatine 
urobilinogen
Gamma-glutamyl transferase (GGT)
phosphokinase (CPK)
Nitrate
Total bilirubin 
Leukocyte 
Alkaline phosphatase 
esterase
Lactic acid dehydrogenase (LDH)
Fasting lipid profile: triglycerides, HDL-C, LDL-C (using Friedewald [1972] equation), total cholesterol
(Note, C-peptide, insulin, proinsulin are collected as efficacy assessments as described in Section 9.5)
*Urine glucose will not be measured by the central laboratory 
At run-in visit: Follicle stimulating hormone (FSH) only for women >45 years of age with amenorrhea for
at least 6 months and <18 months before screening
Central laboratory will report the eGFR according to the Modification of Diet in Renal Disease Study 
(MDRD) equation (Levey 2006) at study visits when serum creatinine is measured. 
The 4-variable MDRD eGFR includes serum creatinine, age, race, and sex according to the equation below: 
For creatinine in mg/dL: 
eGFR (mL/min/1.73 m2) = 175 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.21 if black)
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Attachment 7:
Algorithm for Monitoring Abnormal Liver Function Tests
Repeat testing* and perform additional 
diagnostic follow-up.**
Continue with study drug. 
ALT! 3 x ULN
ALT !5 x ULN
Tbili <2 x ULN
ALT !3 x ULN
Tbili !2 x ULN
ALT !3 x ULN <5 x ULN
TBili <2 x ULN
Laboratory notifies investigator by telephone and fax, and sponsor by fax. 
If confirmed, permanently discontinue study drug, perform 
EOT visit assessments, and follow until LFT abnormalities 
resolve.**
Repeat testing* and perform additional diagnostic follow-
up.** If elevation confirmed, discontinue, and follow 
algorithm. If not confirmed, contact Medical Monitor.
If the investigator feels that the subject cannot safely continue administration 
of study drug regardless of algorithm, the subject should discontinue study 
drug and continue to the EOT visit. 
1. ALT !5 x ULN
2. Symptoms of hepatitis 
occur
3. Tbili !2 x ULN
Permanently discontinue 
study drug, perform EOT 
visit assessments, and 
follow until LFT 
abnormalities resolve.
Continue study drug. Repeat 
LFT twice weekly until one of 
the following occurs:‡
ALT !3 x ULN <5 x ULN
Permanently discontinue study drug, perform 
EOT visit assessments, and follow until LFT 
abnormalities resolve.**
Follow-up as per 
usual study visit 
schedule
ALT <2 x ULN
ALT !3 x ULN
Tbili !2 x ULN
ALT !3 x ULN
Symptoms of 
hepatitis
ALT !5 x ULN
*
LFT (ie, ALT, AST, total bilirubin, alkaline phosphatase, GGT)
within 2 to 3 days of investigator receipt of report, with earlier
testing (ie, within 1 day of receipt of laboratory report) for more
substantial elevations in ALT (!5xULN) or total bilirubin
(!2xULN)
levels. An alternate frequency of laboratory
assessments may be considered in consultation with the
sponsor’smedical monitor.
** Focused medical history (including review of prior history of
liver or biliary disorders, concurrent symptoms, review of all
concomitant
medications
[eg,
acetaminophen-containing
medications, over-the-counter or herbal medications, nutritional
supplements] including any changes in medications, detailed
review of alcohol use and a complete physical examination);
liver ultrasound and follow-up imaging as appropriate; hepatitis
serology
(anti-HAV, HBsAg, anti-HBs, anti-HB core, anti-
HCV, HCV RNA, EBV and CMV screen) and autoantibodies
(eg, ANA, anti-smooth muscle antibody) should be obtained as
appropriate, with additional evaluation as clinically indicated.
The extent of the evaluations should be made in consultation
with the sponsor’smedical monitor.
Key: ALT=alanine aminotransferase; EOT=End of 
Treatment;  GGT= gamma-glutamyl transferase; 
LFT=liver function test; Tbili=total bilirubin; 
ULN=upper limit of normal
‡ If the subject’s ALT value is  ≥2XULN and 
<3xULN upon retest, then repeat LFT weekly 
until one of the subsequent events occurs. An 
alternate frequency of laboratory assessments 
may be considered in consultation with the 
sponsor’s medical monitor.
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Attachment 8:
Candidate Gene List for Part 1 of Pharmacogenomics
Absorption, Distribution, Metabolism, and Excretion Genes: ABCB family, ABCC family, ABCG2, ADH 
family, AHR, ALDH family, AOX1, ARNT, ATP7A, ATP7B, BDH2, CDA, CHST family, COMT, CYP11A1, 
CYP11B1, CYP11B2, CYP17A1, CYP19A1, CYP1A1, CYP1A2, CYP1B1, CYP20A1, CYP21A2, CYP24A1, 
CYP26A1, CYP27A1, CYP2A13, CYP2A6, CYP2A7, CYP2B6, CYP2B7, CYP2C family, CYP2D6, CYP2E1, 
CYP2J2, CYP2S1, CYP39A1, CYP3A family, CYP46A1, CYP4B1, CYP4F family, CYP4Z1, CYP51A1, 
CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, DHRS family, DHRSX, DPYD, EPHX1, EPHX2, FMO 
family, FOM3, GPX family, GSR, GSS, GSTA family, GSTCD, GSTK1, GSTM family, GSTO1, GSTO2, 
GSTP1, GSTP2, GSTT1, GSTT2, GSTZ1, HAGH, HNMT, MAOA, MAOB, MGST1, MGST2, MGST3, MPO, 
NAT1, NAT2, NFE2L2, NNMT, NQO1, NR1I2, NR3C1, POR, PPARA, PPARD, PPARG, RALBP1, RLIP76, 
SLC10A1, SLC10A2, SLC13A1, SLC15A1, SLC15A2, SLC16A1, SLC19A1, SLC22A family, SLC28A 
family, SLC29A1, SLC29A2, SLC5A6, SLC7A5, SLC7A7, SLCO1A2, SLCO1B1, SLCO1B3, SLCO1C1, 
SLCO2A1, SLCO2B1, SLCO3A1, SLCO4A1, SLCO4C1, SLCO5A1, SLCO6A1, SPG7, STE, SULT1A1, 
SULT1A2, SULT1B1, SULT1C1, SULT2A1, SULT2B1, SULT4A1, TPMT, UGT1A family, UGT2A1, 
UGT2B family, UGT8, XDH.
Target related genes: SGLT gene family (SLC5 family), GLUT gene family (SLC2 family).
Diabetes related genes: ABCA1, ABCC8, ABCG5, ACE, ACP1, ACTN4, ADA, ADAMTS9, ADIPOQ, 
ADRB3, AKR1B1, ALB, ALMS1, ALX4, ANGPTL4, APOA1, APOA4, APOA5, APOB, APOC3, APOE, 
ARG1, ASIP, ASPN, BBS4, BCHE, CAMK1D, CAPN10, CART, CCK, CCKAR, CCL2, CD36, CD59, 
CDC123, CDKAL1, CDKN2A-2B, CELSR2, CETP, CIDEA, CILP2, COL2A1, CPE, CTLA4, CTNNBL1, 
CXCL12, CYP19A1, DF, DIANPH, DOCK7, DPP4, ENPP1, ESR1, EXT2, FABP10, FABP2, FABP4, 
FABP5, FADS1-3, FASN, FOLH1, FOXC2, FRZB, FTO, FXN, GAD1, GAD2, GAL, GALNT2, GCG, 
GCGR, GCK, GCKR, GDF8, GH1, GH2, GHRL, GIP, GIPR, GNB3, GPD2, GPKOW, GYS1, HBA1, HFE, 
HHEK1, HHEX-IDE, HK1, HK2, HK3, HLA-DQA1, HLA-DQB1, HMGA2, HMGCR, HNF4A, HSD11B1, 
HSD17B7, IAPP, IDE, IGF1, IGF1R, IGF2BP2, IKBKB, IL1R1, IL gene family, INS, INSIG2, INSR, IPF1, 
IRS1, IRS2, IRS4, ISL1, JAZF1, JPH3, KCNJ11, KCNJ9, KCNQ1, KIF11, LACT, LDLR, LEP, LEPR, 
LGR5, LIPC, LIPE, LIPG, LMNA, LPA, LPAL2, LPL, LRPAP1, MADD, MANT3, MAPK8, MAPK8IP1, 
MBL2, MC3R, MC4R, MIA3, MKKS, MLXIPL, MMAB, MMP13, MVK, NEGR1, NEUROD1, NEUROG3, 
NFKB1, NOS3, NOTCH2, NPY, NR0B2, NR3C1, NUCB2, PBX1, PCSK1, PCSK9, PDE3B, PFKP, PGC, 
PGR, PLG, PLIN, PNPLA3, POMC, PON1, PON2, PPARG, PPARGC1A, PPARGC1B, PPP1R1A, 
PPP1R3A, PRL, PSRC1, PTPN1, PTPRN, RBP4, REG1A, RETN, RPS6KB1, SCARB1, SERPINE1, SH2B1, 
SIM1, SLC2A1, SLC2A10, SLC2A2, SLC2A4, SLC30A8, SORBS1, SORT1, SPINK1, SREBF1, SST, TCF1, 
TCF2, TCF7L2, TGFB1, TH, THADA, TMEM18, TNF, TRAPPC2, TRIP1, TSPAN8, TUB, TULP2, UCN, 
UCP1, UCP2, UCP3, VDR, WFS1, WRN, XBP1, ZDHHC23 and ZFP36.
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129
Attachment 9:
Medical Resource Utilization Review
The questions below are representative but may not be exact wording of those that will be asked in the 
Diary.
When To Use Your Diary:
∃
Complete this diary any time you seek medical care that is not part of your study visit. 
How To Use Your Diary:
∃
Do not list medical care received during an overnight hospitalization. 
∃
Please indicate whether the medical care is planned
∃
Please be as accurate and complete as you can.
Sample Medical Care Visit Chart
Visit Date
Health-Care Provider
Type
Planned
Location of Visit 
05 February 2010 
Primary Care Doctor 
Yes
Home
11 March 2010
ER Doctor
No
Emergency Room
13 March 2010
Cardiologist
No
Doctor’s Office
Medical Care Chart
Visit Date
Health-Care Provider 
Type
Planned
Location of Visit
LAST PAGE
NCT01032629

SAP_001.pdf: 
1
Approved, Date: 20 March 2017     
Janssen Research & Development 
Statistical Analysis Plan
A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the 
Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects with Type 2 
Diabetes Mellitus
The CANVAS Trial (CANagliflozin cardioVascular Assessment Study)
Protocol 28431754DIA3008; Phase 3
JNJ-28431754 (canagliflozin)
Status:
Approved
Date:
20 March 2017
Prepared by:
Janssen Research & Development, LLC  
Document No.:
EDMS-ERI-130802595, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT01032629


JNJ- 28431754 (canagliflozin)
Statistical Analysis Plan 28431754DIA3008
2
Approved, Date: 20 March 2017     
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 3
LIST OF IN-TEXT FIGURES ........................................................................................................................ 3
SUMMARY OF AMENDMENT ..................................................................................................................... 4
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Design ...................................................................................................................................... 6
1.2.
Randomization ................................................................................................................................. 8
1.3.
Trial Objectives ................................................................................................................................ 8
1.3.1.
Primary Objectives........................................................................................................................ 8
1.3.2.
Secondary Objectives................................................................................................................... 9
1.3.3.
Exploratory Objectives.................................................................................................................. 9
1.4.
Statistical Hypotheses.................................................................................................................... 10
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 10
2.1.
Analysis Populations...................................................................................................................... 10
2.2.
Analysis Sets.................................................................................................................................. 11
2.3.
Data Handling ................................................................................................................................ 11
2.3.1.
Censoring Rules ......................................................................................................................... 11
2.3.2.
Handling of Key Milestone Dates ............................................................................................... 11
2.3.3.
Visit Windows ............................................................................................................................. 12
3.
SUBJECT INFORMATION................................................................................................................ 13
3.1.
Baseline Anthropometric and Demographic Characteristics ......................................................... 13
3.2.
Baseline Disease Characteristics .................................................................................................. 14
3.3.
Disposition Information................................................................................................................... 15
3.4.
Extent of Exposure and Follow-Up ................................................................................................ 15
3.5.
Prior and Concomitant Medications ............................................................................................... 15
4.
EFFICACY ......................................................................................................................................... 16
4.1.
Primary Efficacy Endpoint.............................................................................................................. 16
4.1.1.
Definition..................................................................................................................................... 16
4.1.2.
Analysis Methods........................................................................................................................ 16
4.1.3.
Subgroup Analyses..................................................................................................................... 17
4.1.4.
Supportive Analyses................................................................................................................... 18
4.1.4.1.
On-Study Analysis ................................................................................................................... 18
4.1.4.2.
On-Treatment Analysis............................................................................................................ 18
4.1.4.3.
Additional Supportive Analyses............................................................................................... 18
4.1.4.3.1.
MACE in the First 30, 60 and 90 Days................................................................................. 18
4.1.4.3.2.
Hazard Ratio Estimation for Individual MACE Components................................................ 18
4.1.4.3.3.
Assessment of Missing Data................................................................................................ 19
4.2.
Secondary Efficacy Endpoints ....................................................................................................... 20
4.2.1.
Definition..................................................................................................................................... 20
4.2.2.
Analysis Methods........................................................................................................................ 21
4.2.2.1.
HOMA-B .................................................................................................................................. 21
4.2.2.2.
Progression of Albuminuria ..................................................................................................... 21
4.2.2.3.
Additional Secondary Endpoints.............................................................................................. 22
4.3.
Multiplicity Adjustment.................................................................................................................... 22
4.4.
Exploratory Efficacy Endpoints ...................................................................................................... 22
4.4.1.
Definition..................................................................................................................................... 22
4.4.2.
Analysis Methods........................................................................................................................ 23
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Statistical Analysis Plan 28431754DIA3008
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Approved, Date: 20 March 2017     
4.4.2.1.
CV Endpoints........................................................................................................................... 23
4.4.2.2.
All-Cause Mortality .................................................................................................................. 23
4.4.2.3.
Renal Endpoints ...................................................................................................................... 24
4.4.2.3.1.
Composite Endpoints ........................................................................................................... 24
4.4.2.3.2.
Progression of Albuminuria.................................................................................................. 24
4.4.2.3.3.
Regression of Albuminuria................................................................................................... 24
4.4.2.3.4.
eGFR Slope.......................................................................................................................... 24
5.
SAFETY............................................................................................................................................. 25
5.1.
Adjudicated MACE Events............................................................................................................. 25
5.2.
Adverse Events .............................................................................................................................. 25
5.2.1.
Adverse Event Collection............................................................................................................ 25
5.2.2.
Analysis Methods........................................................................................................................ 26
5.2.2.1.
General Adverse Events.......................................................................................................... 27
5.2.2.2.
Male Mycotic Genital Infections............................................................................................... 28
5.2.2.3.
Hypoglycemia .......................................................................................................................... 29
5.2.2.4.
Selected Malignancies............................................................................................................. 30
5.2.2.5.
Photosensitivity........................................................................................................................ 31
5.2.2.6.
Venous Thromboembolic Events............................................................................................. 31
5.2.2.7.
Fracture ................................................................................................................................... 32
5.2.2.8.
Amputation............................................................................................................................... 32
5.2.2.9.
Diabetic Ketoacidosis .............................................................................................................. 34
5.2.2.10.
Pancreatitis.............................................................................................................................. 34
5.3.
Clinical Laboratory Tests................................................................................................................ 34
5.4.
Vital Signs ...................................................................................................................................... 34
5.5.
Electrocardiogram.......................................................................................................................... 35
REFERENCES............................................................................................................................................ 36
APPENDIX.................................................................................................................................................. 37
Appendix 1.1: 
List of Key Analyses of CV and Mortality Endpoints .................................................. 37
Appendix 1.2:
Clinical Laboratory Tests............................................................................................ 38
Appendix 1.3:
Pre-defined Limit of Change (PDLC) Criteria............................................................. 39
Appendix 1.4:
List of Preferred Terms for Selected AEs of Interest.................................................. 40
Appendix 1.5:
Adverse Events with Potential Amputation Association ............................................. 49
LIST OF IN-TEXT TABLES
Table 1: 
Summary of Analysis Sets........................................................................................................ 11
Table 2: 
Time Intervals for Analysis (in clinic) Visit Windows................................................................. 13
Table 3: 
Adverse Events of Interest........................................................................................................ 26
Table 4: 
Baseline Factors Included in the Logistic Regression Analysis ............................................... 33
LIST OF IN-TEXT FIGURES
Figure 1: 
Diagram of Study Design............................................................................................................ 7
Figure 2: 
Follow-up of Randomized Subjects with Respect to the GTED ................................................. 8
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Statistical Analysis Plan 28431754DIA3008
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Approved, Date: 20 March 2017     
SUMMARY OF AMENDMENT
Relative to the statistical analysis plan (SAP) dated 20 September 2016, the major amendments 
made in this version are summarized as follows.
Applicable 
Section(s)
Description of Change(s)
1.3.3
4.4
Removed ‘Change in eGFR from baseline to the last off-drug value’ from 
objectives and exploratory efficacy endpoints. 
2.2
The On-Study analysis set was added for MACE and replaced the ITT analysis 
set for several adverse events of interest.  The upper bound of the data period for 
the On-Treatment analysis set was clarified as last dose plus 2 days for 
laboratory parameters except ACR.
4.1
Consistent with the analytic approach described in the Cardiovascular Endpoint 
adjudication charter, it is clarified that undetermined death is considered as CV 
death.
4.1.3
Additional subgroups were added for the analysis of MACE.
4.1.4.3.1
Added an analysis of MACE in the first 30, 60 and 90 days.
4.1.4.3.3
Updated the multiple imputation analysis section
4.2
Added analysis based on MMRM for continuous secondary efficacy endpoints.
4.4
Clarified that any adjudicated non-CV death event where the adjudication 
committee assigned a renal proximate cause is considered a renal death.
5.2.2.10
Added a section on the analysis of adjudicated pancreatitis.
Appendix 1.3
Additional lab analytes were included in the Pre-defined Limit of Change 
(PDLC) criteria.
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Approved, Date: 20 March 2017     
ABBREVIATIONS
ACR
albumin creatinine ratio 
AE
adverse event
AHA
antihyperglycemic agent
ANCOVA
analysis of covariance
BL
baseline
BMI
body mass index
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CV
cardiovascular
DBP
diastolic blood pressure
DKA
diabetic ketoacidosis
EAC
Endpoint Adjudication Committee
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
FPG
fasting plasma glucose
GTED
Global Trial End Date
HbA1c
hemoglobin A1c
HDL-C
high-density lipoprotein cholesterol
HR
hazard ratio
IDMC
independent data monitoring committee
ITT
intent-to-treat
IWRS
interactive web response system
LDL-C
low-density lipoprotein cholesterol
LLN
lower limit of normal
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
PDLC
pre-defined limit of change
PT
preferred term
QTcF
QTc using the Fridericia
RAAS
renin angiotensin aldosterone system
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
steering committee
SCr
serum creatinine
SD
standard deviation
SGLT2
sodium-glucose co-transporter 2
SI
standard international
SOC
System Organ Class
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent AE
ULN
upper limit of normal
UTI
urinary tract infection
VTE
venous thromboembolic events
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Approved, Date: 20 March 2017     
1.
INTRODUCTION
Canagliflozin (JNJ-28431754) is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2) that 
has been developed as an oral anti-hyperglycemic agent (AHA) for the treatment of patients with 
type 2 diabetes mellitus (T2DM). To meet the FDA guidance on assessing cardiovascular (CV)
safety of AHAs, the sponsor initiated the CV outcomes study 28431754DIA3008 (CANVAS) in 
December, 2009 intended to supply data to support the CV safety of canagliflozin and to also 
evaluate whether canagliflozin reduces CV risk.
As part of the marketing authorization application, the sponsor performed an integrated analysis of 
CV events from the Phase 2 and Phase 3 canagliflozin program using data from 9,632 subjects, 
which included interim data harvested on 31 January 2012 from the ongoing CANVAS study of 
4,330 subjects at high risk for CV disease. Subsequently, in response to a request arising during 
review of the canagliflozin Marketing Authorization Application by the Committee for Medicinal 
Products for Human Use (CHMP), the sponsor conducted a second integrated CV analysis of the 
Phase 2 and Phase 3 studies, which included interim data from CANVAS harvested on 
19 November 2012. Data on major adverse cardiovascular events (MACE) and mortality outcomes 
beyond 19 November 2012 have remained blinded to the sponsor.
The primary endpoint of CANVAS was to evaluate whether there was a risk reduction in MACE 
associated with canagliflozin treatment. Due to unblinding of the interim summary results of 
CANVAS at the time of marketing approval, the planned expansion of enrollment in CANVAS 
was eliminated. Accordingly, the study itself is underpowered for the primary hypothesis of the 
reduction in CV risk as measured by the hazard ratio (HR) for MACE.
As a result of the discussions with FDA, the sponsor proposed to conduct a second CANVAS-like 
study (referenced as CANVAS-R) with approximately 5,700 randomized subjects. As such, the 
CANVAS and CANVAS-R trials are purposefully similar in design and in subject characteristics.
Data from these studies are to be harvested for an integrated analysis to meet the FDA 
post-approval CV safety requirement and if safety is demonstrated, to assess whether canagliflozin 
reduces all-cause mortality no later than June 2017 with study reports submitted to FDA by 
September 2017.
This statistical analysis plan (SAP) stipulates definitions of analysis sets, key derived variables and 
statistical methods for analysis of efficacy and safety specific for CANVAS based on the latest 
amendment INT-8 (5 May 2016) of the protocol. Additional CV and renal outcome endpoints are 
added in this SAP for exploratory analysis. Since the Clinical Study Reports of the 18-week 
substudies were submitted in the NDA of canagliflozin and the 52-week interim results were 
published, the analyses in these sub studies will not be addressed in this plan.
1.1.
Trial Design
The CANVAS study enrolled the first subject in December 2009. The original design called for the 
study to be conducted in 2 cohorts (an initial cohort of 4,500 subjects enrolled prior to regulatory 
submissions followed by a subsequent cohort of 14,000 subjects to be enrolled post approval). 
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JNJ- 28431754 (canagliflozin)
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Approved, Date: 20 March 2017     
However, due to unblinding of the interim summary results of CANVAS at the time of marketing 
approval, the planned expansion of enrollment in CANVAS was eliminated. 
The study enrolled 4,330 subjects who met all inclusion criteria and none of the exclusion criteria. 
Subjects were randomly assigned to treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) 
or placebo, in a 1:1:1 ratio. The CANVAS and CANVAS-R studies will complete when the last 
subject randomized has approximately 78 weeks of follow-up or when 688 MACE events are 
accumulated between both studies (estimated to occur between January 2017 and April 2017). The 
announcement of the Global Trial End Date (GTED) will mark the anticipated date on which one 
of these requirements for ending the study will occur.
Following announcement of the projected GTED and for subjects remaining on double-blind study 
drug, sites will schedule the End of Treatment (EOT) and the 30-day off-drug follow-up contact as 
per the Time and Events schedule in the protocol; for subjects that have prematurely discontinued 
study drug prior to the announcement of the projected GTED, sites will be required to make a final 
contact or vital status check as soon as possible after the announcement of the GTED. 
A single Steering Committee (SC) and an Independent Data Monitoring Committee (IDMC) are
commissioned for this and the CANVAS-R study. The SC oversees the study conduct, and the 
IDMC regularly (and on an ad hoc basis) reviews safety data. 
Figure 1 shows an overview of the study design and Figure 2 shows the scheduled follow-up of 
randomized subjects prior to the GTED.
Figure 1:
Diagram of Study Design 
AHA=antihyperglycemic agent; CV=cardiovascular; HbA1c=hemoglobin A1c; GTED=global trial end date; 
R=randomization; SU=sulfonylurea; T2DM=type 2 diabetes mellitus
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Approved, Date: 20 March 2017     
Figure 2:
Follow-up of Randomized Subjects with Respect to the GTED
Note: Following the announcement of the GTED, investigators are not expected to continue collecting data for 
purposes of the clinical trial after the 30-day post-treatment contact.
1.2.
Randomization 
Subjects were stratified into one of 6 predefined strata based on AHA use at the run-in visit 
through to the randomization visit. The investigators were instructed to hold AHA use constant 
through Week 18 and to adjust the subject’s AHA regimen after Week 18 so as to achieve target 
glycemic control throughout the remainder of the study.
Central randomization was implemented in this study. Subjects were randomly assigned to 1 of 
3 treatment groups based on a computer-generated randomization schedule prepared by the 
sponsor before the study. The randomization was balanced by using randomly permuted blocks 
and was stratified based on the use of specific concomitant AHA medications at baseline.
1.3.
Trial Objectives
1.3.1.
Primary Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history or high risk of CV 
disease: 

To assess the effect of canagliflozin plus standard of care relative to placebo plus standard of 
care on CV risk as measured by the HR for a composite endpoint (MACE including CV death,
nonfatal MI, or nonfatal stroke);

To assess the safety and tolerability of canagliflozin plus standard of care relative to placebo 
plus standard of care.
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1.3.2.
Secondary Objectives 
In subjects with T2DM, with inadequate glycemic control, who have a history or high risk of CV 
disease, to assess the effect of canagliflozin plus standard of care relative to placebo plus standard 
of care at the end of the treatment period on:

Fasting measures of beta-cell function (HOMA-B and the proinsulin/insulin ratio) (note: this 
assessment will be conducted in a subset of subjects at sites that elected to participate, 
including only subjects who did not receive insulin at randomization);

The proportion of subjects with progression of albuminuria (progression defined as the 
development of microalbuminuria or macroalbuminuria in a subject with baseline
normoalbuminuria or the development of macroalbuminuria in a subject with baseline 
microalbuminuria);

Urinary albumin/creatinine ratio (ACR);

Change from baseline in estimated glomerular filtration rate (eGFR);

Change from baseline in HbA1c and fasting plasma glucose (FPG);

Change in body weight;

Change in blood pressure (systolic and diastolic);

Change in fasting plasma lipids (triglycerides, high-density lipoprotein cholesterol [HDL-C], 
low-density lipoprotein cholesterol [LDL-C], total cholesterol, and the ratio of LDL-C to 
HDL-C).
1.3.3.
Exploratory Objectives
In subjects with T2DM, with inadequate glycemic control, who have a history or high risk of CV 
disease, to assess the effect of canagliflozin plus standard of care relative to placebo plus standard 
of care on:

Hospitalization for heart failure;

The composite of hospitalization for heart failure or CV death;

The composite of 40% decrease in eGFR, renal death or requirement for renal replacement 
therapy;

The composite of doubling of serum creatinine (SCr), renal death or requirement for renal 
replacement therapy;

The composite of 40% decrease in eGFR, renal death, requirement for renal replacement 
therapy or CV death;

The composite of doubling of SCr, renal death, requirement for renal replacement therapy or
CV death;

The composite of 40% decrease in eGFR, conversion to macroalbuminuria, renal death or
requirement for renal replacement therapy;

The composite of doubling of SCr, conversion to macroalbuminuria, renal death or
requirement for renal replacement therapy;
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
Progression of albuminuria
(defined as the development of microalbuminuria or 
macroalbuminuria in a subject with baseline normoalbuminuria or the development of 
macroalbuminuria in a subject with baseline microalbuminuria), accompanied by an ACR 
value increase of greater than or equal to 30% from baseline;

Regression of albuminuria (regression defined as the development of normoalbuminuria in a 
subject with baseline microalbuminuria or macroalbuminuria or the development of 
microalbuminuria in a subject with baseline macroalbuminuria), accompanied by an ACR 
value decrease of greater than or equal to 30% from baseline;

Change in eGFR determined from a between-group comparison of the eGFR slopes using all 
on-drug measurements (ie, off-drug values will not be included) of eGFR made from the first 
on-drug measurement to the final on-drug measurement.
1.4.
Statistical Hypotheses
The following hypotheses are specified in the study protocol, however they are considered to be 
exploratory in the canagliflozin CV outcome consisting of CANVAS and CANVAS-R. The 
hypotheses in this trial are not included as part of the testing sequence of the program. 
Accordingly, any p-value reported will be considered as nominal and 95% confidence intervals
(CIs) for the treatment effect will be presented for descriptive purposes.    
In subjects with T2DM with inadequate glycemic control, who have a history of or a high risk of 
CV disease, relative to placebo plus standard of care, canagliflozin plus standard of care:

Reduces CV risk (as measured by the HR for MACE including CV death, nonfatal MI, and 
nonfatal stroke);

Improves beta-cell function (change from baseline in HOMA-B) at the end of the treatment 
period;

Reduces progression of albuminuria (ie, proportion of subjects with a 1-step progression of 
albuminuria measured by the urine ACR) at the end of the treatment period.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Analysis Populations

Randomized subjects—subjects who are randomized via the Interactive Web Response 
System (IWRS); 

Treated subjects—randomized subjects who received at least one dose of double-blind study 
medication. 
For efficacy analyses and baseline summaries, subjects will be analyzed according to their 
randomization assignment. For safety analyses (eg, adverse events [AEs]) and the summary of 
exposure, subjects will be analyzed according to the predominant treatment received (defined as 
the treatment to which the subject was exposed for the greatest duration), in the event that subjects 
receive a treatment other than the one to which they were randomized.
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2.2.
Analysis Sets
Analysis sets consist of 2 components: 1) analysis population (Section 2.1), which specifies the 
subjects included in an analysis; 2) data period, defining the time window during which data will 
be included in the analysis.
Safety data collection in CANVAS was streamlined after protocol amendment INT-6 (effective 
starting on 07 January 2014) such that AEs were only collected if they were serious or leading to 
study drug discontinuation, with the exception of selected AEs of interest. For the purpose of 
summarizing safety data prior to amendment INT-6, the On-Treatment Pre-INT6 analysis set was
created as described below.
Table 1: 
Summary of Analysis Sets
Analysis Set
Analysis Population
Data Period
ITT
Randomized subjects
Day 1 to the last trial contact date (refer to 
Section 2.3.2) up to the GTED
On-Study
Treated subjects
Day 1 to the last trial contact date (see Section 2.3.1) 
up to GTED
On-Treatment
Treated subjects
Day 1 to the last dose date (refer to Section 2.3.2) plus 
Xa days or the last trial contact date, whichever is 
earlier
On-Treatment
Pre-INT6
Treated subjects
Day 1 to the last dose date plus Xa days or the last trial 
contact date, whichever is earlier, up to 
07 January 2014
a 
X is 2 days for laboratory (except ACR) and vital sign measurements, and 30 days for CV and mortality endpoints, 
and adverse events.
2.3.
Data Handling
2.3.1.
Censoring Rules
For each analysis set, events that occur any time during the data period of the corresponding 
analysis set (refer to Table 1) will be considered as eligible events; otherwise subjects not 
experiencing an event will be censored at the earlier of the last trial contact date or end of the 
respective data period, if not otherwise specified.
2.3.2.
Handling of Key Milestone Dates

Trial reference start date (Day 1): the first double-blind dose date for each subject (First dose 
date). If missing or incomplete, the first dose date will be imputed as the randomization date. 

Last dose date: the date on which the last dose of double-blind study drug was taken by the 
subject. If only the day is missing, impute the last day of the month. If the month or the year is 
missing, impute the date as the date of the scheduled visit subsequent to the last visit when the 
study drug was dispensed. The imputed last dose date should be no later than the end of 
treatment visit date or the last trial contact date. In addition, the imputed last dose date should 
be no earlier than the first dose date. The last dose date is the date of permanent study drug 
discontinuation regardless of any temporary drug interruption.
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
Last trial contact date: the date when the last trial-related procedure is conducted. It is defined 
as the latest of: 

The date of last visit (scheduled or unscheduled visit; office or phone visit), or

The latest known date of an AE or the study endpoint event status, concomitant 
medication, vital sign measurements or laboratory results as reported on their respective 
electronic case report form (eCRF), or 

The date of alternate contact made (eg, family members, relatives, friends, health care 
providers, public search) confirming the subject’s survival status at the time of the GTED.

For subjects who die during the study, the last trial contact date will be defined as the date 
of death.
2.3.3.
Visit Windows
The Time and Events schedule of the protocol indicates the visit timing and procedures 
(eg, laboratory, vital signs, and other key safety variables) for each visit; however, the timing of a 
subject’s actual visit may not be exactly as per the protocol indicated target day / visit window. 
Consequently, for by-visit or over-time summaries, depending on the time period(s) involved in 
the summaries, the conventions outlined below will be used to allocate the data collected at each 
actual visit to a planned protocol visit by defining visit windows. 
Baseline will be defined as the pre-dose measurement closest to or including Day 1 (prior to dose 
administration). If the pre-dose measurement on Day 1 is missing, the missing value will be 
imputed by the latest available measurement prior to Day 1.
If a subject has 2 or more actual visits in one analysis visit window, the visit closest to the target 
day will be used as the study visit for that analysis visit window. However, results from all visits 
will be included in the safety analyses (eg, pre-defined limits of change analysis) to assure that all 
results are included. If 2 study visits are the same number of days from the target day within the 
same visit window, the later visit will be considered the study visit for that target day. Even though 
all visits will be allocated an analysis visit window, only planned protocol visits for each variable 
will be included in the by-visit summaries or repeated measure analyses.
Note that the algorithms for calculating visit windows are the same for all the data periods (refer to 
Table 1). Table 2 summarizes the analysis visit windows for laboratory, vital signs, and other key 
safety variables.
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Table 2:
Time Intervals for Analysis (in clinic) Visit Windows
Scheduled Visit Time
(label on output)
Time Interval 
(Day)a
Target Time 
Point (Day)
Baseline
1b
1
Week 6
1c – 64
43
Week 12
65 – 99
85
Week 18
100 – 155
127
Week 26
156 – 197
183
Week 39
198 – 288
274
Week 52
289 – 456
365
Week 78
457–638
547
Week 104
639–820
729
Week 130
821–1002
911
Week 156
1003–1184
1093
Week 182
1185–1366
1275
Week 208
1367–1548
1457
Week 234
1549 – 1730
1639
Week 260
1731 – 1912
1821
Week 286
1913 – 2094
2003
Week 312
2095 – 2276
2185
Week 338
2277 – 2458
2367
Week 364
2459 – 2640
2549
Week 390
2641 – 2822
2731
a
Relative to the day of the first dose of double-blind study drug.
b
Up to the first dose of double-blind study drug.
c 
Immediately following the first dose of double-blind study drug. For variables with no 
time or reference collected at baseline, the first window after baseline starts on Day 2 
according to the protocol.
3.
SUBJECT INFORMATION
3.1.
Baseline Anthropometric and Demographic Characteristics
Baseline anthropometric and demographic characteristics will be summarized by treatment group
(each canagliflozin dose and all canagliflozin group, as well as placebo). Descriptive statistics (N, 
mean, standard deviation, median, and range) will be provided by treatment group for baseline age 
and baseline body weight. 
Additionally, the number and percentage of subjects in the categories of the following variables at 
baseline will also be summarized by treatment group: 

Age group: <65, ≥65 years old;

Sex: Male, Female;

Race: White, Black or African American, Asian, Others;

Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Unknown, Not reported;

Region: North America, Central/South America, Europe, Rest of the World.
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3.2.
Baseline Disease Characteristics
Descriptive statistics (N, mean, SD, median, and range) will be provided by treatment group and 
overall for the following baseline continuous variables: duration of diabetes (in years), eGFR, 
ACR, systolic blood pressure (SBP), weight, body mass index (BMI), HbA1c, LDL-C, HDL-C, 
triglycerides, total cholesterol, and LDL-C/HDL-C.
Additionally, the number and percentage of subjects will be summarized by treatment group and 
overall for the following:

Baseline BMI categories (<30, ≥30 kg/m2);

Currently daily cigarette smoker: Yes/No;

Baseline HbA1c  ≥ 8%: Yes/No;

Duration of T2DM ≥ 10 years: Yes/No;

Baseline systolic blood pressure categories (≤140, >140 mmHg);

Baseline LDL-C categories (≤70, >70 mg/dL);

Baseline HDL-C categories (<39, ≥39 mg/dL); 

Baseline eGFR categories (<30, 30 to <60, 60 to <90, ≥90 mL/min/1.73m2);

Baseline albuminuria categories:

Normoalbuminuria (0 ≤ACR <30 mg/g); Microalbuminuria (ACR ≥30 mg/g and 
≤300 mg/g); Macroalbuminuria (ACR > 300 mg/g: ACR >300 mg/g and ≤3000 mg/g,
ACR > 3000 mg/g).

History of hypertension: Yes/No;

History of CV disease: Yes/No;

History of coronary artery disease: Yes/No;

History of cerebrovascular disease: Yes/No;

History of peripheral vascular disease: Yes/No;

History of heart failure: Yes/No;

Microvascular diabetes complications (Any, 1, 2 or 3 of retinopathy, neuropathy [diabetic or 
autonomic neuropathy] and nephropathy);

History of fracture: Yes/No;
The number and percentage of subjects with a history of medical conditions by system organ class 
and preferred term (based upon the general medical history eCRF) will be summarized by 
treatment group and overall.
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3.3.
Disposition Information
Disposition will be summarized for all randomized subjects by treatment group using the 
categories listed below:

Screen failure;

Subjects who are randomized (ITT);

Subjects who are treated;

Subjects who complete the study (ie, defined as having been followed until a time point 
between the notification of the GTED and the GTED, or if the subject has died prior to the 
GTED);

Subjects who prematurely discontinued study medication;

Subjects without final vital status.
The reasons for non-randomization, withdrawal from study (eg, lost to follow-up, consent 
withdrawal), and discontinuation from study medication will be summarized. The distribution of 
time to premature discontinuation of study medication will be displayed using a Kaplan-Meier 
plot, where one minus the survival function will be shown. 
Listings will be provided for subjects whose predominant treatment differs from their randomized 
treatment.
3.4.
Extent of Exposure and Follow-Up
Total exposure time for each subject is defined as the number of days from Day 1 to the last dose 
date (inclusive), regardless of any temporary drug interruption(s). Follow-up time is defined as the 
number of days from Day 1 to the last contact day (inclusive) for each subject. Descriptive 
statistics (N, mean, SD, median, and range) for total exposure or follow-up time will be presented
by treatment group.
The number of subjects with duration in each of the following categories (<3 week, 3 to <13 week, 
13 to <26 weeks, 26 to <52 weeks, 52 to <78 weeks, 78 to <104 weeks, 104 to <130 weeks, 130 to 
<156 weeks, 156 to <182 weeks, 182 to <208 weeks, 208 to <234 weeks, 234 to <260 weeks, 
260 to <286 weeks, 286 to <312 weeks, 312 to <338 weeks, and ≥338 weeks) will also be 
presented by treatment group as well as overall.
3.5.
Prior and Concomitant Medications
Concomitant medication usage is collected on the eCRF at baseline, and during the on-drug period.
The number of subjects receiving medication in pre-specified categories will be presented by 
treatment group at baseline and on-drug period. In addition, SGLT2 inhibitor use during the off-
drug follow-up period will also be summarized by treatment group.
All study medications are coded using World Health Organization Drug Utilization Research 
Group (WHODRUG) and Anatomical Therapeutic Chemical (ATC) codes. 
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Additionally, the number and percentage of subjects taking the following concomitant medications 
at baseline will be summarized by treatment group and overall:

Baseline insulin use: Yes/No;

Baseline sulphonylurea use: Yes/No;

Baseline metformin use: Yes/No;

Baseline statin use: Yes/No;

Baseline anti-thrombotic use: Yes/No;

Baseline diuretic use: Yes/No;

Baseline loop diuretic use: Yes/No;

Baseline non-loop diuretic use: Yes/No;

Baseline renin angiotensin aldosterone system (RAAS) inhibitor use: Yes/No.
4.
EFFICACY
The primary analysis will be performed based on the ITT analysis set and secondary efficacy 
endpoints will be based on the On-treatment analysis set, if not otherwise specified.
As noted in Section 1, there will be no formal statistical hypothesis testing and therefore all 
statistical tests will be considered nominal and reported using a 2-sided 95% confidence level.
Unless otherwise stated, all efficacy analyses and summaries will be performed using the treatment 
groups assigned by IWRS.
A tabulation of all the key analyses planned for the CV endpoints and the mortality endpoint is 
presented in Appendix 1.1.
4.1.
Primary Efficacy Endpoint
4.1.1.
Definition
The primary efficacy endpoint is the time to MACE (ie, composite of CV deatha, non-fatal MIb, 
and non-fatal stroke), which is calculated as the time from Day 1 to the first occurrence of MACE.
Adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) will be done in a 
blinded fashion.
4.1.2.
Analysis Methods
The primary analysis will be based on the ITT analysis set for adjudicated MACE. The HR of 
canagliflozin (all canagliflozin group as well as each canagliflozin dose) compared to placebo and 
                                                
a Undetermined death is considered CV death.
b Silent MIs are excluded from the analysis.
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its 95% CI will be estimated using a stratified Cox proportional hazards model with a term for 
treatment as the explanatory variable and history of CV disease (secondary and primary 
prevention) as a stratification factor.
The percentage of subjects who experience a MACE and the corresponding incidence rate per 
1,000 patient-years will be reported. The cumulative event rate over time will be presented using a 
Kaplan-Meier plot by treatment (all canagliflozin group and placebo as well as each canagliflozin 
dose and placebo).
4.1.3.
Subgroup Analyses
The homogeneity of treatment effect on the occurrence of the primary endpoint across subgroups 
will be examined (at a 2-sided significance level of 0.05) via a test for the treatment by subgroup 
interaction by adding this term and the subgroup as covariates (treated as class variables) to the 
primary efficacy analysis (Section 4.1.2) model. Subgroup analysis will be conducted when the 
total number of events is greater than 10 for two treatment groups (all canagliflozin group and 
placebo) and at least 1 event in both groups. Factors exhibiting interactions at a significance level 
of p ≤0.05 will be identified as suggesting treatment effect heterogeneity, recognizing the 
multiplicity in testing multiple subgroups such that one or more p-values ≤0.05 may be expected 
to be observed by chance alone.
If a significant interaction is observed, the Gail-Simon test will be used to further examine the 
nature of the interaction (qualitative or quantitative).
The HR of canagliflozin (all canagliflozin group) compared to placebo and its 95% CI will be 
estimated for each of the following subgroups:

Age group: <65, ≥65 years old;

Sex: Male, Female;

Race: White, Black or African American, Asian, Other;

Region: Central/South America, Europe, North America, Rest of the World;

Baseline BMI categories (<30, ≥30 kg/m2);

Baseline composite blood pressure categories ([SBP<140or DBP<90 mmHg] vs. [SBP ≥140 
and DBP ≥90 mmHg]);

Baseline eGFR categories (30 to <60, 60 to <90, ≥90 mL/min/1.73m2);

Baseline HbA1c ≥ 8%: Yes/No;

Duration of diabetes ≥ 10 years: Yes/No;

History of CV disease: Yes/No;

History of peripheral vascular disease: Yes/No;

History of amputation: Yes/No;

Baseline use of statin;
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
Baseline use of anti-thrombotics;

Baseline use of RAAS inhibitor;

Baseline use of Beta blocker;

Baseline use of insulin;

Baseline use of diuretics.
4.1.4.
Supportive Analyses
If not otherwise specified, the supportive analyses will use the same analysis set as in the primary 
efficacy analysis.
4.1.4.1.
On-Study Analysis
The stratified Cox proportional hazards model (as described in Section 4.1.2) will be repeated 
using the On-Study analysis set, in which data of treated subjects from Day 1 to the last trial 
contact date up to the GTED are used.
The percentage of treated subjects who experience a MACE and the corresponding incidence rate 
per 1,000 patient-years will be reported.
4.1.4.2.
On-Treatment Analysis
The primary analysis (as described in Section 4.1.2) will be repeated using the On-Treatment 
analysis set, in which data from Day 1 to 30 days after the last dose of the study drug are used. 
4.1.4.3.
Additional Supportive Analyses
4.1.4.3.1.
MACE in the First 30, 60 and 90 Days
In addition to the Kaplan-Meier plot described in Section 4.1.2, frequency counts (n and %) of 
subjects experiencing the first occurrence of MACE within the first 30 days, 60 days and 90 days 
will be provided in the ITT analysis set.
4.1.4.3.2.
Hazard Ratio Estimation for Individual MACE Components
A separate analysis will be performed for each individual MACE component (CV death, nonfatal 
MI, or nonfatal stroke) in both the ITT analysis set and the On-Treatment analysis set. 
Additionally, analyses of fatal/non-fatal MI as well as fatal/non-fatal stroke will be performed. For 
subjects who experience more than one MACE component, all events will be counted in the 
analysis for the relevant component (eg, if a subject has both non-fatal MI and non-fatal stroke, the 
subject will be counted as having each event). The percentage of subjects who experience each 
MACE component and the corresponding incidence rate per 1,000 patient-years will be 
summarized by treatment. The HR of canagliflozin (all canagliflozin group as well as each 
canagliflozin dose) compared to placebo and its 95% CI will be estimated using a stratified Cox 
proportional hazards model with a term for treatment as the explanatory variable and history of CV 
disease (secondary and primary prevention) as a stratification factor. 
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4.1.4.3.3.
Assessment of Missing Data
The impact of missing data in the interpretation of the primary efficacy analysis will be explored. 
For subjects who are lost to follow-up or withdrew consent before the development of a MACE in 
the ITT analysis set, data collected between the last trial contact date and the GTED will be 
considered missing. 
The proportion of data missing, defined as the ratio of the duration of missing follow-up (eg, days 
between last contact date + 1 day and the GTED) and the duration of intended follow-up (eg, days 
between randomization date and the GTED) will be summarized.
Multiple Imputation 
The estimate of interest is the hazard ratio to develop MACE among all randomized subjects 
regardless of adherence to study medication over the period between randomization and the global 
trial end date (GTED). For subjects who are lost to follow up or withdrew consent before the 
development of a MACE, data between the last trial contact date and the GTED will be considered 
missing.
The subjects who discontinued from study medication prematurely prior to the announcement of 
the GTED can have a different hazard from those who stay on treatment throughout the trial, and 
their corresponding drop-out could be considered informative. This subpopulation is defined to be 
the subjects who 

discontinued from study medication prior to the announcement of the GTED, and

for whom death is not the reason for the discontinuation of study medication.  
The data used to model imputed outcomes for subjects with missing data will be those of the 
subpopulation including the retrieved drop-out data. The definition of the retrieved drop-out data is 
the follow up data between treatment discontinuation and the GTED. Subjects who developed 
MACE prior to the treatment discontinuation are included in the subpopulation and their time to 
MACE data will be used for the imputation modeling. With these subjects included, the model 
estimate of hazard should fully reflect the potential hazard of the subjects with missing outcome.
A Weibull parametric time to event model (the imputation model) will be fit using the observed 
time to MACE data from the subpopulation described above. The model will be stratified by study 
and prior cardiovascular disease (Yes/No), and adjust for treatment and the following covariates 
potentially correlated with missing mechanism and risk of MACE so that bias due to informative 
censoring in the estimation of hazard could be minimized and the precision could be optimized.

Completion of follow up to GTED: Yes/No

Age group: <65, ≥65 years old;

Sex: Male, Female;

Baseline use of Metformin: Yes/No;
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
History of heart failure: Yes/No;

Baseline SBP >140 mmHg: Yes/No;

Baseline HbA1c ≥ 8%: Yes/No;
In case the model does not converge, covariates will be removed from the model in the descending 
order as listed.
For subjects with missing data, follow up time post drop-out will be imputed with random values 
derived from the conditional distribution of the missing data, given the observed data and the 
parameters estimated from the imputation model with the pre-specified covariates. If the sum of 
the observed time and the simulated time is less than the expected follow-up time, ie, from 
randomization to the GTED, an event is imputed for the corresponding subject. Otherwise, the 
subjects will be censored at GTED.
The imputed events and follow-up times will be integrated with the observed data. The primary 
efficacy model will be reanalyzed with the imputed dataset. This process will be repeated 
1,000 times. The multiple analysis results will be combined into a single inferential summary 
(ie, HR and 95% CI) using Rubin’s rules.1
4.2.
Secondary Efficacy Endpoints
4.2.1.
Definition
The secondary efficacy endpoints are:

Change from baseline to the end of treatment in HOMA-B;

The proportion of subjects with progression of albuminuria at the end of treatment (ie, the 
development of microalbuminuria or macroalbuminuria in a subject with baseline
normoalbuminuria or the development of macroalbuminuria in a subject with baseline 
microalbuminuria);

Change in proinsulin/insulin ratio;

Change in urinary ACR;

Change in eGFR;

Change in HbA1c;

Change in FPG;

Percent change in body weight;

Change in blood pressure (systolic and diastolic);

Percent change in fasting plasma lipids (triglycerides, HDL-C, LDL-C, total cholesterol, and 
the ratio of LDL-C to HDL-C).
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4.2.2.
Analysis Methods
Unless otherwise specified, the analyses for the secondary efficacy endpoints will be using the 
On-Treatment analysis set. Only subjects with a baseline and at least 1 post-baseline measurement 
will be included in the analysis.
4.2.2.1.
HOMA-B
The analyses for beta-cell function will be conducted in a subset of subjects at sites that elected to 
participate, including only subjects who are not receiving insulin at randomization. For subjects 
who initiated insulin during the study, all HOMA-B data after the initiation of insulin will be 
censored.
Changes in HOMA-B from baseline will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment as the explanatory variable and baseline HOMA-B value as a covariate. The 
treatment difference in the least-squares means and the 2-sided 95% CI will be estimated based on 
this model. 
Change from baseline in HOMA-B over time will be analyzed using a mixed model for repeated 
measures (MMRM) based on restricted maximum likelihood (REML). The analysis will be based 
on observed data and will include the fixed, categorical effects of treatment, visit, and treatment-
by-visit interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit 
interaction. An unstructured covariance will be used to model the within-patient errors. The 
treatment comparison will be based on the least squares means and the 2-sided 95% CI will be 
estimated.
Descriptive statistics will be calculated for the change from baseline over time based on observed 
data.
4.2.2.2.
Progression of Albuminuria
The proportion of subjects with progression of albuminuria at the end of treatment will be 
analyzed using the logistic model with treatment as the explanatory variable and baseline 
albuminuria status as a covariate. Subjects without baseline and/or post-baseline ACR 
measurements will be excluded from the analysis. Furthermore, subjects with macroalbuminuria at 
baseline (ACR >300 mg/g) will also be excluded from the analysis. Baseline ACR value is derived 
as the geometric mean of all predose ACR measurements. For ACR values below the lower 
quantifiable limit, the lower quantifiable limit itself will be used for analysis. The odds ratios and 
the 2-sided 95% CIs for the treatment comparisons will be derived from the model. Albuminuria 
will be assessed according to the categorizations defined in the National Kidney Foundation 
Kidney Disease Outcomes Quality Initiative Guideline #1:2 microalbuminuria is defined as ACR
of 30 to 300 mg/g and macroalbuminuria is defined as an ACR greater than 300 mg/g.
Data obtained up to last dose plus 30 days will be included this analysis.
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4.2.2.3.
Additional Secondary Endpoints
The analyses for the additional secondary efficacy endpoints will be based on the On-Treatment 
analysis set. Only subjects with baseline and at least one post-baseline measurement will be 
included in the analysis.
Changes at the end of treatment from baseline in proinsulin/insulin ratio, eGFR, HbA1c, FPG, 
blood pressure, percent change in body weight and fasting lipids (HDL-C, LDL-C, triglycerides, 
total cholesterol, and LDL-C/HDL-C) will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment and the corresponding baseline value as covariates. The 
treatment difference in the least-squares means and the 2-sided 95% CI will be estimated based on 
this model.
Given the skewed nature of the ACR, the analysis will be performed similarly as described above 
on the log scale. The percentage of treatment difference, ie, treatment difference in mean ACR 
relative to placebo, can be calculated by taking the anti-logarithm of the estimated coefficient for 
the treatment group and subtracting 1. The ratio of mean ACR in treatment compared to placebo 
and its 95% CI will be presented.
Only subjects with baseline and at least one post-baseline measurement will be included in the 
analysis. The analysis for proinsulin/insulin ratio will be conducted on subjects who are not 
receiving insulin at randomization. For subjects who are started on insulin during the study, all 
proinsulin/insulin data after initiation of insulin will be censored.
Given the skewed nature of the distribution of the percent change in triglycerides, this additional 
secondary endpoint will be analyzed using nonparametric methods as outlined below. A Wilcoxon 
rank sum test will be performed. The Hodges-Lehman estimator for the difference in the medians 
and the distribution-free 95% CIs based on the Wilcoxon rank sum test3 will also be presented.
The change in these additional secondary endpoints from baseline over time will be explored using 
an MMRM model similar to the one used to analyze the change in HOMA-B (Section 4.2.2.1).
4.3.
Multiplicity Adjustment
Per the SAP for the integrated summary, only one alpha is proposed for the testing of the multiple 
hypotheses based on the integrated data and the data from CANVAS-R alone. The Type I error for 
these tests will be strictly controlled via a gatekeeping procedure. No alpha is preserved for 
evaluating hypotheses in CANVAS and all tests will be considered nominal with 2-sided 95% CIs 
provided for descriptive purposes.
4.4.
Exploratory Efficacy Endpoints
4.4.1.
Definition
The following exploratory endpoints will be analyzed:

Time to the first occurrence of hospitalization for heart failure;
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
Time to the first occurrence of the composite endpoint of hospitalization for heart failure or
CV death;

Time to all-cause mortality;

Time to the first occurrence of composite endpoint of 40% decrease in eGFR, renal deatha or 
requirement for renal replacement therapy;

Time to the first occurrence of composite endpoint of doubling of SCr, renal death or
requirement for renal replacement therapy;

Time to the first occurrence of composite endpoint of 40% decrease in eGFR, renal death, 
requirement for renal replacement therapy or CV death;

Time to the first occurrence of composite endpoint of doubling of SCr, renal death, 
requirement for renal replacement therapy or CV death;

Time to the first occurrence of composite endpoint of 40% decrease in eGFR, conversion to 
macroalbuminuria, renal death or requirement for renal replacement therapy;

Time to the first occurrence of composite endpoint of doubling of SCr, conversion to 
macroalbuminuria, renal death or requirement for renal replacement therapy;

Time to first progression of albuminuria, accompanied by an ACR value increase of greater 
than or equal to 30% from baseline;

Time to first regression of albuminuria, accompanied by an ACR value decrease of greater 
than or equal to 30% from baseline;

Change in eGFR from baseline to the last off-drug measurement;

Change in eGFR determined from a between-group comparison of the eGFR slopes using all 
on-drug measurements of eGFR made from the first on-drug measurement to the final on-drug
measurement.
4.4.2.
Analysis Methods
4.4.2.1.
CV Endpoints
The analyses of hospitalization for heart failure and the composite of hospitalization for heart 
failure or CV death will be based on both the ITT analysis set and the On-Treatment analysis set.
The HR of canagliflozin (all canagliflozin group as well as each canagliflozin dose) compared to 
placebo and its 95% CI will be estimated using a stratified Cox proportional hazards regression 
model with treatment as the explanatory variable and the history of CV disease (secondary and 
primary prevention) as the stratification factor. 
4.4.2.2.
All-Cause Mortality
All-cause mortality will be analyzed in both the ITT analysis set and the On-Treatment analysis set
using a stratified Cox proportional hazards model with treatment as the explanatory variable and 
                                                
a Adjudicated non-CV death with a renal proximate cause is considered as renal death
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history of CV disease (secondary and primary prevention) as a stratification factor. The HR of 
canagliflozin (all canagliflozin group as well as each canagliflozin dose) compared to placebo and 
its 95% CI will be estimated from the model.
4.4.2.3.
Renal Endpoints
4.4.2.3.1.
Composite Endpoints
The components of the renal composite endpoints, such as requirement for renal replacement 
therapy and doubling of serum creatinine, identified by the investigator or the sponsor for meeting 
the criteria pre-specified in the charter will be sent to the independent EAC.
The time to the first occurrence of each of the renal composite endpoints (refer to Section 4.4.1) 
will be analyzed in the ITT analysis set using a Cox proportional hazards model with treatment and 
baseline eGFR (< 60, ≥ 60 mL/min/1.73m2) as explanatory variables. The HR of canagliflozin (all 
canagliflozin as well as each canagliflozin dose) compared to placebo and its 95% CI will be 
estimated from the model.
4.4.2.3.2.
Progression of Albuminuria
For the purpose of an exploratory analysis, progression of albuminuria will be assessed as in 
Section 4.2.2.2 with the additional condition that it must be accompanied by an increase in ACR 
value greater than or equal to 30% from baseline. The time to the first occurrence of the event will 
be analyzed in the ITT analysis set using a Cox proportional hazards regression model with 
treatment and baseline albuminuria status as the explanatory variables, excluding subjects with 
baseline macroalbuminuria. The HR of canagliflozin (all canagliflozin as well as each 
canagliflozin dose) compared to placebo and its 95% CI will be estimated from the model. 
4.4.2.3.3.
Regression of Albuminuria
Regression of albuminuria is defined as at least a one stage improvement of albuminuria,
accompanied by an ACR value decrease of greater than or equal to 30% from baseline. The time to 
the first occurrence of the event will be analyzed in the ITT analysis set, using a Cox proportional 
hazards regression model with treatment and baseline albuminuria status as the explanatory 
variables, excluding subjects with baseline normal albuminuria. The HR of canagliflozin (all 
canagliflozin as well as each canagliflozin dose) compared to placebo and its 95% CI will be 
estimated from the model.
4.4.2.3.4.
eGFR Slope
The time slope of eGFR will be analyzed in the On-Treatment analysis set using a linear mixed 
effects model with eGFR as a dependent variable, and treatment, baseline eGFR value, time (as a 
continuous variable), treatment by time interaction as fixed effects, and intercept and time as 
random effects. The parameter of interest is the coefficient for the treatment-by-time interaction 
term, which measures the slope difference between canagliflozin and placebo over time. Data will 
be censored at the date of last study medication plus 2 days.
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5.
SAFETY
Unless otherwise specified, 2 sets of summaries of AEs will be provided. The first set will be
based on the data collected up to 07 January 2014 when INT-6 was first approved. The second set
of summaries will focus on the serious AEs and AEs leading to study drug discontinuation
throughout the entire study periods.
All other safety analyses and summaries (laboratory tests and vital signs) will be based on data 
collected throughout the entire study period using either the On-Treatment analysis set or the 
On-Treatment Pre-INT-6 analysis set, unless otherwise specified. 
There will be no imputation of missing values for clinical laboratory test results, vital sign 
measurements in the safety analyses and there will be no hypothesis testing for results from safety 
analyses.
The treatment groups will be canagliflozin 100 mg, canagliflozin 300 mg, all canagliflozin, and 
placebo.
5.1.
Adjudicated MACE Events
Please refer to Section 4.1 for the primary efficacy analysis of adjudicated MACE events.
5.2.
Adverse Events
Adverse events (AEs) will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA) at the time of database lock.
A treatment-emergent adverse event (TEAE) is defined as an AE with an onset after the initiation 
of double-blind study medication and before the last study medication date plus 30 days. AEs with 
a start date prior to initiation of double-blind study medication which are reported to have an 
increase in intensity, or AEs reported to have an attribution in relationship to study medication 
(ie, attribution to possible, probably, very likely) after the initiation of double-blind study 
medication will also be considered as TEAEs. Most of the AE analyses will pertain to the TEAEs.
5.2.1.
Adverse Event Collection
As one of the initial studies in the Phase 3 program, CANVAS was designed to collect detailed 
information on AEs. Upon the approval of canagliflozin in the United States, the safety profile of 
canagliflozin had been well established. The AE collection was then streamlined following the 
approval of INT-6 to include only: 

Serious adverse events (SAEs);

Adverse events that resulted in study drug discontinuation;

All AEs (serious and non-serious) for AEs of interest (refer to Table 3 below).
For selected AEs of interest, additional data will be collected on supplementary CRF pages 
primarily for the purposes of narrative description of certain events. Table 3 lists the AEs of 
interest that will be summarized. 
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Table 3: 
Adverse Events of Interest 
Section A. All AEs (serious and non-serious) listed below were collected in CANVAS 
through INT-6. After INT-6, only the AEs that were serious or that led to study drug 
discontinuation were collected:
Osmotic diuresis
Volume depletion
Hypoglycemia 
Urinary tract infection (UTI) 
Female mycotic genital infection
Severe hypersensitivity /cutaneous reactions
Pancreatitis 
Hepatic injury 
Renal related AEs (including Nephrotoxicity/ acute kidney injury)  
Section B. The AEs listed below were collected regardless of whether they were
serious and/or led to study drug discontinuation for the entire study:
Male mycotic genital infection (balanitis, phimosis, events leading to circumcision)
Malignancy
Renal cell cancer
Bladder cancer
Pheochromocytoma
Leydig cell tumors
Breast cancer
Photosensitivity
Venous thromboembolic events (VTE)
Amputation 
Fracture 
Diabetic ketoacidosis (DKA)
The AEs listed above will be identified using a MedDRA preferred term list (Appendix 1.4).
5.2.2.
Analysis Methods
The study duration of CANVAS is long relative to the rest of the canagliflozin Phase 3 program. 
Accordingly, the incidences of AEs (ie, proportion of subjects reporting an AE) reported from this
study are not comparable to the incidences generated in the Phase 3 program. Therefore, the 
exposure-adjusted incidence rate will also be reported in addition to the incidence. The exposure-
adjusted incidence rate is calculated as the total number of subjects with the AE divided by the on-
treatment exposure in subject-years. For some particular AEs such as malignancy where the off-
drug follow up is included, the follow-up-adjusted incidence rate will be estimated. The rate is 
calculated as the total number of subjects with the related AE divided by the follow-up time in 
subject-years. 
For general AEs and selected AEs of interest that are not routinely collected (refer to Section A of 
Table 3) after implementation of INT-6, the focus of the summary will be the serious AEs and the 
AEs leading to discontinuation of study medication.
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5.2.2.1.
General Adverse Events
Prior to the Approval of INT-6
On-Treatment Pre-INT6 analysis set will be used for the summary of general AEs prior to the 
approval of INT-6 unless otherwise specified. 
The overall incidence and the exposure-adjusted incidence rate of AEs, AEs leading to 
discontinuation, drug-related AEs, drug-related AEs leading to discontinuation, SAEs, SAEs 
leading to discontinuation, serious drug-related AEs, serious drug-related AEs leading to 
discontinuation, and deaths will be summarized by treatment group. 
AEs by System Organ Class (SOC) will be summarized by treatment group. 
For each AE, the percentage of subjects who experienced at least one occurrence of the given 
event will be provided by preferred term, grouped by SOC, and presented by treatment group. In 
addition, the incidence of severe AEs and drug-related AEs (possibly related, probably related and 
very likely related, as reported by the investigator) will be summarized by preferred term, grouped 
by SOC, and presented by treatment group). The incidence of AEs (by preferred term, grouped by 
SOC, and presented by treatment group) will also be summarized by the action taken regarding the 
study medication, as well as by the outcome. 
For reference, as a screening tool, the 95% CIs for incidence difference between treatment groups 
will be calculated for the AEs which are reported in at least 4 subjects in any treatment group. Four 
(rule-of-4) was chosen based on the recommendation from the Safety, Planning, Evaluation, and 
Reporting Team (SPERT).4 The exclusion of “0” from the 95% CI for the between-group 
difference in incidence for a particular AE does not necessarily imply that the difference is due to 
the drug. The intent of providing the 95% CIs is as a filter to identify AEs that require additional 
assessment. AEs identified by the above screening procedure will be presented and subject to 
further evaluation. 
Through the Entire Study
Serious AEs and the AEs leading to discontinuation collected throughout the entire study will be 
analyzed based on On-Treatment analysis set unless otherwise specified. 
An overview summary table with the incidence and the exposure-adjusted incidence will be 
generated for:

Serious AEs;

Deaths;

AEs leading to discontinuation of study medication;

Serious AEs leading to discontinuation of study medication;

Serious AEs considered drug-related;

AEs considered drug-related leading to discontinuation of study medication.
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SAEs by SOC and preferred term will be summarized by treatment group using the On-Treatment 
analysis set. The same summary will be provided for AEs leading to discontinuation of study 
medication using the On-Treatment analysis set.
The incidence of all SAEs (by preferred term, grouped by SOC, and presented by treatment group) 
will also be summarized by the relationship to study drug, by the action taken regarding the study 
drug, as well as by the outcome. The relationship to study drug will be presented by 2 categories: 
related (which includes possibly related, probably related and very likely related, as reported by 
the investigator) and not related (which includes not related and doubtfully related, as reported by 
the investigator).
For reference, as a screening tool, the 95% CIs for incidence difference between treatment groups 
will be calculated for the AEs (regardless of seriousness) which are reported in at least 4 or more 
subjects in any treatment group. Only the AEs identified by the above screening procedure will be 
presented and subject to further evaluation. 
Listings will also be provided for deaths, SAEs, and AEs leading to study drug discontinuation.
For AEs of interest in Section A of Table 3 (with the exception of hypoglycemia, see 
Section 5.2.2.3), a summary similar to the analysis of general AEs will be provided. The AEs will 
be identified using the MedDRA preferred terms listed in Appendix 1.4.
5.2.2.2.
Male Mycotic Genital Infections
Balanitis and phimosis AEs will be identified using the MedDRA preferred terms listed in 
Appendix 1.4 and the analyses will be based on On-Treatment analysis set only. 
Using the On-Treatment analysis set, an overview summary table with the incidence and the 
exposure-adjusted incidence will be provided for:

All AEs;

Serious AEs;

AEs considered drug-related AEs leading to discontinuation of study medication;

Serious AEs leading to discontinuation of study medication;

Serious AEs considered drug-related;

AEs considered drug-related leading to discontinuation of study medication.
AEs by preferred term will be summarized by treatment group. A Kaplan-Meier plot for the time 
to first occurrence of balanitis will be provided by treatment group.
In addition, circumcision events will be identified based on blinded medical review of the clinical 
database prior to the database lock and summarized by treatment group.
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Based on the additional information collected on the designated supplemental eCRF page in 
CANVAS, the following additional study-specific analyses will be performed:

The incidence of male subjects with any genital mycotic infections will be summarized by 
treatment group and by circumcision status.

Descriptive statistics (N, mean, SD, median, and range) will be calculated by treatment group 
for the duration (days) and severity (grouped as mild or moderate vs. severe) of all infections. 
If a subject experienced multiple events, all durations will be included in the summary.

Descriptive statistics (N, mean, SD, median, and range) will be calculated by treatment group 
for the number of days from start of the AE treatment to the resolution of the symptoms.
5.2.2.3.
Hypoglycemia
Hypoglycemia episodes were collected by a specific, dedicated eCRF for all hypoglycemia up to 
INT-6. Hypoglycemia episodes reported on the supplemental eCRF up to 07 January 2014 will be 
analyzed based on On-Treatment Pre-INT6 analysis set. For hypoglycemia reported on the general 
AE page throughout the study period, focus will be the serious events or the events leading to 
study drug discontinuation. 
Prior to the Approval of INT-6
A subject will be counted as having a documented hypoglycemia episode when there is either a 
biochemically documented hypoglycemic episode (ie, concurrent fingerstick glucose or plasma 
glucose 70 mg/dL [3.9 mmol/L]), and/or a severe hypoglycemic episode as reported on the 
hypoglycemia eCRF, as follows: 

Biochemically documented hypoglycemia episode: a hypoglycemia episode with a concurrent 
reported glucose value of 70 mg/dL (3.9 mmol/L), regardless of whether the episode is 
associated with symptoms (symptomatic hypoglycemia) or not (asymptomatic hypoglycemia).

Severe hypoglycemia episode: a hypoglycemia episode that has the answer “Yes” recorded for 
any of the following 3 questions on the hypoglycemia eCRF: “Did the subject require the 
assistance of others to treat?”, “Did the subject lose consciousness during the episode?”, or 
“Did the subject have a seizure during the episode?” 
Only treatment emergent hypoglycemia episodes, reported on the eCRF for hypoglycemia, will be 
summarized. Treatment emergent is defined the same way as TEAEs (defined in Section 5.2).
The percentages of subjects with documented hypoglycemia episodes (ie, biochemically 
documented and/or severe) and subjects with biochemically documented, and with severe 
hypoglycemia episodes separately, will be summarized by treatment group. For subjects with 
biochemically documented hypoglycemia episodes, the percentage of subjects will be summarized 
for each of the following glucose levels (70 mg/dL [3.9 mmol/L], <56 mg/dL [3.1 mmol/L], and 
<36 mg/dL [2.0 mmol/L], “Low” results will be included in all 3 categories) by treatment group. 
For subjects with severe hypoglycemia episodes, the percentage of subjects by each answer of the 
3 questions for severe hypoglycemia on the eCRF will be summarized by treatment group. The 
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event rate by person-year (total number of episodes/total exposure) will be calculated by treatment 
group separately for documented and for severe hypoglycemia. 
Subjects who had 0, 1, 2, or ≥3 documented episodes and subjects who had 0, 1, 2, or ≥3 severe 
hypoglycemic episodes will be summarized by treatment group.
In addition, the incidence of all episodes of hypoglycemia reported on the eCRF for hypoglycemia 
will be summarized (this includes events without concurrent fingerstick glucose reported and 
events with fingerstick glucose > 70 mg/dL [3.9 mmol/L]) by treatment group.
Through the Entire Study 
Using the On-Treatment analysis set, an overview summary table with the incidence and the 
exposure-adjusted incidence will be provided for:

Serious AEs;

AEs leading to discontinuation of study medication;

Serious AEs leading to discontinuation of study medication;

Serious AEs considered drug-related;

AEs considered drug-related leading to discontinuation of study medication;
SAEs by preferred term will be summarized by treatment group.
5.2.2.4.
Selected Malignancies
The selected malignancies of interest are renal cell cancer, bladder cancer, testicular cancer 
(Leydig cell tumors), pheochromocytomas, and breast cancer. Selected malignancy AEs will be 
identified using the MedDRA preferred terms listed in Appendix 1.4 and the analyses will be 
based on the On-Study analysis set. 
For each selected malignancy of interest, an overview summary table with the incidence and the 
follow-up-adjusted incidence will be provided for:

All AEs;

Serious AEs;

AEs considered drug-related (investigator assessment of possible, probable or very likely);

AEs leading to discontinuation of study medication;

Serious AEs leading to discontinuation of study medication;

Serious AEs considered drug-related;

AEs considered drug-related leading to discontinuation of study medication.
The preferred terms associated with each selected malignancy type will be summarized by 
treatment.
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5.2.2.5.
Photosensitivity
Photosensitivity AE will be identified using the MedDRA preferred terms listed in Appendix 1.4
and the analyses will use the On-Treatment analysis set. 
An overview summary table with the incidence and the exposure-adjusted incidence will be 
provided for:

All AEs;

Serious AEs;

AEs considered drug-related (investigator assessment of possible, probable or very likely);

AEs leading to discontinuation of study medication;

Serious AEs leading to discontinuation of study medication;

Serious AEs considered drug-related;

AEs considered drug-related leading to discontinuation of study medication.
AEs by preferred term will be summarized by treatment group.
5.2.2.6.
Venous Thromboembolic Events
Venous thromboembolic (VTE) events will be identified using the list of MedDRA terms in 
Appendix 1.4. Adverse events identified by the investigator or the sponsor for meeting the criteria 
pre-specified in the charter will be sent to the independent EAC for confirmation. The analyses 
will use the On-Treatment analysis set of adjudicated VTEs. Additionally, a similar analysis of 
investigator reported VTE events will also be provided.
An overview summary table with the incidence and the exposure-adjusted incidence will be 
provided for:

All AEs;

Serious AEs;

AEs considered drug-related (investigator assessment of possible, probable or very likely);

AEs leading to discontinuation of study medication;

Serious AEs leading to discontinuation of study medication;

Serious AEs considered drug-related;

AEs considered drug-related leading to discontinuation of study medication.
AEs by preferred term will be summarized by treatment group.
The incidence of VTEs identified by the MedDRA preferred terms listed in Appendix 1.4 will also 
be summarized by preferred term. A summary table of all VTEs (regardless of adjudication) will 
also be provided by preferred term.
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5.2.2.7.
Fracture
Fracture events identified by the investigator or the sponsor for meeting the criteria pre-specified 
in the charter will be sent to the independent Fracture Adjudication Committee to confirm that 
events were fractures, to determine fracture location (anatomic region) and type (low trauma or 
not). The main analysis will be based on the adjudicated low trauma fractures in the On-Study 
analysis set.
An overview summary table with the incidence and the follow-up-adjusted incidence will be 
provided for:

Adjudicated fractures;

Adjudicated fractures considered serious  (investigator assessment);

Adjudicated fractures considered drug-related (investigator assessment of possible, probable 
or very likely);

Adjudicated fractures leading to discontinuation of study medication;

Adjudicated fractures considered serious and drug-related (investigator assessment);

Adjudicated fractures considered drug-related (investigator assessment) and leading to 
discontinuation of study medication.
A summary of adjudicated fracture stratified by anatomical region by treatment will be provided. 
The incidence as well as the incidence rate will be presented.
A Kaplan-Meier plot for the time to the first occurrence of adjudicated fracture event will be 
provided by treatment group. The HR and the 95% CI will be derived from a Cox proportion 
hazards model with a term for treatment as an explanatory variable. The HR will be estimated in 
subgroups based on sex, baseline age (<65 and ≥65 years), duration of T2DM (<10 and ≥10 years), 
baseline eGFR (<60 and ≥60 mL/min/1.73 m2), and prior fracture history (yes or no). 
A summary of all adjudicated fractures by anatomic location will be provided. The HR and its
95% CI as well as a Kaplan-Meier plot for the first occurrence of all adjudicated fractures will be 
provided using the same analysis as low trauma fracture.
5.2.2.8.
Amputation
The main analysis of lower extremity amputations as documented in the dedicated eCRF will be 
based on the On-Study analysis set. An overview summary table with the incidence and the 
follow-up-adjusted incidence will be provided for:

All lower limb amputations;

Traumatic lower limb amputation;

Atraumatic lower limb amputation.
Summary of anatomical region (toe, ankle, trans-metatarsal, below knee, above knee) of lower 
extremity atraumatic amputations will be reported by treatment group.
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For atraumatic lower limb amputation, a Kaplan-Meier plot for the time to the first occurrence of 
event will be provided by treatment group. The association of amputation with treatment and the 
baseline risk factors listed in Table 4 will be assessed via logistic regression modeling. The 
relationship between amputation and some post-treatment factors such as volume depletion will 
also be explored.
For the post-treatment AEs that may be associated with amputation, groupings of selected 
MedDRA preferred terms used to identify events to be included in each of the following SOC 
categories are presented in Appendix 1.5:

Infections and Infestations;

Vascular disorders;

Nervous System disorders;

Skin and subcutaneous tissue disorders;

Osteomyelitis.
The selected preferred terms in infections and infestation are further split into “Reversible 
Infection” and “Irreversible Infections”. In addition, the preferred terms grouped under the 
MedDRA high level term of “skin and subcutaneous tissue ulcerations” are also of interest.
For each AE group listed above, the incidence of the respective preferred terms will be
summarized by treatment. Stratified by treatment, the odds ratio of amputation and each AE group 
listed above will be estimated.
Table 4: 
Baseline Factors Included in the Logistic Regression Analysis
Baseline Categorical Factors

Gender

Cardiovascular disease history

Peripheral vascular disease history a

Amputation history

Neuropathy history

Retinopathy history

Nephropathy  history

Any diuretic use

Loop diuretic use

Non-loop diuretic use

Smoking

Use of insulin

Baseline Systolic Blood Pressure
o > 120  vs  120 mmHg
o > 140  vs  140 mmHg

Baseline eGFR (ml/min/1.73m2)
o < 60  vs  60 
o < 45  vs  45 

Diabetes duration (< 10 vs 10 yrs.)

Baseline HbA1c (> 8 vs 8%)
Baseline Continuous Factors

Age (yrs.)

Diabetes duration (yrs.)

Systolic blood pressure (mmHg)

eGFR (mL/min/1.73m2)

HbA1c (%)

Hemoglobin (g/L)
a
Excludes amputation history
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5.2.2.9.
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) and related AEs will be identified using the list of MedDRA terms in 
Appendix 1.4. Adverse events identified by the investigator or the sponsor for meeting the criteria 
pre-specified in the charter will be sent to the independent DKA Adjudication Committee. The
main analysis of the DKA events will be based on adjudicated events of DKA in the On-Study
analysis set. Events occurring at any time post-randomization, regardless of the timing of the last 
dose of study medication, will be included. 
For the adjudicated DKA events, a table will summarize the incidence and the follow-up-adjusted 
incidence rate.
A listing of all DKA events identified by the sponsor’s medical monitoring team and the subset of 
the events that went for adjudication will be provided.
5.2.2.10.
Pancreatitis
Pancreatitis and related AEs identified by the sponsor using the list of MedDRA terms pre-
specified in the charter will be sent to the independent Pancreatitis Adjudication Committee. The
main analysis of events will be based on adjudicated, confirmed events in the On-Treatment
analysis set. Analysis based on events occurring at any time post-randomization, regardless of the 
timing of the last dose of study medication, will be performed. The incidence rate and proportion 
of adjudicated pancreatitis events by severity will be summarized. The total number of subjects 
with an event not confirmed by the Pancreatitis Adjudication Committee will also be summarized.
5.3.
Clinical Laboratory Tests
A list of clinical laboratory assessments made during the study is provided in Appendix 1.2. The 
percentage of subjects with specific treatment-emergent laboratory values meeting pre-defined 
limit of change (PDLC) criteria listed in Appendix 1.3 will be summarized. The 95% CI for the 
percentage difference between canagliflozin compared to the placebo group will be provided for 
each PDLC criterion which has at least 4 or more subjects in any treatment group. A
corresponding listing will also be provided. As described above, PDLC values will be presented 
based on measurements on study drug, and up to a maximum of 2 days after the last dose of study 
drug, as well as all measurements regardless of the time of the last dose of double-blind study 
drug. Summaries based on both standard units (SI) and conventional units will be provided.
5.4.
Vital Signs 
A treatment-emergent vital sign abnormality is defined as a change from baseline and subsequent 
post-baseline value that satisfies the PDLC criteria listed in Appendix 1.3. For each vital sign 
parameter, the proportion of subjects with a treatment-emergent abnormality will be tabulated by 
treatment group. PDLC values will be presented based on measurements up to a maximum of 
2 days after the last dose of study drug.
The blood pressure measurements will be based on the average of the consecutive sitting blood 
pressure readings that were to be collected at each visit.
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5.5.
Electrocardiogram 
The decision was made to stop collecting ECG measurements after Week 52 since INT-6. The 
analyses will use all the ECG data available up to the approval of INT-6. The ECG variables that 
will be analyzed are heart rate, PR interval, QRS interval, QT interval, and QTc using the 
Fridericia (QTcF) correction methods. The QTcF corrected interval values are based on the 
following formula:5

Fridericia: QTcF (msec) = QT(msec) * (HR(bpm)/60)1/3.
The PDLC criteria for defining an ECG abnormality for PR interval, QRS interval, QTcF values, 
and changes from baseline within each category are listed in Appendix 1.3. The number and the 
percentage of subjects in each category will be summarized by treatment group up to 2 days after 
the last dose of study drug.
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REFERENCES
1.
Little R et al. The treatment of missing data in a large cardiovascular clinical outcomes study. Clin Trials. 
2016;13(3):344-51.
2.
KDOQI 2007. National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). Amer J of 
Kidney Diseases 2007;49(2, Suppl 2):S1-S180.
3.
Hollander M, Wolfe DA. Nonparametric Statistical Methods, Second edition. John Wiley and Sons, Inc., 1999.
4.
Crowe BJ, Xia HA, Berlin JA, et al. Recommendations for safety planning, data collection, evaluation and 
reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and 
reporting team. Clin Trials. 2009;6:430-440.
5.
Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and of patients with heart 
disease. Acta Medica Scandinavica. 1920; 53:469 – 486.
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APPENDIX
Appendix 1.1: List of Key Analyses of CV and Mortality Endpoints
Analysis Set
Endpoint
Section
Primary Efficacy Assessment of MACE 
ITT
MACE
4.1.2
On-Study
MACE
4.1.4.1
On-Treatment
MACE
4.1.4.2
ITT
MACE components
4.1
On-Treatment
MACE components
4.1
ITT
Subgroup analysis of MACE
4.1.3
Exploratory Assessment of Additional CV Endpoints
ITT
Hospitalization for heart failure
4.4.2.1
On-Treatment
Hospitalization for heart failure
4.4.2.1
ITT
Composite of hospitalization for heart failure or CV Death
4.4.2.1
On-Treatment
Composite of hospitalization for heart failure or CV Death
4.4.2.1
ITT
All-cause Mortality
4.4.2.2
On-Treatment
All-cause Mortality
4.4.2.2
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Appendix 1.2: Clinical Laboratory Tests
The clinical laboratory tests include following panels and assessments:

Hematology panel 
o
hemoglobin
o
platelet count
o
hematocrit
o
red blood cell (RBC) count
o
white blood cell (WBC) count with differential

Serum chemistry panel
o
Sodium
o
alkaline phosphatase
o
potassium
o
creatine phosphokinase (CPK)
o
chloride
o
lactic acid dehydrogenase (LDH)
o
bicarbonate
o
uric acid
o
BUN
o
calcium
o
creatinine
o
phosphate
o
aspartate aminotransferase (AST)
o
albumin
o
alanine aminotransferase (ALT)
o
total protein
o
gamma-glutamyltransferase (GGT)
o
magnesium
o
total bilirubin

Fasting serum lipid profile (triglycerides, LDL-C, HDL-C, total cholesterol).

HbA1c

Urinalysis (dipstick analysis; from spot urine collection in the clinic on Day 1; performed at 
central laboratory; microscopic analysis is not required). Urine glucose will not be measured 
by the central laboratory.
o
specific gravity - ketones
o
pH - bilirubin/urobilinogen
o
protein - nitrite
o
blood - leukocyte esterase

Central laboratory will report the estimated glomerular filtration rate (eGFR) according to the
Modification of Diet in Renal Disease Study (MDRD) equation (Levey 2006) at study visits 
when serum creatinine is measured. The 4-variable MDRD eGFR includes serum creatinine, 
age, race, and sex according to the equation below:
For creatinine in mg/dL:
eGFR (mL/min/1.73 m2) = 175 x (serum creatinine) -1.154 x (age) -0.203 x (0.742 if female) x 
(1.21 if black)
For creatinine in µmol/L:
eGFR (mL/min/1.73m2) = 175 x (serum creatinine x 0.0113) -1.154 x (age) -0.203 x (0.742 if 
female) x (1.21 if black)
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Appendix 1.3: Pre-defined Limit of Change (PDLC) Criteria
Laboratory Test
Parameter for ANY value and LAST value
CHEMISTRY
Albumin
Composite: <LLN and >25% decrease from BL
ALT    
Absolute Value: >3X ULN
Absolute Value: >5X ULN
Absolute Value: >8X ULN
AST
Absolute Value: >3X ULN
Absolute Value: >5X ULN
Absolute Value: >8X ULN
ALT >3X ULN and Tbili >2X ULN
Composite:  ALT >3X ULN and Tbili >2X ULN [with the Tbili elevation >2 
X ULN within 30 days of the ALT elevation >3x ULN]
AST >3X ULN and Tbili >2X ULN
Composite:  AST >3X ULN and Tbili >2X ULN [with the Tbili elevation >2 X 
ULN within 30 days of the AST elevation >3x ULN]
Bilirubin
Composite:  >ULN and > 25% increase from BL
Absolute Value: >2XULN
Bicarbonate
Absolute Value: <16 mEq/L
Calcium
Composite: >ULN and > 10 % increase from BL
Creatinine Kinase 
Absolute Value: >1000U/L
eGFR
Composite: < 80 and decrease>30% from BL
Change:  decrease>50% from BL
Magnesium
Composite: <LLN and >25% decrease from BL
Composite: >ULN and >25% increase from BL
Phosphorus
Composite: >ULN and >25% increase from BL
Potassium  
Composite: <LLN and >15% decrease from BL
Composite: >ULN and >15% increase from BL
Absolute Value: ≥ 6.5 mEq/L
Sodium   
Composite: <LLN and decrease >5 mEq/L or more from BL
Composite: >ULN and increase>5 mEq/L or more from BL
Uric Acid 
Composite: <LLN and >25% decrease from BL
HEMATOLOGY
Hemoglobin
Change: ≥ 2 g/dl decrease from BL
Change: ≥ 2 g/dL increase from BL
Platelets
Composite: >ULN and increase >25% from BL
White Blood Count
Composite: < LLN and >25% decrease from BL
Composite: > ULN and >50 % increase from BL
VITAL SIGNS
Pulse
Absolute Value: ≤50 beats per minute
Absolute Value: ≥100 beats per minute
Systolic Blood Pressure
Composite: ≥ 20 mm Hg decrease from BL and  ≤90 mm Hg
Composite: ≥ 20 mm Hg increase from BL and ≥ 160 mm Hg
Diastolic Blood Pressure
Composite: ≥ 15 mm Hg decrease from BL and  ≤ 50 mm Hg
Composite: ≥ 15 mm Hg increase  from BL and  ≥ 100 mm Hg
ECG PARAMETERS
QTcF
Change: >30-60 ms
Change: >60 ms
Absolute Value: > 450-480 ms
Absolute Value: > 480-500 ms
Absolute Value: >500 ms
PR Interval
Absolute Value: ≥ 200 ms
QRS Interval
Absolute Value: ≤ 50 ms
Absolute Value: ≥ 120 ms
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Appendix 1.4: List of Preferred Terms for Selected AEs of Interest
Diabetic ketoacidosis
Female Mycotic Genital 
Infections
Fracture
Acidosis
Genital candidiasis
Acetabulum fracture
Acidosis aggravated
Genital infection
Ankle fracture
Acidosis diabetic
Genital infection female
Atypical femur fracture
Acidosis metabolic
Genital infection fungal
Atypical fracture
Acidosis NOS
Urogenital infection fungal
Avulsion fracture
Acute acidosis
Vaginal infection
Bone fragmentation
Anion gap acidosis
Vaginal inflammation
Cervical vertebral fracture
Blood ketone body
Vulvitis
Chance fracture
Blood ketone body increased
Vulvovaginal candidiasis
Clavicle fracture
Blood ketone body present
Vulvovaginal mycotic 
infection
Closed fracture manipulation
Diabetes mellitus with ketoacidosis
Vulvovaginitis
Comminuted fracture
Diabetes with hyperosmolarity
Complicated fracture
Diabetes with ketoacidosis
Compression fracture
Diabetic acidosis
Craniofacial fracture
Diabetic hyperglycemic coma
Elevation skull fracture
Diabetic hyperosmolar coma
Epiphyseal fracture
Diabetic ketoacidosis
External fixation of fracture
Diabetic ketoacidotic hyperglycemic 
coma
Facial bones fracture
Diabetic metabolic decompensation
Femoral neck fracture
High anion gap metabolic acidosis
Femur fracture
Hyperglycemic seizure
Fibula fracture
Hyperosmolar hyperglycemic state
Foot fracture
Hyperosmolar state
Forearm fracture
Ketoacidosis
Fracture
Ketonuria
Fracture debridement
Ketosis
Fracture delayed union
Metabolic acidosis
Fracture displacement
Metabolic acidosis exacerbated
Fracture malunion
Metabolic acidosis NOS exacerbated
Fracture nonunion
Metabolic acidosis not otherwise 
specified (NOS)
Fracture pain
Metabolic acidosis worsened
Fracture reduction
Type I diabetes mellitus with 
ketoacidosis
Fracture treatment
Type II diabetes mellitus with 
ketoacidosis
Fractured coccyx
Fractured ischium
Fractured maxilla elevation
Fractured sacrum
Fractured skull depressed
Fractured zygomatic arch elevation
Greenstick fracture
Hand fracture
Hip fracture
Humerus fracture
Ilium fracture
Impacted fracture
Internal fixation of fracture
Jaw fracture
Limb crushing injury
Limb fracture
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Diabetic ketoacidosis
Female Mycotic Genital 
Infections
Fracture
Loss of anatomical alignment after fracture 
reduction
Lower limb fracture
Lumbar vertebral fracture
Multiple fractures
Open fracture
Open reduction of fracture
Open reduction of spinal fracture
Osteochondral fracture
Osteoporotic fracture
Patella fracture
Pathological fracture
Pelvic fracture
Periprosthetic fracture
Pubis fracture
Radius fracture
Rib fracture
Sacroiliac fracture
Scapula fracture
Skull fracture
Skull fractured base
Spinal compression fracture
Spinal fracture
Spinal fusion fracture
Sternal fracture
Stress fracture
Thoracic vertebral fracture
Tibia fracture
Torus fracture
Traumatic fracture
Ulna fracture
Upper limb fracture
Wrist fracture
Hepatic Injury
Hypoglycaemia
Male Mycotic Genital Infections
Acute graft versus host disease in liver
Hypoglycaemia
Balanitis
Acute hepatic failure
Hypoglycaemic coma
Balanitis candida
Acute yellow liver atrophy
Hypoglycaemic seizure
Balanoposthitis
Allergic hepatitis
Balanoposthitis infective
Ammonia increased
Erosive balanitis
Ascites
Gangrenous balanitis
Asterixis
Genital candidiasis 
Autoimmune hepatitis
Genital infection
Bacterascites
Genital infection fungal
Biliary ascites
Genital infection male
Biliary cirrhosis
Penile infection
Biliary cirrhosis primary
Posthitis
Biliary fibrosis
Bilirubin excretion disorder
Biopsy liver abnormal
Child-Pugh-Turcotte score increased
Cholaemia
Cholestasis
Cholestatic liver injury
Cholestatic pruritus
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Hepatic Injury
Hypoglycaemia
Male Mycotic Genital Infections
Chronic graft versus host disease in 
liver
Chronic hepatic failure
Chronic hepatitis
Coma hepatic
Cryptogenic cirrhosis
Diabetic hepatopathy
Drug-induced liver injury
Duodenal varices
Focal nodular hyperplasia
Gallbladder varices
Gastric varices
Gastric varices haemorrhage
Graft versus host disease in liver
Haemangioma of liver
Haemorrhagic ascites
Haemorrhagic hepatic cyst
Hepatectomy
Hepatic adenoma
Hepatic atrophy
Hepatic calcification
Hepatic cirrhosis
Hepatic cyst
Hepatic cyst ruptured
Hepatic encelalopathy
Hepatic encephalopathy prophylaxis
Hepatic failure
Hepatic fibrosis
Hepatic fibrosis marker abnormal
Hepatic haemangioma rupture
Hepatic hydrothorax
Hepatic infiltration eosinophilic
Hepatic lesion
Hepatic necrosis
Hepatic steatosis
Hepatitis
Hepatitis acute
Hepatitis cholestatic
Hepatitis chronic active
Hepatitis chronic persistent
Hepatitis fulminant
Hepatitis toxic
Hepatobiliary disease
Hepatocellular foamy cell syndrome
Hepatocellular injury
Hepatopulmonary syndrome
Hepatorenal failure
Hepatorenal syndrome
Hepatotoxicity
Hyperbilirubinaemia
Icterus index increased
Intestinal varices
Ischaemic hepatitis
Jaundice
Jaundice cholestatic
Jaundice hepatocellular
Liver and small intestine transplant
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Hepatic Injury
Hypoglycaemia
Male Mycotic Genital Infections
Liver disorder
Liver injury
Lupoid hepatic cirrhosis
Lupus hepatitis
Mixed liver injury
Nodular regenerative hyperplasia
Non-alcoholic steatohepatitis
Non-cirrhotic portal hypertension
Ocular icterus
Oedema due to hepatic disease
Oesophageal varices haemorrhage
Parenteral nutrition associated liver 
disease
Peripancreatic varices
Periportal oedema
Portal hypertension
Portal hypertensive enteropathy
Portal hypertensive gastropathy
Portal triaditis
Portal vein cavernous transformation
Portal vein dilatation
Portopulmonary hypertension
Radiation hepatitis
Renal and liver transplant
Retrograde portal vein flow
Reye's syndrome
Reynold's syndrome
Splenic varices
Splenic varices haemorrhage
Subacute hepatic failure
Varices oesophageal
Varicose veins of abdominal wall
Malignancy Bladder Cancer
Malignancy Breast Cancer
Malignancy Phaeochromocytoma
Bladder adenocarcinoma recurrent
Apocrine breast carcinoma
Phaeochromocytoma
Bladder adenocarcinoma stage 0
Breast angiosarcoma
Phaeochromocytoma crisis
Bladder adenocarcinoma stage I
Breast angiosarcoma 
metastatic
Phaeochromocytoma excision
Bladder adenocarcinoma stage II
Breast cancer
Phaeochromocytoma malignant
Bladder adenocarcinoma stage III
Breast cancer female
Bladder adenocarcinoma stage IV
Breast cancer in situ
Bladder adenocarcinoma stage unspecified
Breast cancer male
Bladder cancer
Breast cancer metastatic
Bladder cancer recurrent
Breast cancer recurrent
Bladder cancer stage 0, with cancer in situ
Breast cancer stage I
Bladder cancer stage 0, without cancer in 
situ
Breast cancer stage II
Bladder cancer stage I, with cancer in situ
Breast cancer stage III
Bladder cancer stage I, without cancer in 
situ
Breast cancer stage IV
Bladder cancer stage II
Breast neoplasm
Bladder cancer stage III
Breast sarcoma
Bladder cancer stage IV
Breast sarcoma metastatic
Bladder squamous cell carcinoma recurrent
Breast sarcoma recurrent
Bladder squamous cell carcinoma stage 0
Contralateral breast cancer
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Malignancy Bladder Cancer
Malignancy Breast Cancer
Malignancy Phaeochromocytoma
Bladder squamous cell carcinoma stage I
HER-2 positive breast cancer
Bladder squamous cell carcinoma stage II
Hormone refractory breast 
cancer
Bladder squamous cell carcinoma stage III
Inflammatory carcinoma of 
breast recurrent
Bladder squamous cell carcinoma stage IV
Inflammatory carcinoma of 
breast stage III
Bladder squamous cell carcinoma stage 
unspecified
Inflammatory carcinoma of 
breast stage IV
Bladder transitional cell carcinoma
Inflammatory carcinoma of 
the breast
Bladder transitional cell carcinoma 
metastatic
Intraductal papillary breast 
neoplasm
Bladder transitional cell carcinoma 
recurrent
Intraductal proliferative breast 
lesion
Bladder transitional cell carcinoma stage 0
Invasive breast carcinoma
Bladder transitional cell carcinoma stage I
Invasive ductal breast 
carcinoma
Bladder transitional cell carcinoma stage II
Invasive lobular breast 
carcinoma
Bladder transitional cell carcinoma stage 
III
Invasive papillary breast 
carcinoma
Bladder transitional cell carcinoma stage 
IV
Lobular breast carcinoma in 
situ
Metastases to bladder
Malignant nipple neoplasm
Metastatic carcinoma of the bladder
Malignant nipple neoplasm 
female
Transitional cell carcinoma
Malignant nipple neoplasm 
male
Medullary carcinoma of breast
Metaplastic breast carcinoma
Metastases to breast
Mucinous breast carcinoma
Neuroendocrine breast tumour
Nipple neoplasm
Oestrogen receptor positive 
breast cancer
Paget's disease of nipple
Phyllodes tumour
Triple negative breast cancer
Tubular breast carcinoma
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Malignancy Renal Cell Cancer
Malignancy Testicular
Osmotic Diuresis 
Clear cell renal cell carcinoma
Benign neoplasm of testis
Dry mouth
Clear cell sarcoma of the kidney
Leydig cell tumour of the testis
Dry throat
Denys-Drash syndrome
Sertoli cell testicular tumour
Micturition disorder
Hereditary leiomyomatosis renal cell carcinoma
Spermatocytic seminoma
Micturition urgency
Hereditary papillary renal carcinoma
Testicle adenoma
Nocturia
Metastatic renal cell carcinoma
Testicular cancer metastatic
Pollakiuria
Nephroblastoma
Testicular neoplasm
Polydipsia
Non-renal cell carcinoma of kidney
Testicular papilloma
Polyuria
Renal cancer
Testis cancer
Thirst
Renal cancer metastatic
Tongue dry
Renal cancer recurrent
Urine output increased
Renal cancer stage I
Renal cancer stage II
Renal cancer stage III
Renal cancer stage IV
Renal cell carcinoma
Renal cell carcinoma recurrent
Renal cell carcinoma stage I
Renal cell carcinoma stage II
Renal cell carcinoma stage III
Renal cell carcinoma stage IV
Rhabdoid tumour of the kidney
Phimosis
Photosensitivity
Acquired phimosis
Actinic elastosis
Phimosis
Actinic prurigo
Administration site photosensitivity reaction
Application site photosensitivity reaction
Chronic actinic dermatitis
Hartnup disease
Implant site photosensitivity
Infusion site photosensitivity reaction
Injection site photosensitivity reaction
Juvenile spring eruption
Medical device site photosensitivity
Photodermatosis
Photokeratitis
Photoonycholysis
Photosensitivity reaction
Polymorphic light eruption
Solar dermatitis
Solar urticaria
Sunburn
Vaccination site photosensitivity
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Renal Related
Severe Hypersensitivity/Cutaneous AEs
Upper UTI
Acute kidney injury
Acute generalised exanthematous pustulosis
Bacterial pyelonephritis
Acute phosphate nephropathy
Allergic oedema
Emphysematous 
pyelonephritis
Acute prerenal failure
Anaphylactic reaction
Kidney infection
Anuria
Anaphylactic shock
Perinephric abscess
Azotaemia
Anaphylactic transfusion reaction
Pyelocystitis
Blood creatinine increased
Anaphylactoid reaction
Pyelonephritis
Blood urea increased
Anaphylactoid shock
Pyelonephritis acute
Continuous haemodiafiltration
Angioedema
Pyelonephritis chronic
Dialysis
Circulatory collapse
Pyelonephritis fungal
Glomerular filtration rate 
decreased
Circumoral oedema
Pyelonephritis mycoplasmal
Haemodialysis
Conjunctival oedema
Pyelonephritis viral
Haemofiltration
Corneal exfoliation
Pyonephrosis
Hypercreatininaemia
Corneal oedema
Renal abscess
Neonatal anuria
Cutaneous vasculitis
Renal cyst infection
Nephritis
Dermatitis bullous
Urosepsis
Nephropathy toxic
Dermatitis exfoliative
Oliguria
Dermatitis exfoliative generalised
Peritoneal dialysis
Drug eruption
Prerenal failure
Drug hypersensitivity
Renal failure
Drug reaction with eosinophilia and systemic 
symptoms
Renal failure acute
Epidermal necrosis
Renal failure neonatal
Epiglottic oedema
Renal impairment
Erythema multiforme
Renal impairment neonatal
Exfoliative rash
Eye oedema
Eye swelling
Eyelid oedema
Face oedema
First use syndrome
Fixed drug eruption
Gingival oedema
Gingival swelling
Gleich's syndrome
Hereditary angioedema
Hypersensitivity vasculitis
Idiopathic angioedema
Idiopathic urticaria
Kounis syndrome
Laryngeal dyspnoea
Laryngeal oedema
Laryngospasm
Laryngotracheal oedema
Limbal swelling
Lip exfoliation
Lip oedema
Lip swelling
Mucocutaneous ulceration
Mucosa vesicle
Mucosal erosion
Mucosal exfoliation
Mucosal necrosis
Mucosal ulceration
Nikolsky's sign
Oculomucocutaneous syndrome
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Renal Related
Severe Hypersensitivity/Cutaneous AEs
Upper UTI
Oculorespiratory syndrome
Oedema mouth
Oedema mucosal
Oral mucosal blistering
Oral mucosal exfoliation
Orbital oedema
Oropharyngeal blistering
Oropharyngeal swelling
Palatal oedema
Penile exfoliation
Periorbital oedema
Pharyngeal oedema
Scleral oedema
Shock
Shock symptom
Skin exfoliation
Skin necrosis
Small bowel angioedema
Stevens-Johnson syndrome
Stridor
Swelling face
Swollen tongue
Throat tightness
Tongue exfoliation
Tongue oedema
Toxic epidermal necrolysis
Type I hypersensitivity
Urticaria
Urticaria cholinergic
Urticaria chronic
Urticaria papular
Urticarial vasculitis
Vaginal exfoliation
UTI
Venous Thromboembolic events
Volume Depletion 
Bladder candidiasis
Deep vein thrombosis
Blood pressure decreased
Cystitis
Deep vein thrombosis postoperative
Blood pressure orthostatic decreased
Cystitis bacterial
Embolism venous
Dehydration
Cystitis escherichia
Iliac vein occlusion
Diastolic hypotension
Cystitis gonococcal
Inferior vena cava syndrome
Dizziness postural
Cystitis haemorrhagic
Inferior vena caval occlusion
Hypotension
Cystitis interstitial
Jugular vein occlusion
Hypovolaemia
Cystitis klebsiella
Mesenteric vein occlusion
Hypovolaemic shock
Cystitis pseudomonal
Obstructive shock
Orthostatic hypotension
Emphysematous cystitis
Portosplenomesenteric venous 
thrombosis
Orthostatic intolerance
Escherichia urinary tract infection
Post procedural pulmonary embolism
Postural orthostatic tachycardia 
syndrome
Fungal cystitis 
Postpartum venous thrombosis
Presyncope
Funguria
Pulmonary embolism
Shock
Genitourinary tract infection 
Pulmonary infarction
Shock symptom
Streptococcal urinary tract 
infection
Pulmonary microemboli
Syncope
Ureter abscess
Pulmonary oil microembolism
Urine output decreased
Ureteritis
Pulmonary thrombosis
Uretheritis
Renal vein embolism
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UTI
Venous Thromboembolic events
Volume Depletion 
Urethral abscess
Renal vein occlusion
Urethral carbuncle
Subclavian vein thrombosis
Urethral stricture post infection
Vascular occlusion
Urinary bladder abscess
Venous thrombosis
Urinary tract abscess
Venous thrombosis in pregnancy
Urinary tract infection
Venous thrombosis limb
Urinary tract infection bacterial
Visceral venous thrombosis
Urinary tract infection 
enterococcal
Urinary tract infection fungal
Urinary tract infection 
pseudomonal
Urinary tract infection 
staphylococcal
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Appendix 1.5: Adverse Events with Potential Amputation Association
List of selected preferred terms included within the SOCs of infections and infestations, vascular 
disorders, nervous system disorders, and skin and subcutaneous tissue disorders
Infections and 
Infestations
Vascular 
Disorders
Nervous System 
Disorders
Skin and 
Subcutaneous 
Tissue Disorders
High Level Term (HLT) Skin and subcutaneous 
tissue ulcerations
Infected skin ulcer
Arteriosclerosis
Paraesthesia
Diabetic ulcer
Penile ulceration
Medical device site 
erosion
Skin infection
Peripheral arterial 
occlusive disease
Hypoaesthesia
Neuropathic ulcer
Implant site ulcer
Ulcerated 
haemangioma
Staphylococcal skin 
infection
Peripheral vascular 
disorder
Diabetic neuropathy
Fungating wound
Cytomegalovirus 
mucocutaneous ulcer
Incision site erosion
Gangrene
Peripheral artery 
stenosis
Neuropathy peripheral
Diabetic foot
Skin ulcer
Incision site ulcer
Osteomyelitis
Peripheral 
ischaemia
Areflexia
Diabetic 
neuropathic ulcer
Eyelid erosion
Vaccination site 
ulcer
Diabetic gangrene
Arterial stenosis
Hyporeflexia
Skin erosion
Implant site erosion
Fungating wound
Localised infection
Diabetic vascular 
disorder
Polyneuropathy
Diabetic foot infection
Ecthyma
Wound abscess
Femoral artery 
occlusion
Autonomic neuropathy
Application site erosion
Perineal ulceration
Wound infection
Thrombosis
Neuropathy peripheral
Infusion site erosion
Tropical ulcer
Subcutaneous 
abscess
Poor peripheral 
circulation
Burning sensation
Mycobacterium ulcerans 
infection
Injection site erosion
Abscess limb
Microangiopathy
Diabetic autonomic 
neuropathy
Infusion site ulcer
Pyogenic sterile 
arthritis pyoderma 
gangrenosum and 
acne syndrome
Staphylococcal 
osteomyelitis
Peripheral 
coldness
Peripheral sensory 
neuropathy
Neuropathic ulcer
Scleroderma 
associated digital 
ulcer
Diabetic foot 
infection
Diabetic 
microangiopathy
Peripheral 
sensorimotor 
neuropathy
Skin ulcer haemorrhage
Vulval ulceration
Staphylococcal skin 
infection
Arterial occlusive 
disease
Sensory disturbance
Burn infection
Mucocutaneous 
ulceration
Soft tissue infection
Arterial 
thrombosis
Diabetic neuropathic 
ulcer
Diabetic foot
Injection site ulcer
Bone abscess
Peripheral artery 
thrombosis
Diabetic ulcer
Pyoderma 
gangrenosum
Osteitis
Arterial occlusive 
disease
Catheter site erosion
Scrotal ulcer
Cellulitis
Angiopathy
Pyostomatitis vegetans
Application site 
ulcer
Wound a
Intermittent 
claudication
Catheter site ulcer
Genital ulceration
Dry gangrene
Arterial disorder
Medical device site ulcer
Infected skin ulcer
Post-operative 
wound infection
Impaired healing a
Administration site ulcer
Diabetic neuropathic 
ulcer
Post-operative 
wound complication 
a
Instillation site erosion
Varicose ulceration
Wound dehiscence
Breast ulceration
Vaginal ulceration
Burn infection
Instillation site ulcer
Vulvovaginal 
ulceration
Extremity necrosis
Administration site 
erosion
Auditory meatus 
external erosion
Vasculitic ulcer
Skin erosion
Vaccination site erosion
a
Although these PTs belong in the SOC of Injury, Poisoning and Procedural Complications or in the SOC of General Disorders 
and Administration Site Conditions, these terms were retained for the search strategy because of their relevance
NCT01032629


JNJ- 28431754 (canagliflozin)
Statistical Analysis Plan 28431754DIA3008
50
Approved, Date: 20 March 2017     
List of preferred terms classified as reversible infections, irreversible infections and osteomyelitis
Reversible Infections
Irreversible Infections
Osteomyelitis
Abscess limb
Diabetic gangrene
Bone abscess
Burn infection
Dry gangrene
Osteitis
Cellulitis
Extremity necrosis
Osteomyelitis
Diabetic foot infection
Gangrene
Staphylococcal osteomyelitis
Infected skin ulcer
Localised infection
Skin infection
Soft tissue infection
Staphylococcal skin infection
Subcutaneous abscess
Wound
Wound abscess
Wound dehiscence
Wound infection
NCT01032629