Clinical trial NCT01989754
Conditions: Diabetes Mellitus, Type 2 Albuminuria
Keywords: Albuminuria Canagliflozin Cardiovascular outcomes Type 2 Diabetes Mellitus T2DM JNJ-28431754 Antihyperglycemic Agent
Sponsor: Janssen Research & Development, LLC
Start date: 2014-01-16; Completion date: 2017-02-23
Enrollment: 5813 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effect of canagliflozin compared to placebo on progression of albuminuria in participants with Type 2 Diabetes Mellitus receiving standard care but with inadequate glycemic control and at elevated risk of cardiovascular events.

Detailed description:
The study will be conducted in adult participants with Type 2 Diabetes Mellitus (T2DM), receiving standard of care for hyperglycemia and cardiovascular (CV) risk factors, who have either a history of a prior CV event or 2 or more risk factors for a CV event. Participants will be randomly assigned in a 1:1 ratio to canagliflozin or matching placebo to be taken once daily. Canagliflozin will be provided at a dose of 100 mg/day through Week 13 and then increased at the discretion of the investigator to a dose of 300 mg/day, if the participant requires additional glycemic control and is tolerating the 100 mg dose.

The study consists of a 2-week screening period and a double-blind treatment period lasting between 78 and 156 weeks; study completion is targeted for when the last subject randomized has approximately 78 weeks of follow-up or when 688 major adverse cardiovascular events are accumulated between CANVAS and CANVAS-R. A total of 5,700 participants are targeted to be recruited into the study. Participants can be either drug naïve to antihyperglycemic agents, using monotherapy, or using combination of antihyperglycemic therapy for the control of blood glucose levels.

The completion target was reached in February 2017.

Arms: arm 1: Each patient will receive canagliflozin (JNJ-28431754) 100 mg once daily during the first 13 weeks, then the dose may be increased to 300 mg once daily. arm 2: Each patient will receive placebo (inactive medication) once daily.
Interventions: intervention 1: Placebo intervention 2: Canagliflozin, 100 mg intervention 3: Canagliflozin, 300 mg
Intervention descriptions: intervention 1: One placebo capsule taken orally (by mouth) once daily for 156 weeks 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 documents:
Prot_000.pdf: 
1
Approved, Date: 01 September 2016
Janssen Research & Development, LLC*
Clinical Protocol
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
The “CANVAS-R” Trial
(CANagliflozin cardioVascular Assessment Study-Renal)
Protocol 28431754DIA4003; Phase 4**
AMENDMENT INT-5
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).
**This is a Phase 4 postmarketing study required by the US Food & Drug Administration but may be considered a 
Phase 3 study in some countries in which canagliflozin has not been approved.
Status:
Approved
Date:
1 September 2016
Prepared by:
Janssen Research & Development, LLC
EDMS No & Version:
EDMS-ERI-65832346, 8.0
EudraCT No.:
2013-003050-25
GCP 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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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 10
TIME AND EVENTS SCHEDULE: PRETREATMENT AND DOUBLE-BLIND TREATMENT.................. 15
ABBREVIATIONS ...................................................................................................................................... 20
1.
INTRODUCTION................................................................................................................................ 21
1.1.
Background .................................................................................................................................... 22
1.1.1.
Nonclinical Studies ..................................................................................................................... 22
1.1.2.
Clinical Studies ........................................................................................................................... 23
1.2.
Overall Rationale and Goals for the Study..................................................................................... 28
2.
OBJECTIVES AND HYPOTHESES.................................................................................................. 32
2.1.
Objectives ...................................................................................................................................... 32
2.2.
Hypotheses .................................................................................................................................... 33
2.2.1.
Primary Hypothesis..................................................................................................................... 33
2.2.2.
Secondary Hypotheses............................................................................................................... 33
3.
OVERVIEW OF STUDY DESIGN...................................................................................................... 33
3.1.
Study Design.................................................................................................................................. 34
3.2.
Study Design Rationale.................................................................................................................. 38
4.
STUDY POPULATION ...................................................................................................................... 39
4.1.
General Considerations ................................................................................................................. 39
4.2.
Inclusion Criteria ............................................................................................................................ 39
4.3.
Exclusion Criteria ........................................................................................................................... 41
4.4.
Prohibitions and Restrictions ......................................................................................................... 43
4.5.
Rescreening ................................................................................................................................... 43
5.
TREATMENT ALLOCATION ............................................................................................................43
6.
DOSAGE AND ADMINISTRATION ..................................................................................................44
6.1.
Study Drugs ................................................................................................................................... 44
6.2.
Concomitant Antihyperglycemic and Other Therapies .................................................................. 45
6.2.1.
Management of Glycemic Control and CV Risk Factors............................................................45
7.
TREATMENT COMPLIANCE............................................................................................................ 46
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................47
9.
STUDY EVALUATIONS .................................................................................................................... 47
9.1.
Study Procedures........................................................................................................................... 47
9.1.1.
Overview..................................................................................................................................... 47
9.1.2.
Pretreatment Phase.................................................................................................................... 49
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 49
9.1.4.
Post-Treatment Follow-up for Participants who Withdraw from Randomized Treatment 
Early............................................................................................................................................ 50
9.1.5.
Post-Treatment Follow-up for Participants that Complete Randomized Treatment as 
Initially Scheduled....................................................................................................................... 50
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9.1.6.
Post-Randomization Follow-up for Participants Unable to Attend Scheduled Visits.................. 51
9.2.
Reporting/Adjudication of MACE and Other Events for Adjudication ............................................ 51
9.3.
Study Management: Committees................................................................................................... 52
9.3.1.
Academic Research Organization .............................................................................................. 52
9.3.2.
Steering Committee.................................................................................................................... 52
9.3.3.
Medical Safety Review Committee............................................................................................. 52
9.3.4.
Independent Data Monitoring Committee................................................................................... 52
9.3.5.
Endpoint Adjudication Committee .............................................................................................. 52
9.4.
Safety Evaluations ......................................................................................................................... 53
9.5.
Measures of Efficacy/Efficacy Endpoints....................................................................................... 55
10.
SUBJECT COMPLETION, PREMATURE DISCONTINUATION OF TREATMENT, LOSS 
TO FOLLOW-UP AND WITHDRAWAL OF CONSENT ...................................................................56
10.1.
Subject Completion........................................................................................................................ 56
10.2.
Premature Discontinuation of Study Medication............................................................................56
10.3.
Reinstitution of Treatment for Subjects Who Have Prematurely Discontinued Double-
Blind Study Drug to Active Status .................................................................................................. 57
10.4.
Lost to Follow-up............................................................................................................................ 57
10.5.
Circumstances for Reduced Follow-up.......................................................................................... 57
10.6.
Withdrawal of Consent................................................................................................................... 58
11.
STATISTICAL METHODS................................................................................................................. 58
11.1.
Analysis Sets.................................................................................................................................. 58
11.2.
Sample Size Determination ........................................................................................................... 58
11.3.
Efficacy Analyses ........................................................................................................................... 59
11.3.1.
Primary Efficacy Analysis ........................................................................................................... 59
11.3.2.
Secondary Efficacy Analyses ..................................................................................................... 59
11.3.3.
Exploratory Efficacy Analyses .................................................................................................... 60
11.3.4.
Multiplicity Adjustment ................................................................................................................ 60
11.4.
Safety Analyses ............................................................................................................................. 61
12.
ADVERSE EVENT REPORTING ...................................................................................................... 62
12.1.
Definitions ...................................................................................................................................... 64
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 64
12.1.2.
Attribution Definitions.................................................................................................................. 65
12.1.3.
Severity Criteria .......................................................................................................................... 65
12.2.
Procedures..................................................................................................................................... 66
12.2.1.
All Adverse Events...................................................................................................................... 66
12.2.2.
Serious Adverse Events ............................................................................................................. 68
12.2.3.
Pregnancy................................................................................................................................... 68
12.3.
Contacting Sponsor Regarding Safety........................................................................................... 69
13.
PRODUCT QUALITY COMPLAINT HANDLING..............................................................................69
13.1.
Procedures..................................................................................................................................... 69
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................69
14.
STUDY DRUG INFORMATION......................................................................................................... 69
14.1.
Physical Description of Study Drug(s) ........................................................................................... 69
14.2.
Packaging ...................................................................................................................................... 69
14.3.
Labeling.......................................................................................................................................... 70
14.4.
Preparation, Handling, and Storage............................................................................................... 70
14.5.
Drug Accountability ........................................................................................................................ 70
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 70
16.
ETHICAL ASPECTS ......................................................................................................................... 71
16.1.
Study-Specific Design Considerations........................................................................................... 71
16.2.
Regulatory Ethics Compliance....................................................................................................... 72
16.2.1.
Investigator Responsibilities ....................................................................................................... 72
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16.2.2.
Independent Ethics Committee or Institutional Review Board (IEC/IRB)................................... 73
16.2.3.
Informed Consent ....................................................................................................................... 74
16.2.4.
Privacy of Personal Data ............................................................................................................ 75
16.2.5.
Country Selection ....................................................................................................................... 75
17.
ADMINISTRATIVE REQUIREMENTS ..............................................................................................76
17.1.
Protocol Amendments.................................................................................................................... 76
17.2.
Regulatory Documentation ............................................................................................................ 76
17.2.1.
Regulatory Approval/Notification ................................................................................................ 76
17.2.2.
Required Prestudy Documentation............................................................................................. 76
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 77
17.4.
Source Documentation................................................................................................................... 77
17.5.
Case Report Form Completion ...................................................................................................... 78
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 78
17.7.
Record Retention ........................................................................................................................... 79
17.8.
Monitoring ...................................................................................................................................... 79
17.9.
Study Completion/Termination....................................................................................................... 80
17.9.1.
Study Completion ....................................................................................................................... 80
17.9.2.
Study Termination....................................................................................................................... 80
17.10.
On-Site Audits ................................................................................................................................ 80
17.11.
Use of Information and Publication................................................................................................ 81
REFERENCES............................................................................................................................................ 83
INVESTIGATOR AGREEMENT ................................................................................................................. 86
LIST OF ATTACHMENTS
Attachment 1:
Clinical Laboratory Tests............................................................................................ 85
LIST OF IN-TEXT FIGURES 
FIGURES
Figure 1: 
Mean Change in eGFR Over Time (DIA3009) .........................................................................29
Figure 2: 
Mean Change in eGFR Over Time (DIA3004) .........................................................................30
Figure 3: 
Hypotheses Regarding the Effect of ACEI and ARBs on the Progression of Diabetic 
Nephropathy ............................................................................................................................. 31
Figure 4: 
Study Design Outline ................................................................................................................ 35
Figure 5: 
Follow-up of Randomized Subjects with Respect to the GTED ............................................... 36
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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
27 September 2013
INT-1
16 October 2013
INT-2
20 December 2013
INT-3
17 September 2015
INT-4
05May 2016
INT-5
01 September 2016
Amendments are listed beginning with the most recent amendment.
Amendment INT-5 (01 September 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 add secondary 
cardiovascular objectives and exploratory renal objectives.
Applicable Section(s)
Description of Change(s)
Rationale: Added secondary cardiovascular objectives to assess cardioprotective effects of canagliflozin and added
exploratory renal objectives.
Synopsis
Section 2. Objectives 
and Hypotheses,
Section 11.3.2. 
Secondary Efficacy 
Analyses
Section 11.3.3. 
Exploratory Efficacy 
Analyses
Section 11.3.4. 
Multiplicity 
Adjustment
Section 11.4. Safety 
Analyses
Added secondary cardiovascular objectives of the composite endpoint of cardiovascular 
death or hospitalization for heart failure, and cardiovascular death.
Added exploratory renal composite endpoints.
Under ‘Multiplicity Adjustment’, removed statements about CV meta-analysis being pre-
specified in the SAP for this study, and that the CV meta-analysis SAP will be pre-
specified in a separate document, since these statements are not necessary and unrelated to 
the multiplicity adjustment.
Rationale: Added checkmark for foot care guidance that was erroneously omitted.
Time and Events 
Schedule; footnote 
“n”
Added checkmark for foot care discussion/assessment and provision of foot care guidance 
during phone/email contact midway between 26-week visits until last on-treatment visit.
Rationale: Added rationale for expanded secondary CV objectives.
Section 1.2: Overall
rationale and goals for 
the study
Added rationale for expanded CV secondary objectives and exploratory renal objectives, 
including a brief summary of EMPA-REG OUTCOME data with empagliflozin.
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Amendment INT-4 (05 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: Include guidance regarding subject management surrounding the event of lower extremity amputations.
Time and Events 
Schedule footnote 
“f”; footnote “n”
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 DKA will be adjudicated by an ad hoc adjudication 
committee, to verify whether or not the event meets a specified definition of DKA.
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 “l”
Section 3.1. Study 
Design;
Section 9.4. Safety 
Evaluations
Section 12. Adverse 
Event Reporting
Section 12.2.1. All 
Adverse Events
Section 16.1. Study-
Specific Design 
Considerations
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, "amputations”.
Rationale: Minor errors were noted.
Throughout the 
protocol.
Minor grammatical, formatting, or spelling changes were made.
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Amendment INT-3 (17 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, in that it does significantly impact 
the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: In response to Agence Nationale de Securite de Medicament et des 
Produits de Sante (ANSM)- France IB addendum 2 - Canagliflozin - where a request 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: To provide clarification of the urinary albumin/creatinine ratio (ACR) analysis and expand analysis 
scope for ACR to cover all the post-baseline data.
Synopsis:
Efficacy Outcome/Evaluation Criteria
Primary Outcomes
Secondary Outcomes
Primary Efficacy Analysis
Secondary Efficacy Analyses
Section 2.1 Secondary Objectives
Section 11.3.2 Efficacy Analysis
Additional wording and more detailed descriptions added 
Rationale: To expand analysis scope for post-treatment eGFR to cover all the post-treatment data
Synopsis:
Secondary Objective
Secondary Outcomes
Secondary Efficacy Analyses
Section 2.1 Secondary Objectives
Section 11.3.2 Efficacy Analysis
Additional wording and more detailed descriptions added 
Rationale: To remove a previously introduced error in the footnotes
Time & Events Schedule
Footnote “k”
Footnote was removed from the double-blind treatment period.
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 & Events Schedule  Footnote 
“l”;
Section 3.1 Study Design;
Section 9.4 Safety Evaluations;
Section 12 Adverse Event Reporting;
Section 12.2.1 All Adverse Events;
Section 16.1 Study-Specific Design
Considerations
An AE  of interest “male genital infections (balanitis, phimosis, events 
leading to circumcision)”and AE of special interest “Diabetic ketoacidosis 
has been designated an adverse event of special interest and therefore 
adverse events related to diabetic ketoacidosis, ketoacidosis, metabolic 
acidosis or acidosis need to be reported to Janssen 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” were added; 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.  
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.
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Applicable Section(s)
Description of Change(s)
Rationale: To provide clarification on study drug interruption
Section 6.1 Study Drugs
Additional wording added to last paragraph to clarify study drug 
interruption requirements.
Rationale: To include an experience of a serious confirmed adverse event of diabetic DKA to the list of  reasons for 
premature discontinuation of study drug.
Section 10.2 Premature 
Discontinuation of Study Medication
The sentence “The subject experiences a serious adverse event of 
biochemically-confirmed (eg, pH, serum ketones, anion gap) DKA” was 
added.
Rationale: To preserve the original randomization, the analysis set for primary analysis of all efficacy endpoints is 
intent-to-treat (ITT) and secondary is modified intent-to-treat (mITT/On-treatment) if applicable.
Synopsis:
Analysis Set
Section 11.1 Analysis Set
ITT set is added and analysis sets for primary and secondary efficacy 
analysis are clarified.
Rationale: To provide  guidance on the monitoring and management of DKA.
Section 12.2.1 All Adverse Events
A paragraph 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: Minor errors were noted
Throughout the protocol
Minor grammatical or formatting changes were made.
Amendment INT-2 (20 December 2013)
This amendment is considered to be nonsubstantial 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, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment:  The overall reason for the amendment is to add a baseline (Day 1) 
urinalysis measurement to provide baseline health status information and safety data.
Applicable Section(s)
Description of Change(s)
Rationale: A baseline (Day 1) urinalysis measurement was added to provide baseline health status information and 
safety data.
Time & Events 
Schedule 
A spot urine collection at the clinic was added at Day 1. (Footnote “g” was also modified 
to add this procedure.)
Rationale: An inconsistency between a footnote and the text was noted.
Time & Events 
Schedule  footnote “h”
The timeframe to return a first morning void specimen to the site (if not provided on the 
day of the visit) was corrected to 7 days (previously 30 days).
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Applicable Section(s)
Description of Change(s)
Rationale: A baseline (Day 1) urinalysis measurement was added to provide baseline health status information and 
safety data.
Rationale: New canagliflozin protocols have added additional bone mineral density data.
Section 1.1.2. Clinical 
Studies
Further clarification of the bone mineral density data in the 28431754DIA3010 study at 
Week 104 was made to ensure consistency in the description with other canagliflozin 
protocols.
Rationale: An update to Attachment 1 was needed to align with updates in the Time & Events schedule for 
urinalysis.
Attachment 1: Clinical 
Laboratory Tests
Baseline (Day 1) urinalysis was added.
Amendment INT-1 (16 October 2013)
This amendment is considered to be nonsubstantial 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, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to ensure consistency with the 
standard protocol template text in the sections listed below.
Applicable Section(s)
Description of Change(s)
Section 12.2.3, 
Pregnancy
Was removed: “If a subject’s partner becomes pregnant any time between the start of 
study drug and 30 days after the last dose, the subject must inform the investigator as 
soon as possible.”
Section 14.5,
Drug Accountability
‘Study drug returned…” was replaced with  “All study drug…”
Was added: “Returned study drug must not be dispensed again, even to the same 
subject.”
Section 16.2.2, 
Independent Ethics 
Committee or 
Institutional Review 
Board (IEC/IRB)
Was added throughout the section: “…excluding the ones that are purely administrative, 
with no consequences for subjects, data or study conduct…”
Section 17.3,
Subject Identification, 
Enrollment, and 
Screening Logs
“…by initials and assigned number only…” was replaced with “…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.”
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical or formatting changes were made.
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SYNOPSIS
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 (“CANVAS-R”)
EUDRACT number: 2013-003050-25
PREAMBLE
Canagliflozin (JNJ-28431754) is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2) that has 
been developed as an oral antihyperglycemic agent (AHA) for the treatment of patients with type 2 
diabetes mellitus (T2DM). 
In March 2013, canagliflozin was approved for marketing by the United States (US) Food and Drug 
Administration (FDA). An ongoing clinical program designed to continue research on the effects of the 
agent on renal and cardiovascular outcomes is underway. The goal of this study is to assess the effects of 
canagliflozin compared to placebo on the progression of albuminuria, an important intermediate marker 
of renal injury and progression of diabetic nephropathy.
OBJECTIVES AND HYPOTHESES
Primary objective
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at elevated 
risk of cardiovascular (CV) events to assess the effect of canagliflozin compared to placebo on 
progression of albuminuria.
Secondary objectives
In subjects with T2DM receiving standard care, but with inadequate glycemic control and at elevated risk 
of CV events, to assess the effect of canagliflozin compared to placebo on:
!
The composite endpoint of death from CV causes or hospitalization for heart failure
!
Death from CV causes
Exploratory objectives
In subjects with T2DM receiving standard care, but with inadequate glycemic control and at elevated risk 
of CV events, to assess the effect of canagliflozin compared to placebo on:
!
Regression of albuminuria. Regression of albuminuria is 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 a decrease in the 
urinary albumin creatinine ratio (ACR) value of greater than or equal to 30% from baseline. If the 
ACR at a visit meets the definition of regression described above, a repeat ACR collection 
approximately 1 to 2 months later (or sooner under unusual circumstances, eg, subject is stopping 
study drug) should be done. If the last value meets the definition of regression and no repeat ACR 
collection can be made, the subject will also be deemed to have regressed Analyses using single 
ACR, as well as duplicate ACR assays will be performed.
!
Change in estimated glomerular filtration rate (eGFR) from baseline to the last off-treatment value
!
Urinary albumin/creatinine ratio (ACR)
!
Change in eGFR determined from a between-group comparison of the eGFR slopes using all 
on-treatment measures of eGFR made from the first on-treatment measurement to the final 
on-treatment measurement
!
Changes in HbA1c  
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!
Utilization of AHA therapy
!
The composite endpoint of 40% reduction in eGFR, renal death, or requirement for renal 
replacement therapy
!
The composite endpoint of doubling of serum creatinine, renal death, or requirement for renal 
replacement therapy
!
The composite endpoint of 40% reduction in eGFR, renal death, requirement for renal replacement 
therapy, or death due to CV cause
!
The composite endpoint of doubling of serum creatinine, renal death, requirement for renal 
replacement therapy, or death due to CV cause
!
The composite endpoint of 40% reduction in eGFR, conversion to macroalbuminuria, renal death, or 
requirement for renal replacement therapy
!
The composite endpoint of doubling of serum creatinine, conversion to macroalbuminuria, renal 
death, or requirement for renal replacement therapy
Safety objective
Cardiovascular safety data from this study will be combined with the data from the other large-scale study 
of the effects of canagliflozin compared to placebo (CANVAS; 28431754DIA3008; A Randomized, 
Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Canagliflozin on 
Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus; NCT01032629) in a 
pre-specified meta-analysis of CV safety outcomes.
Hypotheses
Primary hypothesis
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at elevated 
risk of CV events canagliflozin compared to placebo reduces the rate of progression of albuminuria.
Secondary hypotheses
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at elevated 
risk of CV events canagliflozin compared to placebo:
!
Reduces the composite endpoint of death from CV causes or hospitalization for heart failure
!
Reduces death from CV causes
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the 
effects of canagliflozin compared to placebo on progression of albuminuria, an important intermediate 
marker of renal injury and progression of diabetic nephropathy. The study will be conducted in subjects 
with T2DM, receiving standard of care for hyperglycemia and CV risk factors, who have either a history 
or high risk of CV events. A total of 5,700 subjects will be recruited into the study. The study’s last 
subject last visit is targeted to occur when the last subject randomized has approximately 78 weeks of 
follow-up or when 688 major adverse cardiovascular events (MACE) events (ie, CV death, nonfatal 
myocardial infarction, nonfatal stroke) are accumulated between the CANVAS and CANVAS-R
(DIA4003) studies (estimated to occur between January 2017 and April 2017). The effects of 
canagliflozin will be 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.
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STUDY POPULATION
Men or women with T2DM who have inadequate glycemic control (HbA1c ∀7.0 and #10.5%) with either 
a history of a prior CV event or 2 or more risk factors for a CV event are eligible. Subjects can be 
included whether they are drug naïve to antihyperglycemic agents, using monotherapy, or using 
combination antihyperglycemic therapy for the control of blood glucose levels.
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 taken once-daily)
to assess compliance. 
Individuals that meet inclusion/exclusion criteria and that are compliant during run-in will be randomly 
assigned in a 1:1 ratio to canagliflozin or matching placebo to be taken once daily, before the first meal of 
the day. Canagliflozin will be provided at the dose of 100 mg/day through Week 13 and then increased at 
the discretion of the investigator at Week 13 or a subsequent visit to the dose of 300 mg/day, if the subject 
requires additional glycemic control and is tolerating the 100 mg dose (see Section 3.1). All study drug 
after randomization will be provided in a double-blind manner.
EFFICACY OUTCOME DEFINITIONS/EVALUATION CRITERIA
Primary outcomes
Progression is 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.
The primary outcome is progression of albuminuria (as defined above). If the ACR at a visit meets the 
definition of progression described above, a repeat ACR collection approximately 1 to 2 months later (or 
sooner under unusual circumstances, eg, subject is stopping study drug) should be done. If the last value 
meets the definition of progression and no repeat ACR collection can be made, the subject will also be 
deemed to have progressed. Analyses using single ACR, as well as duplicate ACR assays will be 
performed. Detail about the primary and sensitivity analysis approaches will be specified in the SAP.
ACR assessments will be based upon values obtained from first morning void urines analyzed by the 
central laboratory. In this study, duplicate urine specimens will be collected for all ACR measurements.
Secondary outcomes
The secondary outcomes are:
!
Composite endpoint of death from CV causes or hospitalization for heart failure
!
Death from CV causes
Safety outcomes
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) in a pre-specified meta-analysis of CV safety outcomes to 
satisfy the US FDA Post Marketing Requirements.
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STATISTICAL METHODS
Analysis Sets
The intent-to-treat (ITT) analysis set includes all subjects who are randomized via the Interactive Web 
Response System (IWRS). The assessment of the primary and most of the secondary objectives will be 
based upon this analysis set.
The modified intent-to-treat (mITT) or On-Treatment analysis set includes all subjects who are randomly 
assigned to a treatment group and receive at least one dose of double-blind study. It will be used in the 
analyses assessing on-treatment effects, e.g. time slope of on-treatment eGFR.  
Sample Size Determination
Based on the interim data from the CANVAS study, where ACR was measured periodically at scheduled 
visits, it is projected that the annual progression rate for the CANVAS-R study will be approximately 
7.4%. Assuming a 22% relative risk reduction for albuminuria progression, an annual progression rate in 
the placebo arm of 7.4%, an 18-month accrual period, a maximum treatment period of 36 months, and an 
annual discontinuation (from treatment) rate of 10%, it is estimated that 693 events of ACR progression 
will be reported. With 5,700 subjects enrolled, the power to demonstrate the superiority of canagliflozin 
over placebo for albuminuria progression is 90.5%, with type I error rate of 0.05 (two-sided).
Primary efficacy analysis
In this study, duplicate urine specimens will be collected for all ACR measurements. At each visit, the 
geometric mean of  the duplicate measurements will be computed and used for all subsequent analysis 
unless otherwise specified.
Subjects will be classified as having normoalbuminuria (urinary ACR of <3.5 mg/mmol [<30 mg/g]), 
microalbuminuria (ACR ∀3.5 mg/mmol [∀30 mg/g] and #35 mg/mmol [#300mg/g]), or 
macroalbuminuria (ACR of >35 mg/mmol [>300 mg/g]).
The primary efficacy analysis seeks to demonstrate the superiority of canagliflozin in the reduction of 
albuminuria progression relative to placebo.
The time from first study drug administration to first visit date observing progression (i.e., not using the 
visit date of the repeat sample collection) of albuminuria will be analyzed using a Cox proportional 
hazards regression model. The model will include treatment and baseline albuminuria status as covariates. 
The hazard ratio between canagliflozin and placebo will be provided, including its 95% confidence 
interval. The observation period for this time-to-event analysis will include all available measurements 
from first study drug administration to the visit date of the last ACR measurement. Subjects with no 
progression will be censored at the visit date of the last albuminuria measurement.
As a sensitivity analysis, the actual onset time of progression of albuminuria can be determined to be
within an interval from a sequence of examination times (ie, data are interval censored). As a supportive 
analysis, the accelerated failure time (AFT) model with log normal error structure will be implemented 
considering interval censoring. The dependent variable in AFT model is the logarithm of time to 
progression of albuminuria. The model will include treatment group and baseline albuminuria status as 
covariates. We can use speed of progression to interpret AFT model. For any time (t), the probability of a 
subject on placebo progression-free beyond time t is the probability of a subject on canagliflozin 
progression-free beyond t/α, where α is the acceleration factor which can be estimated from the model.
Additional sensitivity analyses will be specified in the study Statistical Analysis Plan (SAP).
The cumulative progression rate derived from Kaplan-Meier estimate will be displayed graphically to 
evaluate the timing of progression and the consistency of the treatment effect over time.
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Secondary efficacy analyses
The secondary efficacy analysis seeks to demonstrate the superiority of canagliflozin in the reduction of 
the following CV events relative to placebo.
!
Composite of CV death or hospitalization for heart failure
!
CV death
The analysis of these CV endpoints will be based on the time to first occurrence of the events using the 
ITT analysis set. The hazard ratio of all canagliflozin compared to placebo and its 95% CI will be 
estimated using a stratified Cox proportional hazards regression model with treatment (all canagliflozin 
and placebo) as the explanatory variable and prior CV disease subgroup (secondary prevention and 
primary prevention) as the stratification factor.
Exploratory efficacy analyses
Regression of albuminuria will be analyzed in a similar fashion as the analysis for progression of 
albuminuria. 
For change in eGFR from baseline to the off-treatment measurement, an analysis of covariance 
(ANCOVA) model will be used with treatment as a fixed effect and adjusting for the baseline eGFR 
value. The treatment difference in the least-squares means and their 2-sided 95% CI will be estimated.
Since the distribution of ACR is highly skewed, the log-transformed ACR values for all the post-baseline 
and scheduled visits will be modeled using a linear mixed effect model. The model will include treatment
group and logarithm of baseline ACR value, visit, and treatment-by-visit interaction as fixed effects. The 
percentage treatment difference can be calculated by taking the anti-logarithm of  the estimated 
coefficient for the treatment group and subtracting 1.
For on-treatment eGFR measurements, a linear mixed effects model will be fitted to eGFR as a dependent 
variable, including treatment, baseline eGFR value, time (as a continuous variable), and treatment time 
interaction as fixed effects and including subject effect as a random intercept and time as a random slope. 
The parameter of interest is the coefficient for treatment and time interaction term, which measures the 
slope difference between canagliflozin and placebo. 
The effect of canagliflozin relative to placebo on changes in HbA1c over time will be evaluated using a 
linear mixed effects model. The use of AHA therapy over time will also be summarized by treatment 
group.  
Safety analyses
The CV safety data from this study will be evaluated in conjunction with the data from the CANVAS 
study according to a pre-specified meta-analysis plan.
Multiplicity adjustment
A closed testing procedure will be implemented to control the overall type I error at 5% for primary 
(progression of albuminuria) and secondary endpoints (composite of CV death or hospitalization for heart 
failure, and death). There are no interim analyses planned.
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TIME AND EVENTS SCHEDULE: PRETREATMENT AND DOUBLE-BLIND TREATMENT
Pre-treatment
Double-blind treatment
Procedures and Evaluations
Screening a
Baseline
Time point
Week -2
Day 1
Phone/email 
contact at 
Week 6
Week 
13
Week 
26
Phone/email 
contact at 
Week 39
Week 52 and 
every 26 weeks 
thereafter unless 
otherwise 
indicated
Phone/email contact 
midway between 
26-week visits until last 
on-treatment visit 
Last on-
treatment visit 
(or after early 
discontinuation 
of treatment)b
Pretreatment/Administrative
Informed consent d
X
Diet, exercise, SMBG
counseling
X
Inclusion/exclusion criteria
X
X
Medical history and 
demographics
X
Prestudy therapy (drug classes 
of interest) e
X
X
Dispense single-blind placebo
X
Randomize
X
Study Drug
Administer/dispense double-
blind study drug m
X
X
X
X
Increase dose if subject requires 
additional glycemic control (see 
Section 3.1)
X
X
X
Procedures
Vital signs, weight, foot 
examinationf
X
X
X
X
X
Xn
(ask about foot 
problems and provide 
foot care guidance)
X
Serum chemistry panel g
X
X
X
X
X
X
Hematology g
X
Week 52, 104 and 
156
X
Fasting serum lipid profile g
X
X
Week 52, 104 and 
156
X
HbA1c
X
X
X
X
X
X
Duplicate first morning void 
urines for urine 
albumin/creatinine (provide 
collection containers at 
previous visit) g, h
X
X
Weeks 52, 78, 
104 and 156
X
Urinalysis g
X
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Pre-treatment
Double-blind treatment
Procedures and Evaluations
Screening a
Baseline
Time point
Week -2
Day 1
Phone/email 
contact at 
Week 6
Week 
13
Week 
26
Phone/email 
contact at 
Week 39
Week 52 and 
every 26 weeks 
thereafter unless 
otherwise 
indicated
Phone/email contact 
midway between 
26-week visits until last 
on-treatment visit 
Last on-
treatment visit 
(or after early 
discontinuation 
of treatment)b
Urine pregnancy test i
X
Dispense glucose testing 
supplies (optional per 
country/region)
X
X
X
X
Ongoing Review
Concomitant therapy (drug 
classes of interest) j
X
X
X
X
X
X
X
Serious adverse events, and 
AEs causing discontinuation; 
vital status; AEs of interest l
X
X
X
X
X
X
X
X
CV events
X
X
X
X
X
X
X
X
For footnotes, see below
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TIME AND EVENTS SCHEDULE: POSTTREATMENT
Posttreatment
Procedures and Evaluations
Posttreatment Follow-up
All Subjects
Subjects Who Withdraw Prior to End of Study
Time point
Final visit 
30 days after last on-treatment 
visit (or after early 
discontinuation of treatment; 
preferably 30 days after last 
dose of study drug) c
Visit every 26 weeks 
after last dose until 
notification of global 
trial end date (GTED)b
Phone/email contact midway 
between 26 week visits until 
notification of the GTEDb,n
Final phone contact, public record 
search or Vital status check within 3 
months prior to GTED
Procedures
Vital signs, weight, foot examinationf
X
X (ask about foot problems 
and provide foot care 
guidance)
Serum chemistry panel g
X
Hematology g
Fasting serum lipid profile g
HbA1c
Duplicate first morning void urines for urine 
albumin/creatinine (provide collection containers at 
previous visit) g, h
Urine pregnancy test i
Dispense glucose testing supplies (optional per 
country/region)
Ongoing Review
Concomitant AHA therapy j
X
Serious adverse events, and AEs causing 
discontinuation; vital status k,; AEs of interest l
X
X
X
X
CV events
X
X
X
X
See footnotes on the following page
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FOOTNOTES
a
Subjects will receive diet/exercise counseling at the screening visit, be counseled on hypoglycemia recognition and management, and be dispensed single-blind placebo capsules. 
During the 2-week run-in period between screening and randomization, the investigator should adjust/optimize the subject’s antihyperglycemic agents and agents to reduce CV risk 
(eg, lipid-altering, and blood pressure-lowering medications) as necessary. Subjects who fail protocol-specified screening criteria for study entry may be rescreened (Section 4.5), at 
the discretion of the investigator.
b
Every subject who remains on study drug through the end of the double-blind treatment period will have a scheduled date for a last on-treatment visit as soon as possible after site 
notification of the projected global trial end date (GTED) expected to occur between January 2017 and April 2017. Early withdrawal (EW) evaluations will be performed when a 
subject stops the double-blind treatment prematurely prior to the site notification of the GTED. EW evaluations will be performed on the day study drug is discontinued or as soon as 
possible after stopping the study drug. For subjects who prematurely discontinue study drug prior to the announcement of GTED, sites will be required to make a final contact or vital
status check after announcement of GTED. For subjects who prematurely discontinue double-blind study drug prior to the site notification of the GTED, the study’s informed consent
form will enable efforts to achieve follow-up of lost participants 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. 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 (ie between the notification of the GTED and the actual GTED), including using all reasonable means outlined above. 
c
A study visit will be conducted for all subjects approximately 30 days (+/- 12 days) after the last dose of study drug. (note: this applies to subjects who prematurely discontinue study 
drug and also those who discontinue study drug after site notification of the projected GTED) This will require a clinic visit for collection of lab specimens. If a study visit is not 
immediately possible, follow-up information may be collected by telephone, via email or other electronic or non-electronic means, and a subsequent study visit should be attempted.
d
The informed consent form must be signed before any study procedure is performed.
e
Record as prestudy therapy the classes of medications taken from 30 days before screening.
f
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); the average of the 3 blood pressure readings will be recorded on eCRFs. 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 for further 
detail).
g
Specific details about specimen collection, storage, and processing will be provided in operations manuals. Attachment 1 lists the laboratory studies to be performed. Urinalysis will be 
performed from a spot urine collection in the clinic on Day 1.
h
The subject will provide first morning void (FMV) urine specimens (collection of the first urine void after the individual awakes from sleep). At each visit, the subject will bring in 
2 FMV specimens: one from the morning of the visit, and one from the morning of the day prior to the visit. If the urinary albumin/creatinine result reflects progression or regression
of albuminuria from the baseline (eg, progression from normoalbuminuria to microalbuminuria or macroalbuminuria accompanied by a urinary ACR value increase of ∀30% from 
baseline; or regression from macroalbuminuria to microalbuminuria or normoalbuminuria accompanied by a urinary ACR value decrease of ∀30% from baseline), the investigator will 
be notified to have the subject bring 2 additional consecutive-morning FMV specimens to the clinic approximately 1 to 2 months later. If the subject is unable to return the specimens
in person, the site may engage a courier service to deliver the specimen to the site. If the subject does not provide the morning void collection on the day of the visit, the subject may 
bring first morning void specimens to the investigational site during the subsequent 7 days. 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.
i
Urine pregnancy testing will be performed locally for all women unless they are surgically sterile or unless there is a documented history of their postmenopausal status. Additional 
pregnancy tests may be conducted throughout the study in sufficient number, as determined by the investigator or required by local regulations, to establish the absence of pregnancy 
during the study. If positive, the subject is not eligible to enter the study or continue study drug. A urine pregnancy test will be performed as specified, unless a serum pregnancy test is 
preferred at the discretion of the investigator or if required by local regulations; in such situations, the serum pregnancy test will be performed at the screening visit instead of the 
baseline visit, in order to determine the subject’s pregnancy status prior to randomization.
j
Concomitant therapy includes all medications from drug classes of interest taken regularly 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.. 
k
This applies only to subjects who prematurely discontinue study drug any time prior to the site notification of the GTED. As noted above, 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, or other sources, as well as the use of locator agencies and checking public records, as allowed by local law.
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l
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 the 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, 
amputations, and venous thromboembolic 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 diabetic 
ketoacidosis, ketoacidosis, metabolic acidosis or acidosis need to be reported to Janssen 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. 
Amputations have also been designated as adverse events 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..
m
An unscheduled visit may be used for increasing or decreasing the dose of study drug , any time after Week 13.
n
At each telephone contact, investigators should ask subject about any foot problems and remind them about routine preventative foot care and early intervention for foot problems.
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ABBREVIATIONS
ACR
urinary albumin/creatinine ratio
ADA
American Diabetes Association
AHA
antihyperglycemic agent
ALT
alanine aminotransferase
ARO
Academic Research Organization
AST
aspartate aminotransferase
BMI
body mass index
CI
confidence interval
CV
cardiovascular
eCRF
electronic case report form
eDC
electronic data capture
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
FMV
first morning void
FPG
fasting plasma glucose
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GTED
global trial end date
HbA1c
hemoglobin A1c
HDL-C
high-density lipoprotein cholesterol
IB
Investigator Brochure
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IWRS
interactive web response system
LDL-C
low-density lipoprotein cholesterol
MACE
major adverse cardiovascular events
MI
myocardial infarction
mITT
modified intent-to-treat
MSRC
Medical Safety Review Committee
NYHA
New York Heart Association
PG
plasma glucose
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
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
UGE
urinary glucose excretion
ULN
upper limit of normal
US
United States
VTE
venous thromboembolic event
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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.
Pharmacologic inhibition of SGLT2 is a novel mechanism to decrease renal glucose 
reabsorption, as it lowers 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 
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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 as well as an osmotic diuretic effect, 
which can lead to reductions in blood pressure and osmotic diuresis- and volume depletion-
related adverse events.
A Phase 3 development program including 9 controlled studies was conducted providing 
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, involving approximately 10,285 subjects with T2DM and including 
nearly 6,650 subjects treated with 100 mg or 300 mg doses of canagliflozin, indicate that 
canagliflozin has the potential to be a useful addition to currently available antihyperglycemic 
agents. Across all of the studies, clinically meaningful reductions in hemoglobin A1c (HbA1c) and 
fasting plasma glucose (FPG) were seen. Statistically significant (relative to placebo) reductions 
in body weight (predominantly fat mass) were also achieved with canagliflozin 100 mg and 
300 mg across the spectrum of T2DM patients evaluated in the Phase 3 program. Canagliflozin 
also showed benefit in improving other clinical endpoints associated with diabetic comorbidities, 
including systolic and diastolic blood pressure (SBP and DBP), and lipid parameters (high-
density lipoprotein cholesterol [HDL-C], and triglyceride). Improvements in beta-cell function, 
presumably through an indirect effect, such as reductions in glucotoxicity and insulin secretory 
demand, were also seen with canagliflozin treatment. 
In March 2013, canagliflozin was approved for marketing by the United States Food and Drug 
Administration (FDA). An ongoing clinical program designed to continue research on the effects 
of the agent on renal and cardiovascular outcomes is underway. The goal of this study is to 
assess the effects of canagliflozin compared to placebo on the progression of albuminuria, an 
important intermediate marker of renal injury and the progression of diabetic nephropathy.
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.
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.
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 IB.
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1.1.2.
Clinical Studies
Overview
The canagliflozin clinical program was designed to assess the safety and efficacy of 
canagliflozin in patients with T2DM. The program consists of 52 completed or ongoing clinical 
studies, including data from 10,285 subjects as of late 2012 (who received at least 1 dose of 
double-blind study drug) in 9 Phase 3 studies, 1,210 subjects in 3 Phase 2 studies, and 
1,300 subjects in 40 Phase 1 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, two 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.
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. 
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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 DPP-4 inhibitors and GLP-1 agonists.
Glycemic Efficacy
Results of the Phase 3 studies demonstrated the efficacy of canagliflozin in reducing 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). 
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 
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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 FPG as well as 
in the 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 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 (UTIs), 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. 
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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 UTI (mostly lower 
tract infections) was observed with canagliflozin relative to control, without an increase in 
serious adverse events of UTI.
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 no imbalance in the low 
incidence across groups of renal cell cancers. 
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 pool of 8 clinical 
trials with a longer mean duration of exposure, the incidence rate of bone fracture was 14.2, 18.7, 
and 17.6 per 1,000 patient-years of exposure to comparator, canagliflozin 100 mg, and 
canagliflozin 300 mg, respectively. 
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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 of 
0.91 for a pre-specified composite endpoint of CV death, non-fatal MI, non-fatal stroke, and 
hospitalized unstable angina (95% 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 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, diabetic ketoacidosis is considered a rare adverse drug reaction.
During a routine review of unblinded interim data from the ongoing CANVAS study (DIA3008), 
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 with 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 amputations 
include prior amputation, peripheral vascular disease, and neuropathy.
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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. A 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 microalbuminuria that may progress to macroalbuminuria and eventually loss of 
renal function. Hyperglycemia, possibly through production of advanced glycation end products
(Diabetes Control and Complications Trial [DCCT]; Brownlee 2001) and systemic hypertension 
(DCCT) are known to be risk factors for the onset and progression of diabetic nephropathy. By 
virtue of its improvement in glycemic control, which has been shown to reduce albuminuria 
progression in prior studies (ADVANCE 2008; DCCT 1993; UKPDS 1998), and effects to 
reduce blood pressure, canagliflozin may slow the progression of diabetic nephropathy. 
Hyperglycemia increases glucose levels delivered to the proximal tubule, which is reabsorbed, 
predominantly via an SGLT-2-dependent mechanism (Vallon 1999). Increased proximal tubule 
resorption of glucose results in increases in the proximal tubule reabsorption of sodium and 
reduces the delivery of sodium to the distal tubule. Decreases in sodium levels in the distal 
tubule reduce macula densa-dependent tubuloglomerular feedback, which results in afferent 
glomerular arteriole vasodilation and increases in glomerular pressure (Vallon 1999). Increases 
in glomerular pressure are believed to be an important factor in the onset and progression of 
diabetic nephropathy (Anderson 1986; American Diabetes Association [ADA] 2004). ACEI and 
ARB decrease glomerular pressure by stimulating efferent glomerular arteriole vasodilation and 
reduce albuminuria and the progression of diabetic nephropathy (IDNT, Lewis 2001, and 
RENAAL, de Zeeuw 2004).
In preclinical diabetic rodent models, SGLT2 inhibition increases tubuloglomerular feedback and 
reduces
single nephron glomerular
filtration rates, consistent with an increase in 
tubuloglomerular feedback leading to a decrease in glomerular pressure (Vallon 2011). In a 
Phase 1 study in subjects with T1DM who exhibited glomerular hyperfiltration (eGFR 
172 ml/min/1.73 m2), an 8-week treatment with empagliflozin, a selective SGLT2 inhibitor, 
significantly reduced glomerular hyperfiltration (eGFR 139 ml/min/1.73 m2) (Cherney 2013
ADA poster). The reduction in hyperfiltration was associated with increases in renal vascular 
resistance and reductions in renal blood flow, both consistent with an increase in afferent 
glomerular arteriole tone. Thus, in preclinical and clinical models, SGLT2 inhibition reduces 
glomerular pressure, a factor known to be associated with the onset and progression of diabetic 
nephropathy.
In the clinical program, clinically-important, favorable changes were observed with canagliflozin 
compared to placebo in the progression of albuminuria. In a post hoc analysis performed in 
CANVAS 
(28431754DIA3008; 
A 
Randomized, 
Multicenter, 
Double-Blind, 
Parallel, 
Placebo-Controlled Study of the Effects of Canagliflozin on Cardiovascular Outcomes in Adult 
Subjects With Type 2 Diabetes Mellitus), after approximately 20 months of mean follow-up,
253/1390 (18.2%) of placebo-treated subjects showed albuminuria progression (defined by 
albuminuria status change and 30% increase in albumin/creatinine ratio (ACR) from baseline)
relative to baseline versus 221/1406 ( 15.7%) with canagliflozin 100 mg, 191/1397 ( 13.7%) with 
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canagliflozin 300 mg, and 412/2803 (14.7%) with canagliflozin overall. In a pooled analysis of 
subjects with moderate renal impairment (defined as a baseline eGFR of ∀30 mL/min/1.73 m2
and #60 mL/min/1.73 m2) that included subjects from the CANVAS study and other studies in 
the Phase 3 program, the observed mean change from baseline in the albumin/creatinine ratio 
was 28 mg/g, -22 mg/g, and -41 mg/g for placebo, canagliflozin 100 mg, and canagliflozin 
300 mg, respectively. The corresponding observed median changes from baseline in the 3 groups 
respectively were 1.2 mg/g, -0.6 mg/g, and -0.7 mg/g.
In the Phase 3 program, treatment with canagliflozin was associated with a dose-dependent, 
reversible reduction in eGFR that was maximal at the first post baseline visit and was either 
stable or attenuated with continued treatment. The time course of eGFR changes over a 
104-week, active comparator study and over a 52-week week study in subjects with moderate 
renal impairment are shown in Figure 1 and Figure 2 below. 
Figure 1: 
Mean Change in eGFR Over Time (DIA3009)
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Figure 2: 
Mean Change in eGFR Over Time (DIA3004)
Based on these data, it is hypothesized that SGLT2 inhibition with canagliflozin will reduce 
glomerular pressure by increasing afferent glomerular arteriole tone, which will lead to a 
hemodynamically mediated decrease in glomerular pressure, as reflected by an acute, mild 
decrease in GFR. The reduction in glomerular pressure is hypothesized to mediate the reduction 
in albuminuria seen with canagliflozin treatment and to potentially lead to a reduction in 
progression of diabetic nephropathy. A schematic of these hypotheses and the effect of ACEI 
and ARBs on the progression of diabetic nephropathy is shown in Figure 3, below.  
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Figure 3: 
Hypotheses Regarding the Effect of ACEI and ARBs on the Progression of Diabetic 
Nephropathy
The present study is intended to determine if treatment of subjects with T2DM with canagliflozin 
reduces the progression of albuminuria, a biomarker for renal injury and for progression of 
diabetic nephropathy. The study will also explore the effects of canagliflozin on the regression of
albuminuria, and changes in eGFR.
Data from this study will also be used for a pre-specified meta-analysis with data from CANVAS 
for the assessment of CV safety, examining a composite endpoint of the major adverse 
cardiovascular events (MACE) of cardiovascular death, nonfatal MI, and nonfatal stroke. The 
details of the meta-analysis are described in a separate statistical analysis plan (SAP).
Results of a CV outcomes trial with another SGLT2 inhibitor were recently reported. EMPA-
REG OUTCOME was a randomized, double-blind, placebo-controlled CV outcome trial to 
examine the long-term effects of empagliflozin versus placebo, in addition to standard of care, on 
CV outcomes in patients with T2DM and established CV disease, ie, EMPA-REG was a 
secondary prevention study (Zinman 2015). This study had a median observation time of 
3.1 years and was conducted in 7,020 subjects. In this study, empagliflozin, compared to 
placebo, was associated with a reduction in the MACE primary outcome (CV death, nonfatal MI, 
and nonfatal stroke; hazard ratio 0.86 [0.74, 0.99], p=0.04), but the key secondary outcome of 
MACE-Plus (CV death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina; 
hazard ratio 0.89 [0.78, 1.01], p=0.08) did not achieve statistical significance. The effect on the 
primary MACE outcome was numerically smaller than the effects on the secondary endpoints of 
CV death (hazard ratio 0.62 [0.49, 0.77], p<0.001), and the composite endpoint of CV death and 
hospitalization for heart failure (hazard ratio 0.66 [0.55, 0.79] , p<0.001). The reductions in CV 
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death and hospitalization for heart failure with empagliflozin treatment were apparent within 3 
months after randomization. No statistical differences were seen relative to placebo on non-fatal 
MI and non-fatal stroke. In order to assess whether these effects are specific to the SGLT2 
inhibitor class, the composite event of death from CV causes or hospitalization for heart failure 
and the event of death from CV causes are being added as secondary endpoints to CANVAS-R.
Post-hoc analysis of data from EMPA-REG OUTCOME also demonstrated a benefit on renal 
endpoints, particularly on the composite endpoint of doubling of serum creatinine, initiation of 
renal replacement therapy, or death due to renal cause. These and other renal events are being 
added as exploratory endpoints to CANVAS-R.
2.
OBJECTIVES AND HYPOTHESES
2.1.
Objectives
Primary Objective
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at 
elevated risk of CV events, to assess the effect of canagliflozin compared to placebo on
progression of albuminuria.
Secondary Objectives
In subjects with T2DM receiving standard care but with inadequate glycemic control and at 
elevated risk of CV events, to assess the effect of canagliflozin compared to placebo on:
!
The composite endpoint of death from CV causes or hospitalization for heart failure
!
Death from CV causes
Exploratory objective
In subjects with T2DM receiving standard care, but with inadequate glycemic control and at 
elevated risk of CV events, to assess the effect of canagliflozin compared to placebo on:
!
Regression of albuminuria 
!
Change in eGFR from baseline to the last off-treatment value.
!
Urinary ACR
!
Change in eGFR determined from a between group comparison of the eGFR slopes using all 
on-treatment measures of eGFR made from the first on-treatment measurement to the final 
on-treatment measurement
!
Changes in HbA1c  
!
Utilization of AHA therapy
!
The composite endpoint of 40% reduction in eGFR, renal death or requirement for renal 
replacement therapy
!
The composite endpoint of doubling of serum creatinine, renal death, or requirement for 
renal replacement therapy
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!
The composite endpoint of 40% reduction in eGFR, renal death, requirement for renal 
replacement therapy, or death due to CV cause
!
The composite endpoint of doubling of serum creatinine, renal death, requirement for renal 
replacement therapy, or death due to CV cause
!
The composite endpoint of 40% reduction in eGFR, conversion to macroalbuminuria, renal 
death, or requirement for renal replacement therapy
!
The composite endpoint of doubling of serum creatinine, conversion to macroalbuminuria, 
renal death, or requirement for renal replacement therapy
Safety Objective
Cardiovascular safety data from this study will be combined with the data from the other 
large-scale study of the effects of canagliflozin compared to placebo (CANVAS) in a 
pre-specified meta-analysis of cardiovascular safety outcomes.
2.2.
Hypotheses
2.2.1.
Primary Hypothesis
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at 
elevated risk of CV events, canagliflozin compared to placebo reduces the rate of progression of 
albuminuria.
2.2.2.
Secondary Hypotheses
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at 
elevated risk of CV events, canagliflozin compared to placebo:
!
Reduces the composite endpoint of death from CV causes or hospitalization for heart failure
!
Reduces death from CV causes
3.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to 
evaluate the effects of canagliflozin compared to placebo on progression of albuminuria, an 
important intermediate marker of renal injury and progression of diabetic nephropathy. The 
study will be conducted in subjects with T2DM, receiving standard of care for hyperglycemia 
and CV risk factors, who have either a history or high risk of CV events. A total of 
5,700 subjects will be recruited into the study. The study’s last subject last visit is targeted to 
occur when the last subject randomized has approximately 78 weeks of follow-up or when 
688 MACE events are accumulated between the CANVAS and CANVAS-R (DIA4003) 
studies(estimated to occur between January 2017 and April 2017). The effects of canagliflozin 
will be 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.
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3.1.
Study Design
The following section provides an overview of subject management including screening, run-in, 
and double-blind treatment. 
Screening Period 
Subjects will undergo a screening visit for a preliminary determination of eligibility. Men or 
women with T2DM who are known to have inadequate glycemic control (HbA1c ∀7.0 and 
#10.5%), not on an AHA, or on an AHA (oral or injectable [eg, insulin or GLP-1 analogue] in 
monotherapy or combination therapy, and who have known CV events or who have 2 or more 
risk factors for CV events are eligible (refer to Section 4.2, Inclusion Criteria). 
At this visit, potentially-eligible subjects will enter a 2-week single-blind placebo run-in period. 
All subjects should receive diet/exercise counseling at the screening visit, be counseled on 
hypoglycemia recognition and management, and be dispensed single-blind placebo capsules.
During this period, the investigator should also adjust/optimize the subject’s medications to 
reduce CV risk (eg, anti-hyperglycemic, lipid-altering or blood pressure-lowering medications)
as 
necessary.
If 
in 
the 
investigator’s 
opinion 
additional 
time 
is 
required 
for 
adjustment/optimization of these medications, the 2-week period between screening and 
randomization may be extended by having the subject continue single-blind placebo up to 
2 additional weeks. Subjects should be counseled to perform fasting self-monitored blood 
glucose (SMBG) determinations, according to standard guidelines. This counseling, as well as 
the counseling regarding diet/exercise and hypoglycemia recognition/management, should begin 
with a focus during the screening phase and be reinforced as needed throughout the study.
An overview of the study design is illustrated in Figure 4.
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Figure 4:
Study Design Outline
AHA=antihyperglycemic agent; CV=cardiovascular; R = randomization; SU=sulfonylurea; T2DM= type 2 diabetes mellitus
Double-Blind Treatment Phase 
Subjects meeting all inclusion and none of the exclusion criteria, and successfully completing the 
2-week run-in period, will be randomly allocated to initial treatment with canagliflozin 100 mg 
or matching placebo administered once daily (in a 1:1 ratio). A total of 5,700 subjects will be 
randomized. After 13 weeks, the dose of canagliflozin (or matching placebo) may be increased
from 100 mg to 300 mg if the subject requires additional glycemic control, provided the 100 mg 
dose is well tolerated. The dose should be increased if the subject requires additional glycemic 
control (eg, ∀50% of the subject’s glucose determinations from the fasting SMBG [finger stick] 
readings [a minimum of 3 readings recommended] are >110 mg/dL [6 mmol/L] during the 
2 weeks preceding the clinic visit or telephone contact) and the subject had no events of 
hypoglycemia or volume depletion in the preceding 2-week interval that in the opinion of the 
investigator would preclude dose titration. After increasing the dose to 300 mg, the dose should 
remain at 300 mg; however, if necessary, in the investigator’s judgment, the dose may be 
decreased to 100 mg at any time point (eg, due to an adverse event of reduced intravascular 
volume). In addition, if there is need for additional glycemic control, the investigator should 
adjust the subject’s AHA regimen as, per standard diabetes care guidelines, individualized as 
considered appropriate by the investigator. Adjustments in the AHA regimen should be carefully 
implemented throughout the study to minimize the risk of hypoglycemia. The investigator should 
optimize agents to
reduce CV risk (eg,
antihyperglycemic, lipid-altering and
blood 
pressure-lowering medications) as required during the course of the trial to assure appropriate 
control consistent with standard care guidelines.
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Study Duration 
Subjects are expected to be followed for a maximum of about 3.5 years with the last visit for the 
last subject targeted to occur when all subjects have approximately 78 weeks of follow-up or 
when 688 MACE events are accumulated between the CANVAS and CANVAS-R (DIA4003) 
studies. All sites will be notified of the projected global trial end date (GTED) (projected to 
occur between January 2017 and April 2017). 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 5 shows the intended follow-up of randomized subjects with respect to the GTED.
Figure 5:
Follow-up of Randomized Subjects with Respect to the GTED
Collection of data about Cardiovascular Safety Outcomes
Investigators will be required to report any cardiovascular (CV) event that they consider could 
possibly be a nonfatal MI or nonfatal stroke (refer to Section 9.2, Reporting/Adjudication of 
Events in the CV Composite Endpoint and Other Events for Adjudication), as well as all deaths.
Additional information and documentation will be requested from investigators for all such 
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events to support a detailed assessment of these outcomes by an Endpoint Adjudication 
Committee.
Collection of Information After Early Discontinuation of Randomized Treatment
It is the intent that subjects who discontinue treatment with the study drug will continue in the 
study according to the visit schedule described in the Post-treatment Time & Events Schedule. 
After early discontinuation of randomized treatment, subjects will continue to be followed up for 
specific data collection, including any MACE events, vital signs, serious adverse events, and 
adverse events of interest.
Participants who prematurely discontinue study drug will require an immediate follow-up 
assessment (either on the day of study drug discontinuation or as soon as possible following 
study drug discontinuation) as well as a follow-up assessment approximately 30 days (%12 days)
after last dose after which they should then continue to be followed for the full originally 
scheduled follow-up period through to study completion. If for some reason the subject is unable 
to be seen shortly after discontinuing study drug, the end of treatment visit may be omitted, but 
the 30-day off-drug follow-up visit should be performed. The follow-up regimen for these 
individuals will require 26-week visits interspersed with phone/email contact exactly as for those 
individuals 
that 
continue 
with 
randomized
therapy 
(refer 
to 
Section 
9.1.4, 
End-of-Treatment/Early Withdrawal, and Section 9.1.5, Posttreatment Phase [Follow-Up] for 
collection of information on CV events and other assessments).Safety Evaluations and Adverse 
Events of Interest
Safety evaluations will include the monitoring of serious adverse events, adverse events resulting 
in discontinuation, adverse events of interest, clinical laboratory tests, vital sign measurements,
and measurement of body weight. For adverse events of interest, investigators will be asked to 
provide additional information, on separate electronic case report forms (eCRFs), so as to 
support more detailed analyses. 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 the supplemental eCRFs or other 
designated forms for any event that is serious or that leads to study drug discontinuation. The 
only exceptions are for malignancies, photosensitivity reactions, fractures, amputations, and 
venous thromboembolic events 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 diabetic ketoacidosis, ketoacidosis, metabolic acidosis or acidosis need to be 
reported to Janssen 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. Amputations have also been designated as adverse events of special interest and 
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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. 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 Independent Data Monitoring Committee (IDMC) (Section 9.3.3, Medical Safety Review 
Committee, and Section 9.3.4, Independent Data Monitoring Committee). Refer to Section 3.2, 
Study Design Rationale, for review of rationale for collection of additional information on these 
selected adverse events.
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 based upon the design of CANVAS and developed both to address the primary 
renal hypothesis and to meet the post-marketing requirements for canagliflozin  defined by the 
US FDA. Broadly, the pretreatment phase allows sufficient time for study-related procedures to 
be performed, for subject eligibility to be determined and for optimization of background therapy 
by the investigators. Randomization, placebo control, and blinding will be used to minimize bias 
in the assignment of subjects to treatment groups and throughout data collection, and to 
maximize the likelihood that the study precisely and reliably addresses the questions it is 
designed to answer.
Study Population 
The study population includes a broad spectrum of subjects on a variety of different AHAs with 
a range of different levels of baseline glycemic control and background risks of vascular and 
renal disease. The ratio of subjects with a history of CV events versus a high risk of CV events 
will be approximately 70% to 30%, respectively. Conducting the trial in this population will 
ensure broad generalizability of the trial results upon study completion. 
Dosage Selection, Route of Administration, Dose Interval, Treatment Period
Both the 100 mg and 300 mg doses of canagliflozin are being used in this study. These are the 
doses that have been filed with health agencies for approval based on the results of the clinical 
program, and have been approved for marketing in some countries.
Choice of Renal Efficacy Measures
The development and progression of renal disease in people with diabetes follows a clearly 
defined pathway starting with microalbuminuria, progressing to macroalbuminuria, 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 urinary albumin/creatinine ratio in the first morning void is the primary endpoint 
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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 
microalbuminuria is urinary albumin/creatinine ratio of 30 to 300 mg/g, and the definition of 
macroalbuminuria is urinary 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, duplicate first morning void urine collections on consecutive days, made by 
subjects at home (collection of the first urine void after the individual awakes from sleep), 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. In addition to the progression and regression of albuminuria, changes in eGFR 
will be analyzed in this study, since it is the basic measurement of renal function and is used to 
assess progression of renal disease (ADA 2004).
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 
events; the ratio of subjects with a history of versus high risk of CV events will be approximately 
70% to 30%, respectively. 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 events defined on the basis of either:
&
Age ∀30 years with documented symptomatic atherosclerotic CV events: 
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 
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micro- or macroalbuminuria (see Section 3.2, Study Design Rationale, for definition)
within one year of screening, or documented HDL-C of <1 mmol/L (<39 mg/dL) within 
one year of screening. 
Note: An overall target ratio of approximately 70%:30% for CV history (first 
category):risk factors (second category) will be implemented (with a maximum of 
approximately 40% in the second category). This target is intended to be a global ratio 
and may vary by region. The proportion of subjects in these categories will be 
monitored centrally.
Note: the term “documented” in the above paragraphs refers to the required information 
being clearly noted in hospital/clinical records or in physician-referral documents, 
copies of which should be retained in the subject’s study files.
!
Women must be: 
&
postmenopausal, defined as 
o
>45 years of age with amenorrhea for at least 18 months, or
o
>45 years of age with amenorrhea for at least 6 months and less than 18 months 
and a known serum follicle stimulating hormone (FSH) level >40 IU/L, or
&
surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal occlusion), 
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 (ie, those subjects who do not meet the postmenopausal 
definition above, regardless of age) must have a negative urine pregnancy test at baseline
(Day 1) and at screening if required by local regulations (Note: a serum pregnancy test is
acceptable in lieu of a urine pregnancy test if required by local regulations).
!
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 
Inclusion Criterion for Randomization
!
Subjects must have taken ∀80% of their single-blind placebo doses during the 2-weeks prior 
to randomization on 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 diabetic ketoacidosis, T1DM, pancreas or beta-cell transplantation, or diabetes 
secondary to pancreatitis or pancreatectomy
!
History of one or more severe hypoglycemic episodes within 6 months before screening 
Note: a severe hypoglycemic episode is defined as an event that requires the help of another 
person.
!
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 (The Criteria 
Committee of the New York Heart Association).
!
Known ECG findings within 3 months before screening that would require urgent diagnostic 
evaluation or intervention (eg, new clinically important arrhythmia
or conduction 
disturbance)
Gastrointestinal
!
Known history of hepatitis B surface antigen or hepatitis C antibody positive (unless known 
to 
be 
associated 
with 
documented 
persistently 
stable/normal 
range 
aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT] levels), or other clinically 
active liver disease
!
Any history of or planned bariatric surgery
Laboratory
!
eGFR <30 mL/min/1.73m2 at screening visit
!
ALT levels >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 times the 
ULN, 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
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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 or prior use of an SGLT2 inhibitor.
!
Prior or current participation in another canagliflozin study.
!
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
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.
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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:
!
Prohibited medications include other SGLT2 inhibitors (including commercially available 
canagliflozin); 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 urine specimens during acute illness with 
fever. The collection and respective visit should be postponed until the subject is recovered 
from the acute illness.
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 if appropriate clinical management leads to study 
eligibility (eg, HbA1c >10.5% that prompts adjustment of the subject’s AHA regimen).
Generally, a subject may only be rescreened once, but an additional rescreening may be allowed 
with concurrence of the sponsor’s Medical Monitor.
Typically, rescreening will require that all screening 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 a documented history of CV events & the highest 
risk group & approximately 70% of subjects (globally) are targeted to be in this group. The
proportion of subjects in these categories will be monitored centrally.
Randomization and Blinding Procedures
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared under 
the supervision of the sponsor before the study. The randomization will be balanced by using 
randomly permuted blocks. 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 logging on to the interactive 
web response system (IWRS) designated by the sponsor. The requestor must use his/her own 
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user identification (ID) and personal identification number (PIN) when contacting the IWRS, and 
will then give the relevant subject details to uniquely identify the subject. Based on this 
information, the 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 IWRS will assign a study drug kit to be dispensed at that visit. New medication numbers will 
be assigned each time the 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, whether canagliflozin or placebo, will be identical in appearance and will be 
packaged accordingly to maintain the blind. The randomization code that links the randomization 
number assigned to the subject with a treatment group assignment will be maintained within the 
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 IWRS. It is recommended that the investigator contact the sponsor or its 
designee if possible to discuss the particular situation, before breaking the blind. The reason for 
unblinding is not captured through IWRS. 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 electronic case report form (eCRF) and in the 
source documents. The documentation received from the IWRS indicating the code break must 
be retained with the subject's source documents in a secure manner (eg, in a 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. 
All randomization codes will be released after completion of the study. The translation of 
randomization codes into treatment and control groups will be disclosed only to those authorized.
Urine glucose measurements will not be performed on first morning void urine specimens, as an 
additional step to ensure the maintenance of the treatment blind. 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
Two-week Single-Blind Placebo period following Screening
Upon completion of initial screening, all potentially eligible individuals will receive single-blind 
placebo capsules (one capsule to be administered once-daily) for 2-weeks to assess compliance. 
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Double-Blind Study Medication
On Day 1, subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups: 
canagliflozin or matching placebo. Initially, canagliflozin will be provided at a dose of 100 mg 
daily, but at Week 13 (or any time thereafter) the dose of canagliflozin (or matching placebo) 
may be increased from 100 mg to 300 mg if the subject requires additional glycemic control, 
provided the 100 mg dose is well tolerated. The dose of study drug should be increased if the 
subject requires additional glycemic control (for example, ∀50% of the subject’s glucose 
determinations from the fasting SMBG [finger stick] readings [a minimum of 3 readings 
recommended] are >110 mg/dL [6 mmol/L] during the 2 weeks preceding the clinic visit or 
telephone contact) and the subject had no events of hypoglycemia or volume depletion in the 
preceding 2-week interval that in the opinion of the investigator would preclude dose titration. 
After increasing the dose to 300 mg, the dose should remain at 300 mg; however, if necessary, in 
the investigator’s judgment, the dose may be decreased to 100 mg at any time point (eg, due to 
an adverse event of reduced intravascular volume).
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 should take the first dose of study drug at the study center on Day 1. 
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 drug may be interrupted (eg, for safety and/or tolerability reasons such as hospitalizations 
for major surgical procedure or serious medical illness). Study drug interruptions, occurring for 
any reason and lasting 7 days or longer, will be documented on the eCRF. Study drug should be 
reinstituted once the subject has recovered and the safety and/or tolerability concern is no longer 
present.
For subjects who develop conditions that are associated with or leading to amputation 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
Screening Management
Subjects will receive diet/exercise counseling at entry into the screening period. During this visit,
subjects should also be counseled to perform fasting self-monitored blood glucose (SMBG)
determinations, according to standard guidelines.
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Double-blind Treatment Phase Glycemic Management 
The background AHA regimen may be adjusted at any time during the study to achieve glycemic 
goals, using standard guidelines, and as considered appropriate by the investigator for the 
individual subject. Adjustment to the AHA regimen should be carefully implemented so as to 
avoid events of hypoglycemia.
Adjustment of AHA therapy after randomization will be performed by the investigator. The 
preferred initial option for enhancing glucose control is to increase the dose of 
canagliflozin/placebo, so if possible, after Week 13 the investigator should increase the dose of 
canagliflozin/placebo from 100 mg to 300 mg (see Section 6.1). If increasing the dose of 
canagliflozin/placebo is not effective, there is no specific AHA treatment algorithm required for 
this study and the responsible clinician is free to adjust therapy as appropriate. Treatment may 
include reinforcement of lifestyle counseling, addition of or up-titration to maximum labeled 
doses of oral and/or injectable AHAs as locally applicable, except the use of any other 
approved SGLT2 inhibitor. 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. 
Adjustments to the AHA regimen should be documented in the appropriate eCRF. 
During the double-blind treatment period, investigators should counsel subjects to perform 
fasting SMBG determinations according to standard guidelines.
Therapeutic Management of CV Risk Factors
Before randomization and throughout the study, investigators will be expected to manage the 
subject’s diet/exercise and other medication regimens so as to achieve goals for CV risk factors 
(eg, HbA1c, lipid levels, blood pressure) based upon standard guidelines for the care of subjects 
with T2DM. 
The 2-week period between screening and randomization provides investigators with the 
opportunity to adjust the subject’s regimen as needed to optimize the subject’s CV risk factors. If
in the investigator’s opinion additional time is required for adjustment/optimization of agents to 
reduce CV risk (eg, anti-hyperglycemia, lipid-altering or blood pressure-lowering medications)
prior to randomization, the 2-week period pre-randomization may be extended by having the 
subject continue single-blind placebo up to 2 additional weeks. Additional amendments can also 
be made to background therapy at any time during the course of follow-up.
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 the study drug (based on capsule counts) should receive counseling on the importance of 
dosing compliance and should continue in the study.
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 
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responsible for providing additional instructions to reeducate any subject who is not compliant 
with taking the study drug or with making required clinic visits.
Study drug interruptions, occurring for any reason and lasting 7 days or longer, will be 
documented on the eCRF.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapy is defined as any therapy used before the first dose of double-blind study 
medication. Concomitant therapy is defined as any therapy used after the first dose of 
double-blind study drug. 
Selected classes of prestudy therapies administered up to 30 days before screening and up to the 
time of the first dose of double-blind study drug will be documented. Likewise, selected classes 
of concomitant therapies taken after the first dose of double-blind study drug will be 
documented. Examples of the classes of interest may include AHAs such as sulfonylureas, 
metformin, pioglitazone, alpha-glucosidase inhibitors, GLP-1 analogs, DPP-4 inhibitors, all 
forms of insulin, as well as non-AHAs such as renin angiotensin aldosterone system (RAAS)
inhibitors, diuretics, beta-blockers, calcium channel blockers, statins, and anti-thrombotics. 
Checkboxes may be used on eCRFs to capture the required information on prestudy and 
concomitant agents. Details will be provided in the eCRF completion guidelines regarding the 
specific types of medications that fall in the categories of interest and what information will be 
collected.
Concomitant therapies will not be provided or reimbursed by the sponsor. 
Disallowed Therapies
Other SGLT2 inhibitors (including canagliflozin) may not be used concurrently, and 
subjects should not take any other investigational agents during the study. If the use of another 
SGLT2 inhibitor or investigational agent is reported during the study, the subject’s physician 
should be contacted, the other agent discontinued, and the subject should continue in the study.
The sponsor must be notified as soon as possible 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
Single-blind pre-randomization period - The recommended visit window for the initial 
single-blind placebo phase of the study is 2 weeks %4 days. If in the investigator’s opinion 
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additional screening time is required for adjustment/optimization of agents to reduce CV risk 
(eg, anti-hyperglycemia, lipid-altering, blood pressure-lowering or other medications), the 
screening period may be extended by having the subject continue single-blind placebo therapy 
for up to 2 additional weeks.
Post-randomization period - Subsequent scheduled in-clinic study visits during the first year of 
the study should occur at Day 1 (baseline, the day of randomization) and Weeks 13, 26, and 52.
After the first year, scheduled in-clinic study visits should occur at 26-week intervals with 
telephone contacts approximately midway between visits. For the Week 13 and Week 26 visits, 
the recommended visit window is %7 days. After Week 26, the recommended visit window is 
%14 days. Phone/email contacts will occur at approximately 26-week intervals in between the 
scheduled in-clinic visits. Similar windows are proposed for the phone/email contacts made 
between visits.
In the event that it is impossible for a subject to make a scheduled clinic visit, telephone contacts 
may be conducted at the time of the missed visit, but a clinic visit should be scheduled as soon as 
possible thereafter. If a telephone contact or study visit is not possible, follow-up information 
may be collected via email or any other appropriate means. Details regarding discussions via
telephone, email, or other such contacts must be properly documented in source records, 
including responses by the subject.
For study visits that are unable to be held within the protocol-recommended visit windows, the 
visit should be conducted as close 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.
For subjects who complete double-blind study drug through the time of site notification of the 
projected GTED, it will be important for sites to schedule the last on-treatment visit as soon as 
possible after the notification date and the 30-day off drug visit prior to the GTED.
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.
Pregnancy Testing
Additional 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).
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9.1.2.
Pretreatment Phase
Screening Visit (Week -2)
Potential subjects will be seen at a screening visit, approximately 2 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 samples for required laboratory tests will be 
collected. Laboratory specimens will be obtained as described in the Time and Events Schedule. 
An operations manual will be provided to describe collection, processing, and shipping 
procedures for the duration of the study. 
At this visit, subjects who appear to meet enrollment criteria may then be dispensed single-blind 
placebo capsules and enter the 2-week single-blind placebo run-in period. An assessment of the 
subjects’ adherence to protocol procedures during this period 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). 
Subjects who do not meet all inclusion criteria or meet a study exclusion criterion should be 
excluded from the study. 
The screening visit and the 2-week run-in period provide investigators with the opportunity to 
evaluate and optimize management of CV risk factors prior to randomization as required (refer to 
Section 6.2.1, Management of Glycemic Control and CV Risk Factors) and to provide subjects 
with counseling regarding diet and exercise consistent with applicable local guidelines.
9.1.3.
Double-Blind Treatment Phase 
Day 1/Day of Randomization
Potential participants who return for the Day 1 (baseline) visit, who have taken ∀80% of the 
scheduled single-blind placebo capsules during the period between screening and randomization, 
and who meet the enrollment criteria will be randomly assigned to once-daily treatment with 
canagliflozin 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). 
At the randomization visit, in some countries or regions (at the option of local sponsor 
representatives), subjects will be given a glucose meter and materials for SMBG measurements 
and instructed on the performance of SMBG.
Visits Following Randomization
Subjects will be seen in the clinic at visits as described in Section 9.1.1, Overview, and in the 
Time and Events Schedule. Procedures and clinical laboratory assessments for each visit or 
contact are outlined in the Time and Events Schedule.
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Subjects who experience nonfatal CV events (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.
On designated visits (see the Time and Events Schedule that follows the Synopsis), subjects will 
bring to the clinic duplicate first morning void urine specimens (collection of the first urine void 
after the individual awakes from sleep), one from the morning of the visit, and one from the 
morning of the day prior to the visit. If the urinary albumin/creatinine result reflects a stage 
change from an earlier measurement (eg, progression from normoalbuminuria to 
microalbuminuria, or regression from macroalbuminuria to microalbuminuria), the subject will 
be contacted to bring 2 additional consecutive-morning first morning void urine specimens to the 
clinic approximately 1 to 2 months later (or sooner under unusual circumstances, eg, subject is 
discontinuing study drug). If the subject is unable to return the specimens in person, the site may 
engage a courier service to deliver the specimen to the site. If the subject does not provide the 
morning void collections 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. Collection containers and directions will be provided to subjects 
at prior visits. The site staff should call subjects a few days prior to visits to remind them to make 
the consecutive urine collections and bring them to the clinic.
9.1.4.
Post-Treatment Follow-up for Participants who Withdraw from 
Randomized Treatment Early
Early withdrawal from randomized treatment will require the immediate collection of key data as 
soon as possible after stopping the study drug as well as an off-drug clinic visit approximately 
30 days (+/-12 days) after discontinuation. The Time and Events Schedule that follows the 
Synopsis describes the evaluation required. It is important to note that subjects who discontinue 
randomized treatment early will be required, wherever possible, to continue with scheduled 
visits. While the data collection required for participants who discontinue randomized treatment 
early will be somewhat modified, comprehensive follow-up, as described in the Time and Events 
Schedule will be essential for every randomized subject.
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.
9.1.5.
Post-Treatment Follow-up for Participants that Complete Randomized 
Treatment as Initially Scheduled
Subjects who complete double-blind study drug through the time of notification of the projected 
GTED will have a final on-treatment visit as soon as possible followed by a 30-day off-drug visit
to occur no later than the GTED. At this visit, a blood specimen for laboratory measurement will 
be collected as well as assessments of any serious adverse event, CV event, or adverse events of 
interest.
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9.1.6.
Post-Randomization Follow-up for Participants Unable to Attend 
Scheduled Visits
Subjects who are no longer able to continue to attend clinic visits for scheduled follow-up must 
have an alternate follow-up plan put in place. The options for this follow-up include:
!
Less frequent clinic visits (eg, annual or to coincide with other care)
!
Telephone, e-mail, letter, social media, fax, or other contact with the subject
!
Telephone, e-mail, letter, social media, fax, or other contact with relatives of the subject
!
Telephone, e-mail, letter, social media, fax, or other contact the subject’s physicians (family 
or specialist)
!
Review of any available medical records
These alternate follow-up methods should be planned to coincide with the visit times outlined in 
Time and Events schedule. Wherever possible follow-up should be made at least once each year 
and in very rare cases where this cannot be achieved arrangements must be made to follow-up 
with the participant at the scheduled completion of the study. Details regarding discussions via
telephone, email, or other such contacts must be properly documented in source records, 
including responses by the subject.
If all means of follow-up fail, at a minimum, the site must attempt to collect vital status data, as 
noted in Section 10.5, Circumstances for Reduced Follow-up, by consulting family members, the 
subject’s physicians and medical records, or public records, including the use of locator agencies 
as permitted by local law.
In the rare instance that a site closes for operational, financial or other reasons and subjects are 
unable to be contacted regarding site closure, data from that site will be transferred to another 
site for a check of public records and/or vital status (at a minimum).
9.2.
Reporting/Adjudication of MACE and Other Events for Adjudication
Investigators will be counseled to report any event that they assess as potentially being a MACE
(CV death, nonfatal MI, nonfatal stroke). In addition, all deaths (to determine cause of death), as 
well as events of hospitalized heart failure, will be submitted for adjudication.
Investigators 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 these events according to the committee’s charter. The Endpoint 
Adjudication Committee will classify the events while blinded to treatment assignment.
Note that events assessed by the investigator as nonfatal MI or nonfatal stroke (ie, nonfatal 
MACE) are not immediately subject to expedited serious adverse experiences reporting 
requirements (refer to Section 12, Adverse Event Reporting). If the event is adjudicated by the 
Endpoint Adjudication Committee as not meeting the nonfatal MACE definition, then the event 
will then be subject to expedited serious adverse experiences reporting requirements, (with 
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reporting timelines starting at the time of notification of this by the Endpoint Adjudication 
Committee).
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 management and monitoring for a portion of the 
sites.
9.3.2.
Steering Committee
The Steering Committee responsible for monitoring the CANVAS study will also be responsible 
for monitoring the current study, CANVAS-R. This 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 of the Steering Committee are
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 
also involve 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
The IDMC responsible for monitoring the CANVAS study to periodically review accumulating
unblinded safety information during the study will also be responsible for monitoring the current 
study, CANVAS-R. Details of the composition, roles, and responsibilities are documented in its 
charter. 
The IDMC will have responsibility for review of serious adverse events, events resulting in study 
drug discontinuation, CV events, and adverse events of interest for this study as well as across 
the broader canagliflozin clinical trials program.
9.3.5.
Endpoint Adjudication Committee
The independent Endpoint Adjudication Committee (EAC) responsible for adjudicating CV
events in the CANVAS study will also be responsible for adjudicating CV events in the current 
study, CANVAS-R. The EAC is composed of external specialists, blinded to treatment 
assignment. The operations, processes, and endpoint definitions to be employed by the 
committee are defined in its charter.
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9.4.
Safety Evaluations
Safety and tolerability will be evaluated on the basis of the overall incidence of serious adverse 
events, adverse events that lead to study drug discontinuation, adverse events of interest, the
incidence of MACE events (overall and within the first 30 days of study drug treatment), vital 
signs (pulse, blood pressure), and body weight. Adverse events that do not meet the definitions
above will not be collected.
The safety data from this study will be combined with the data from the other large-scale study 
of the effects of canagliflozin compared to placebo (CANVAS) in a pre-specified meta-analysis 
of cardiovascular safety outcomes to meet regulatory requirements set at the time marketing 
authorization for canagliflozin was granted. The CV meta-analysis will be described in a separate 
document with a specific statistical analysis plan.
Serious Adverse Events and Adverse Events Leading to Discontinuation
Adverse events 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 from 
when informed consent is provided. Information about all adverse events (serious or not) should
be recorded in source documents (eg, progress notes) according to good clinical practice, and
retained at the investigative sites. Only serious adverse events, nonserious adverse events that 
result in study drug discontinuation, and adverse events of interest will be recorded on eCRFs.
For purposes of reporting serious adverse events for this study, nonfatal MI and nonfatal stroke 
events (ie, nonfatal MACE) will not immediately be subject to expedited serious adverse event 
reporting requirements. Refer to Section 12, Adverse Event Reporting, for details regarding the 
handling of MACE. 
Collection of Additional Information for 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 the 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, amputations, and venous thromboembolic 
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 diabetic ketoacidosis, ketoacidosis, metabolic acidosis or 
acidosis need to be reported to Janssen 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. Amputations have also been designated as adverse events 
of special interest and therefore amputations need to be reported to the sponsor within 24 hours 
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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.
Investigators will be asked to provide additional information so as to support more detailed 
analyses. Investigators may also be asked to provide additional information on other adverse 
events, based upon review by the MSRC or the IDMC (refer to Section 9.3.3, Medical Safety 
Review Committee, and Section 9.3.4, Independent Data Monitoring Committee).
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.
Follow-Up Collection of Safety Information
Any clinically significant abnormalities persisting at the time treatment is discontinued (either 
prematurely or at completion of the study) will be followed by the investigator until resolution or 
until a clinically stable outcome is reached, or until further follow-up is no longer considered by 
the investigator to provide clinically meaningful information. (see Sections 9.1.4, 9.1.5, and 
12.2.2 for additional details regarding follow-up). 
Clinical Safety Laboratory Tests 
Subjects will be monitored with safety laboratory measurements as described in Attachment 1. 
The investigator must review the laboratory reports, document this review, and record any 
serious adverse changes occurring during the study in the adverse event section of the eCRF.
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 an automated blood pressure monitor; 
if neither of these is available, a high-quality aneroid sphygmomanometer will be acceptable. 
Calibration of the blood pressure measuring device is not required for this trial, but if the 
institution has a calibration policy, compliance with this policy is expected. 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; the average of the 3 readings will be recorded in the 
eCRFs.
For each subject, a consistent arm should be used for blood pressure measurements across the 
course of 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.
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Body Weight
Body weight will be measured using a consistent scale at each visit. Scale calibration is not 
required for this trial, but if the institution has a scale calibration policy, compliance with this 
policy is expected. As far as possible, 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 should be dressed as lightly as 
possible, with consistency from visit to visit); subjects will be asked to urinate before being 
weighed.
Urine Pregnancy Testing 
Urine pregnancy testing will be performed on all women unless they are surgically sterile or 
unless there is a documented history of their postmenopausal status. A urine pregnancy test will 
be performed at the baseline visit unless a serum pregnancy test is preferred at the discretion of 
the investigator or if required by local regulations (if a serum pregnancy test is required, it will 
be performed at the screening visit). Additional 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 Section 12.2.3, 
Pregnancy, for instructions in cases of a positive pregnancy test).
9.5.
Measures of Efficacy/Efficacy Endpoints
The categorical efficacy endpoint of the proportion of subjects with progression of albuminuria 
(defined as ∀1 step increase in category of albuminuria [ie, none to micro- or macro, or micro- to 
macroalbuminuria]) will be assessed from urine collections according to the categorizations 
defined in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
Guideline #1 (KDOQI 2007). The definition of microalbuminuria is urinary albumin/creatinine 
ratio of 30 to 300 mg/g and the definition of macroalbuminuria is urinary albumin/creatinine 
ratio greater than 300 mg/g.
On designated visits, subjects will bring to the clinic duplicate first morning void urine 
specimens (collection of the first urine void after the individual awakes from sleep), one from the 
morning of the visit, and one from the morning of the day prior to the visit. If the urinary 
albumin/creatinine result reflects progression or regression of albuminuria from the baseline 
(eg, progression from normoalbuminuria to microalbuminuria or macroalbuminuria accompanied 
by a urinary ACR value increase of ∀30% from baseline; or regression from macroalbuminuria 
to microalbuminuria or normoalbuminuria accompanied by a urinary ACR value decrease of 
∀30% from baseline), the subject will be contacted to bring 2 additional consecutive-morning 
first morning void urine specimens to the clinic approximately 1 to 2 months later (or sooner 
under unusual circumstances, eg, subject is discontinuing study drug). If the subject is unable to 
return the specimens in person, the site may engage a courier service to deliver the specimen to 
the site. If the subject does not provide the morning void collections 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. Collection containers 
and directions will be provided to subjects at prior visits. The site staff should call subjects a few 
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days prior to visits to remind them to make the consecutive urine collections and bring them to 
the clinic.
10.
SUBJECT COMPLETION, PREMATURE DISCONTINUATION OF 
TREATMENT, LOSS TO FOLLOW-UP AND WITHDRAWAL OF CONSENT
10.1.
Subject Completion
A subject will be considered as having completed the study, regardless of whether the subject is 
on or off study drug, if the subject is followed until a time point between the notification of the 
GTED and the GTED (eg, subjects who complete the treatment need to have a final 
posttreatment follow-up visit; subjects who withdraw early from the treatment need to have a 
final contact after the notification of the GTED), or at the time of death for subjects who die 
prior to the GTED. The occurrence of a nonfatal MI, nonfatal stroke or any other safety of 
efficacy outcome does not comprise study completion and is not a criterion for withdrawal from 
the study or study drug.
10.2.
Premature Discontinuation of Study Medication
A subject will discontinue study medication for any of the following reasons:
!
The investigator believes that for safety or tolerability reasons it is essential for the subject 
to stop treatment
!
The investigator formally unblinds the subject’s treatment allocation
!
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 falls to <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 which case an additional 
repeat determination can be performed after resolution of the short-term illness). 
!
Subject requires dialysis or renal transplantation
!
Subject requires 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.
Premature discontinuation of study treatment does not comprise study completion and is 
not a criterion for withdrawal from the study. All subjects who prematurely discontinue study 
treatment should continue study follow-up, although the nature of follow-up may be modified 
(see Section 9.1.4 and the Time and Events Schedule). Treatment should be recommenced 
wherever possible and routinely considered at every visit following discontinuation.
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. Withdrawing 
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subjects should be explicitly asked about the contribution of possible adverse events to their 
decision to withdraw consent, and any adverse event information elicited should be documented. 
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. 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.
10.3.
Reinstitution of Treatment for 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 
should be encouraged to recommence study drug unless there is a clear contraindication at the 
discretion of the investigator, with concurrence from the sponsor’s medical monitor.
Study drug interruptions, occurring for any reason and lasting 7 days or longer, will be 
documented on the eCRF.
10.4.
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 achieve as complete follow-up as possible until after the site 
notification of the GTED. The measures taken to achieve follow-up are discussed in 
Section 10.5, Circumstances for Reduced Follow-up, and must be documented. The informed 
consent form will stipulate that even if double-blind study drug is discontinued, he/she will agree 
to continue follow-up.
10.5.
Circumstances for Reduced Follow-up 
There may be circumstances in which a reduced follow-up schedule is required and the options 
for this are described in Section 9.1.6, Post-Randomization Follow-up for Participants Unable to 
Attend Scheduled Visits. If one of these regimens is not possible, it will be necessary for the site 
investigator to contact the Sponsor representative to indicate the reasons why no further 
follow-up is necessary. It is important to note that a subject declining further follow-up does not 
constitute withdrawal of consent and the alternate follow-up mechanisms that the participant 
agreed to when signing the consent form will still apply (eg, searches of databases, use of locator 
agencies at study completion) as permitted by local regulations.
In this regard, the subject will be asked as a condition of entry into the study 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 status with respect to the CV safety composite endpoint, in the event the 
subject is not reachable by conventional means (eg, office visit, telephone, e-mail, or certified 
mail). The subject is also to be advised 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 
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and medical records, or public records, including the use of locator agencies as permitted by 
local law, to determine the subject’s endpoint status.
10.6.
Withdrawal of Consent
Withdrawal of consent should be a very unusual occurrence in a clinical trial. The investigator 
should make every effort to maintain a good relationship with subjects to avoid this occurrence.
In many instances where withdrawal of consent could potentially be recorded, the subject could 
be expected to be followed-up through one of the alternative follow-up mechanisms discussed in 
Section 10.5, Circumstances for Reduced Follow-up.
Withdrawal of consent in this trial may only be logged in the eCRF after a discussion between 
the investigator and the appropriate sponsor representative. 
For subjects truly requesting withdrawal of consent, it is recommended that the subject withdraw 
consent in writing; if the subject or the subject’s representative refuses or is physically 
unavailable, the site should document and sign the reason for the subject’s failure to withdraw 
consent in writing.
If a 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.
11.
STATISTICAL METHODS
11.1.
Analysis Sets
The intent-to-treat (ITT) analysis set includes all subjects who are randomized via the Interactive 
Web Response System (IWRS). The assessment of the primary and most of the secondary 
objectives will be based upon this analysis set.
The modified intent-to-treat (mITT) or On-Treatment analysis set includes all subjects who are 
randomly assigned to a treatment group and receive at least one dose of double-blind study. It 
will be used in the analyses assessing on-treatment effects, e.g. time slope of on-treatment eGFR.  
Efficacy data will be analyzed according to the initial randomization assignment regardless of 
actual treatment received.
11.2.
Sample Size Determination
Based on the interim data from the CANVAS study, where ACR was measured periodically at 
scheduled visits, it is projected that the annual progression rate for the CANVAS-R study will be
approximately 7.4%. Assuming a 22% relative risk reduction for albuminuria progression, an 
annual progression rate in the placebo arm of 7.4%, an 18-month accrual period, a maximum 
treatment period of 36 months, and an annual discontinuation (from treatment) rate of 10%, it is 
estimated that 693 events will be reported. With 5,700 subjects enrolled, the power to 
demonstrate the superiority of canagliflozin over placebo for albuminuria progression is 90.5%, 
with type I error rate of 0.05 (two-sided).
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11.3.
Efficacy Analyses
11.3.1.
Primary Efficacy Analysis
In this study, duplicate urine specimens will be collected for all ACR measurements. At each 
visit, the geometric mean of the duplicate measurements will be computed and used for all 
subsequent analysis unless otherwise specified.
Subjects will be classified as having normoalbuminuria (urinary ACR of <3.5 mg/mmol 
[<30 mg/g]), microalbuminuria (ACR ∀3.5 mg/mmol [∀30 mg/g] and #35 mg/mmol 
[#300 mg/g]), or macroalbuminuria (ACR of >35 mg/mmol [>300 mg/g]). 
The primary efficacy analysis seeks to demonstrate the superiority of canagliflozin in the 
reduction of albuminuria progression relative to placebo.
The time from first study drug administration to first visit date observing progression (ie, not 
using the visit date of the repeat sample collection) of albuminuria will be analyzed using a Cox 
proportional hazards regression model. The model will include treatment and baseline 
albuminuria status as covariates. The hazard ratio between canagliflozin and placebo will be 
provided, including its 95% confidence interval. The observation period for this time-to-event 
analysis will include all available measurements from first study drug administration to the visit 
date of the last ACR measurement. Subjects with no progression will be censored at the visit date 
of the last albuminuria measurement.
As a sensitivity analysis, the actual onset time of progression of albuminuria can be determined 
to lie within an interval from a sequence of examination times (ie, data are interval censored). As 
a supportive analysis, the accelerated failure time (AFT) model with log normal error structure 
will be implemented considering interval censoring. The dependent variable in AFT model is 
logarithm of time to progression of albuminuria. The model will include treatment group and 
baseline albuminuria status as covariates. We can use speed of progression to interpret AFT 
model. For any time (t), the probability of a subject on placebo progression-free beyond time t is 
the probability of a subject on canagliflozin progression-free beyond t/(, where ( is the 
acceleration factor which can be estimated from the model. Additional sensitivity analyses will 
be specified in the study SAP.
The cumulative progression rate derived from Kaplan-Meier estimate will be displayed 
graphically to evaluate the timing of progression and the consistency of the treatment effect over 
time.
11.3.2.
Secondary Efficacy Analyses
The secondary efficacy analysis seeks to demonstrate the superiority of canagliflozin in the 
reduction of the following CV events relative to placebo.
!
Composite of CV death or hospitalization for heart failure
!
CV death
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The analysis of these CV endpoints will be based on the time to first occurrence of the events 
using the ITT analysis set. The hazard ratio of all canagliflozin compared to placebo and its 95% 
CI will be estimated using a stratified Cox proportional hazards regression model with treatment 
(all canagliflozin and placebo) as the explanatory variable and prior CV disease subgroup 
(secondary prevention and primary prevention) as the stratification factor.
11.3.3.
Exploratory Efficacy Analyses
Regression of albuminuria will be analyzed in a similar fashion as the analysis for progression of 
albuminuria. 
For change in eGFR from baseline to the off-treatment measurement, an analysis of covariance 
(ANCOVA) model will be used with treatment as a fixed effect and adjusting for the baseline 
eGFR value. The treatment difference in the least-squares means and their 2-sided 95% CI will 
be estimated.
Since the distribution of ACR is highly skewed, the log-transformed ACR values for all the post-
baseline and scheduled visits will be modeled using a linear mixed-effect model. The model will 
include treatment group and logarithm of baseline ACR value, visit, and treatment-by-visit 
interaction as fixed effects. The percentage treatment difference can be calculated by taking the 
anti-logarithm of  the estimated coefficient for the treatment group and subtracting 1.
For on-treatment eGFR measurements, a linear mixed effects model will be fitted to eGFR as a 
dependent variable, including treatment, baseline eGFR value, time (as a continuous variable), 
and treatment time interaction as fixed effects and including subject effect as a random intercept 
and time as a random slope. The parameter of interest is the coefficient for treatment and time 
interaction term, which measures the slope difference between canagliflozin and placebo. 
The effect of canagliflozin relative to placebo on changes in HbA1c over time will evaluated 
using a linear mixed effects model. The use of AHA therapy over time will also be summarized 
by treatment group.  
11.3.4.
Multiplicity Adjustment
A testing sequence for the CV program consisting of the integrated database of CANVAS and 
CANVAS-R is specified. The testing of the endpoints in CANVAS-R is specified as part of the 
sequence. To control the type I error in the CV program, testing of the hypotheses in 
CANVAS-R will not proceed until the hypothesis tests related to the integrated database are 
significant. When the hypotheses in the integrated analysis succeed in rejecting the null
hypotheses, all of the alpha for testing (ie, 5%) will pass to CANVAS-R. The primary and the 
key secondary endpoints will be tested as follows.
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Hypothesis
Superiority of Cana in Albuminuria 
progression
)
Superiority of Cana in composite of 
CV death or hospitalization for 
heart failure
)
Superiority of Cana in CV Death
For other efficacy endpoints assessed in CANVAS-R, nominal p-values will be reported.
There are no interim analyses planned.
11.4.
Safety Analyses
The safety analysis will be based on all randomized subjects who receive at least one dose of 
double-blind study medication (ie, the same as the mITT analysis set). There will be no 
imputation for missing values for clinical laboratory test results and vital sign measurements.
The study objective regarding safety and tolerability will be assessed based upon a review of the 
incidence of overall and specific adverse events, discontinuations due to adverse events, 
laboratory results, and other safety and tolerability measurements. 
Major Adverse Cardiac Event (MACE)
Time to the MACE composite of non-fatal myocardial infarction, non-fatal stroke, or CV death 
occurring post-randomization will be analyzed via a stratified Cox proportional hazards model 
treatment (all canagliflozin and placebo) as the explanatory variable and prior CV disease 
subgroup (secondary prevention and primary prevention) as the stratification factor. The hazard 
ratio estimate and the 95% CI will be derived from the model.
For supplementary purpose, the CV risk ratio will be assessed at the early treatment phase. The 
MACE events occurring within the first 30 days and 90 days post-randomization will be 
analyzed in a similar fashion.
Adverse Events
The original terms used in the eCRFs by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
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 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.
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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, Weight
Descriptive statistics for pulse and sitting blood pressure (systolic and diastolic), weight 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.
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 safety composite endpoints (ie, CV deaths, nonfatal MI, nonfatal stroke) should be handled 
as follows:
Investigator Responsibilities:
All SAEs must be reported to the sponsor within 24 hours of knowledge of the event. This 
reporting timeline is also applicable to CV events. The investigator will record the event on 
the AE eCRF and will submit an SAE report to the Sponsor. For CV events, an adjudication 
package will also be submitted; details on assembly and submission of adjudication packages 
will be provided in an Adjudication Manual.
Sponsor Responsibilities:
Nonfatal MACE Events (ie, nonfatal stroke, nonfatal myocardial infarction):
!
The sponsor will submit non-fatal MACE events for adjudication to the Endpoint 
Adjudication Committee. 
!
Nonfatal events that are adjudicated to be components of the primary endpoint will not 
be unblinded or reported to either Health Authorities (HAs) or investigators as safety 
reports. These events will be included in the final analysis which will be unblinded and 
submitted to HAs. 
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!
Non-fatal events that are adjudicated NOT to be components of the primary endpoint, 
and are considered possibly, probably or definitely related by the investigator will be 
unblinded and subject to reporting requirements to both HAs and investigators. The 
reporting timeline starts when the Adjudication Committee notifies the sponsor of the 
decision. 
Fatal Events: 
!
The sponsor will submit all deaths for adjudication to the Endpoint Adjudication 
Committee. 
!
Fatal events will be submitted to HAs but to protect the integrity of the trial, the event 
will not be unblinded prior to review of the death by the EAC. The US FDA has agreed 
to receive these fatal cases blinded. These will also be submitted blinded to other HAs
worldwide, if allowed by local regulation (eg, where local regulations do not allow for 
submission of blinded safety reports, those regulations should be followed).
!
Fatal events that are adjudicated to be a component of the primary endpoint (ie, CV 
death) will remain blinded and will not be reported to either HAs or investigators as 
safety reports. These events will be included in the final analysis which will be 
unblinded and submitted to HAs.
!
Fatal events that are adjudicated NOT to be a component of the primary endpoint 
(ie, non-CV death) and considered possibly, probably or definitely related will be 
unblinded and subject to reporting requirements to both HAs and investigators. The 
reporting timeline starts when the Adjudication Committee notifies the sponsor of the 
adjudication decision. 
For specific adverse events of interest, investigators will be asked to provide additional 
information so as to support more detailed analyses.
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 the 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, amputations, and venous thromboembolic 
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 diabetic ketoacidosis, ketoacidosis, metabolic acidosis or 
acidosis need to be reported to Janssen 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. Amputations have also been designated as adverse events 
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 
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concerning the reporting of those events may be provided to investigators via appropriately-
documented study communications.
Additional information and documentation will be requested from investigators to support a 
detailed assessment and all deaths. Investigators may also be asked to provide additional 
information on other adverse events, based upon review by the MSRC or the IDMC (refer to 
Sections 9.3.3, Medical Safety Review Committee, and 9.3.4, Independent Data Monitoring 
Committee). Refer to Section 3.2, Study Design Rationale, for review of rationale for collection 
of additional information on these selected adverse events.
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 Harmonization [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).
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.
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. 
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.
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.
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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
For this study, all serious adverse events, nonserious adverse events that result in study drug 
discontinuation and other selected adverse events as specified later in this section are to be 
reported from the time a signed and dated informed consent form is obtained until completion of 
the study (including subjects who withdraw prematurely). For specific adverse events of interest, 
a supplemental eCRF page or other designated form will be used to collect additional 
information. 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 the 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, amputations, 
and venous thromboembolic 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 diabetic ketoacidosis, ketoacidosis, 
metabolic acidosis or acidosis need to be reported to Janssen 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. Amputations have also been designated as 
adverse events 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.
Data will be collected in source documents and on the eCRF for these adverse events.
Serious adverse events, including those spontaneously reported to the investigator 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. 
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Adverse events, regardless of severity or presumed relationship to study therapy, 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 (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 
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.
Consistent with standard diabetes treatment guidelines, all study participants should be provided 
with routine preventative foot care and early intervention for foot problems. Specifically:
!
Provide or ensure that all subjects have had general foot self-care education. 
!
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. 
!
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) will be provided with a “study card” indicating the 
name of the investigational study drug, the study number, the investigator’s name, a 24-hour 
emergency contact number, and, if applicable, excluded concomitant medications.
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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.
Nonfatal MI and nonfatal stroke events will be reported on the AE eCRF pages; the entry must 
be completed within 24 hours of the investigator staff’s knowledge of the event. Events that are
adjudicated as not meeting with charter-specified event definitions 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 a CV safety event 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 after a reasonable time following the discontinuation of study drug, 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)
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:
!
Social reasons in absence of an adverse event
!
Surgery or procedure planned before entry into the study or a procedure to treat or explore a 
non-worsened pre-existing condition (eg, elective knee replacement, routine coronary 
angiogram without intervention, elective bariatric surgery); the non-worsening of the 
pre-existing condition must be documented in the source documents and 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.
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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 as soon as possible 
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.
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.
14.2.
Packaging
The study drug will be packaged as individual bottles. The study drug will be packaged 
according to good manufacturing practices and local regulations. The study supplies will be 
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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 15∗C to 30∗C 
(59∗F to 86∗F) and kept out of reach of children.
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. 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 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 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
!
IWRS manual and worksheets
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!
eCRF completion guidelines
!
Study binder with all other necessary documentation (eg, protocol, IB, clinical trial 
agreement)
!
Manual 
of 
instructions 
regarding 
CV 
events, 
documentation 
required, 
and
adjudication-related procedures
!
Home blood glucose monitoring system, glucose strips, lancets, and calibration solution
(optional by country/region)
!
Materials to promote healthy dietary and exercise habits
!
Laboratory operations 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
This study is being conducted under U.S. FDA IND regulations as part of a post-approval 
commitment. The protocol was submitted to and reviewed by the FDA prior to implementation.
The primary ethical concern of this study is that, though the safety profile of canagliflozin has 
been demonstrated in a clinical program involving more than 10,000 subjects, long-term safety 
data under conditions of extensive market use have not yet been established. Thus, 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. The investigator is 
asked to appropriately manage glycemic control and CV risk according to standard guidelines 
across the study. The potential risks in the present study include exposure to study drug, with the 
potential for side effects (Section 1.1.2, “Safety”) and the inherent risks associated with 
venipuncture and multiple blood sample collections. The study has been designed to mitigate 
these inherent risk factors. As per Section 9.3.4, an IDMC is commissioned for this study to 
review unblinded safety information on a periodic basis during the study.
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
(Section 1.1.2, “Safety”). The following adverse of interest have been identified for follow-up in 
post-marketing 
studies 
by 
the 
US 
FDA:
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 the 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, amputations, and
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venous thromboembolic events. 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 diabetic ketoacidosis, ketoacidosis, metabolic acidosis or acidosis need to be 
reported to Janssen 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. These events will be recorded and analyzed in this study, as will all serious 
adverse events, adverse events that result in study drug discontinuation, all deaths, nonfatal MI 
and nonfatal stroke. Amputations have also been designated as adverse events 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.
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 6 months. 
Subjects will be followed after prematurely discontinuing study drug until scheduled study 
completion in line with the Time and Event Schedule to obtain comprehensive information about 
their health and well-being. 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 about 3.5 years would be approximately 300 mL. The maximum amount that would be 
collected at a single visit would be approximately 30 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).
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.
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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:
!
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.
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 (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)
!
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)
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!
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 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 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 
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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.
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.
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.
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.
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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 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 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.
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!
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)
!
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 sub-investigators
!
Documentation of sub-investigator 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 medications of interest; 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.
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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 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 eCRF, and transmitted in a secure manner to 
the sponsor within 3 working days of the subject’s visit or in the time frame specified in the 
clinical trial agreement. 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 an authorized member of the investigational staff 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 or in the time frame specified in the clinical trial agreement.
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, preparation, and shipment of blood, plasma, 
and urine 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.
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 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 
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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 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 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 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.
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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. 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 pharmacogenomic 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. 
The sponsor shall have the right to publish such data and information without approval from the 
investigator. If an investigator wishes to publish information from the study, a copy of the 
manuscript must be provided 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 
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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.
Clinical Study Report CANVAS; 28431754DIA3008; A Randomized, Multicenter, Double-Blind, Parallel, 
Placebo-Controlled Study of the Effects of Canagliflozin on Cardiovascular Outcomes in Adult Subjects With 
Type 2 Diabetes Mellitus. Janssen R&D (13 Dec 2012).
de Zeeuw D, Remuzzi G, Parving HH, Keane W, Zhang Z, Shahinfar S, Snapinn S, Cooper M, Mitch W, Brenner B. 
Albuminuria, a Therapeutic Target for Cardiovascular Protection in Type 2 Diabetic Patients With Nephropathy. 
Dallas, 
TX. 
American 
Heart 
Association, 
2004. 
The 
online 
version 
is 
located 
on 
the 
http://circ.ahajournals.org/content/110/8/921.
DCCT 1993. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of 
diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. 
N Eng J Med. 1993;329(14):977-986.
Ganong W (2005) Review of Medical Physiology. McGraw-Hill Professional. 2005.
IB-JNJ-28431754 Edition 6. Document ID No. EDMS-PSDB-5839974. Johnson & Johnson Pharmaceutical 
Research and Development, L.L.C. Investigator’s Brochure (2 June 2009).
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.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin antagonist irbesartan in patients 
with nephropathy due to type 2 diabetes. New England Jounral of Medicine. 2001;345:851-860.
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.
Seifter J (2005), Sloane D, Rather A: Concepts in Medical Physiology. Lippincott Williams & Wilkins, 2005.
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.
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.
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Vallon V (2011), Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T. SGLT2 mediates 
glucose reabsorption in the early proximal tubule. J Am Soc Nephrol 2011;22(1):104-112. 
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.
Zinman B (2015), Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 
diabetes. N Engl J Med 2015;373(22):2117-2128.
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Attachment 1: Clinical Laboratory Tests
Blood samples for serum chemistry and hematology, and a baseline random urine sample for urinalysis 
will be collected. 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 and 
take appropriate action (eg, repeating abnormal laboratory result or further evaluation as considered 
clinically appropriate). The following tests will be performed by the central laboratory.
!
Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential
!
Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
-phosphate
-aspartate aminotransferase (AST)
-albumin
-alanine aminotransferase (ALT)
-total protein
-gamma-glutamyltransferase (GGT)
-magnesium
-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)*
- specific gravity
- ketones
- pH
- bilirubin/urobilinogen
- protein
- nitrite
- blood
- leukocyte esterase
*Urine glucose will not be measured by the central laboratory
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)
For creatinine in μmol/L:
eGFR (mL/min/1.73 m2) = 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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INVESTIGATOR AGREEMENT
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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 Canagliflozin on Renal Endpoints in Adult Subjects With Type 2 Diabetes 
Mellitus
The CANVAS-R Trial (CANagliflozin cardioVascular Assessment Study-Renal)
Protocol 28431754DIA4003; Phase 4**
JNJ-28431754  (canagliflozin)
**This is a Phase 4 postmarketing study required by the US Food & Drug Administration but may be considered a 
Phase 3 study in some countries in which canagliflozin has not been approved.
Status:
Approved
Date:
20 March 2017
Prepared by:
Janssen Research & Development, LLC  
Document No.:
EDMS-ERI-130850882, 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.
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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 Objective..........................................................................................................................8
1.3.2.
Secondary Objectives ...................................................................................................................8
1.3.3.
Exploratory Objectives ..................................................................................................................8
1.4.
Statistical Hypotheses ......................................................................................................................9
2.
GENERAL ANALYSIS DEFINITIONS.................................................................................................9
2.1.
Analysis Populations.........................................................................................................................9
2.2.
Analysis Sets ..................................................................................................................................10
2.3.
Data Handling .................................................................................................................................10
2.3.1.
Censoring Rules..........................................................................................................................10
2.3.2.
Handling of Key Milestone Dates ................................................................................................10
2.3.3.
Visit Windows ..............................................................................................................................11
3.
SUBJECT INFORMATION ................................................................................................................12
3.1.
Baseline Anthropometric and Demographic Characteristics..........................................................12
3.2.
Baseline Disease Characteristics ...................................................................................................12
3.3.
Disposition Information ...................................................................................................................13
3.4.
Extent of Exposure and Follow-Up .................................................................................................13
3.5.
Prior and Concomitant Medications................................................................................................14
4.
EFFICACY..........................................................................................................................................14
4.1.
Primary Efficacy Endpoint...............................................................................................................14
4.1.1.
Definition......................................................................................................................................14
4.1.2.
Analysis Methods ........................................................................................................................15
4.1.3.
Subgroup Analyses .....................................................................................................................15
4.1.4.
Supportive Analyses....................................................................................................................16
4.1.4.1.
On-Treatment Analysis ............................................................................................................16
4.1.4.2.
Additional Supportive Analyses................................................................................................16
4.1.4.3.
Assessment of Missing Data....................................................................................................17
4.2.
Secondary Efficacy Endpoints........................................................................................................19
4.2.1.
Definition......................................................................................................................................19
4.2.2.
Analysis Methods ........................................................................................................................19
4.2.2.1.
The Composite of CV Death or Hospitalization for Heart Failure ............................................19
4.2.2.2.
CV Death..................................................................................................................................20
4.3.
Multiplicity Adjustment ....................................................................................................................20
4.4.
Exploratory Efficacy Endpoints.......................................................................................................21
4.4.1.
Definition......................................................................................................................................21
4.4.2.
Analysis Methods ........................................................................................................................22
4.4.2.1.
Renal Endpoints.......................................................................................................................22
4.4.2.1.1.
Composite Endpoints............................................................................................................22
4.4.2.1.2.
Regression of Albuminuria....................................................................................................22
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4.4.2.1.3.
Urinary ACR..........................................................................................................................22
4.4.2.1.4.
Change in eGFR...................................................................................................................23
4.4.2.1.5.
eGFR Slope ..........................................................................................................................23
4.4.2.2.
Changes in HbA1c.....................................................................................................................23
4.4.2.3.
AHA Utilization .........................................................................................................................23
5.
SAFETY..............................................................................................................................................23
5.1.
Adjudicated MACE Events..............................................................................................................23
5.1.1.
Analysis Methods ........................................................................................................................24
5.1.2.
Supplementary Analysis..............................................................................................................24
5.2.
Adverse Events...............................................................................................................................24
5.2.1.
Adverse Event Collection ............................................................................................................25
5.2.2.
Analysis Methods ........................................................................................................................25
5.2.2.1.
General Adverse Events ..........................................................................................................26
5.2.2.2.
Male Mycotic Genital Infections ...............................................................................................27
5.2.2.3.
Selected Malignancies .............................................................................................................27
5.2.2.4.
Photosensitivity ........................................................................................................................28
5.2.2.5.
Venous Thromboembolic Events .............................................................................................28
5.2.2.6.
Fracture....................................................................................................................................28
5.2.2.7.
Amputation ...............................................................................................................................29
5.2.2.8.
Diabetic Ketoacidosis...............................................................................................................30
5.2.2.9.
Pancreatitis...............................................................................................................................30
5.3.
Clinical Laboratory Tests ................................................................................................................30
5.4.
Vital Signs.......................................................................................................................................31
5.5.
Electrocardiogram...........................................................................................................................31
REFERENCES ............................................................................................................................................32
APPENDIX...................................................................................................................................................33
Appendix 1.1:
Clinical Laboratory Tests.............................................................................................33
Appendix 1.2:
Criteria for Pre-defined Limit of Change (PDLC) and Abnormal Values.....................35
Appendix 1.3:
List of Preferred Terms for Selected AEs of Interest ..................................................36
Appendix 1.4:
Adverse Events with Potential Amputation Association..............................................45
LIST OF IN-TEXT TABLES
Table 1: 
Summary of Analysis Sets ........................................................................................................10
Table 2: 
Time Intervals for Analysis (in clinic) Visit Windows .................................................................11
Table 3: 
Adverse Events of Interest ........................................................................................................25
LIST OF IN-TEXT FIGURES
Figure 1: 
Diagram of Study Design.............................................................................................................7
Figure 2: 
Follow-up of Randomized Subjects with Respect to the GTED..................................................7
Figure 3: 
Hypothesis Testing Sequence...................................................................................................21
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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)
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.
4.1.3
Additional subgroups were added for the analysis of ACR progression.
4.1.4.2
(4.4.1.2)
To be consistent with the protocol, confirmed progression (regression) is now 
changed to confirmed progression (regression) plus the unconfirmed progression
(regression) from the last ACR measures.
4.1.4.3
Updated the multiple analysis section
4.2.1
Consistent with the analytic approach described in the Cardiovascular Endpoint 
adjudication charter, it is clarified that undetermined death is considered as CV 
death.
4.2.2.1
Additional subgroups were added for the analysis of secondary efficacy 
endpoints.
4.4.1
Clarified that any adjudicated non-CV death event where the adjudication 
committee assigned a renal proximate cause is considered a renal death.
4.4.2.1.3
Mixed model of repeated measure (MMRM) will include baseline and visit 
interaction.
5.1.2
Added examination of MACE data in the first 60 and 90 days on the top of the 
first 30 days analysis.
5.2.2.9
Added a section on the analysis of adjudicated pancreatitis.
Appendix 8
Additional lab analytes were included in the Pre-defined Limit of Change 
(PDLC) criteria.
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ABBREVIATIONS
ACR
albumin creatinine ratio 
AE
adverse event
AFT
accelerated failure time model
AHA
antihyperglycemic agent
ANCOVA
analysis of covariance
BL
baseline
BMI
body mass index
CI
confidence interval
CSR
clinical study report
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
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
MH
medical history
MI
myocardial infarction
PDLC
Pre-defined Limit of Change
PT
preferred term
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 cotransporter 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
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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). In March 2013, canagliflozin was approved for marketing 
by the United States (US) Food and Drug Administration (FDA).
Following market authorization, the sponsor is required to demonstrate that the upper bound of 
the 2-sided 95% confidence interval (CI) of the cardiovascular (CV) risk ratio of test drug to 
comparator be less than 1.3 in accord with FDA Guidance on assessing CV safety of AHAs.1 As a 
result of the discussions with FDA, 28431754DIA4003 (CANVAS-R) was initiated in 
January 2014. The design and the subject characteristics of CANVAS-R are purposefully similar 
to 28431754DIA3008 (CANVAS), an ongoing CV outcome study initiated in December 2009. 
This SAP stipulates definitions of analysis sets, key derived variables and statistical methods for 
analysis of efficacy and safety specific for CANVAS-R based on the latest amendment INT-5 
(September 2016) of the protocol.
1.1.
Trial Design
The CANVAS-R study enrolled the first subject in January 2014. The study recruited
5,812 subjects who met all inclusion criteria and none of the exclusion criteria. Subjects were
randomly assigned to initial treatment with canagliflozin 100 mg or matching placebo 
administered once daily (in a 1:1 ratio). The randomization was balanced by using permutated 
blocks with no stratification factor. After 13 weeks, the dose of canagliflozin (or matching 
placebo) may be up titrated from 100 mg to 300 mg if the subject requires additional glycemic 
control, provided the 100 mg dose is well tolerated. The CANVAS and CANVAS-R studies will 
complete when the last subject randomized has approximately 78 weeks of follow-up or when 
688 MACE are accumulated between both studies (estimated to occur between January 2017 and 
April 2017). The announcement of the GTED will mark the anticipated date on which one of 
these requirements for ending the study will occur.
Following announcement of the projected GTED, for subjects who remain on double-blind study 
drug, sites will be required to schedule the End of Treatment (EOT) and the 30-day off-drug
follow-up visits as per the Time and Events schedule in the protocol; for subjects who 
prematurely discontinue study drug, sites will be required to make a final contact (ie, schedule the 
last follow-up visit) or vital status check as soon as possible after announcement of the GTED. All 
visits (including the 30-day off-drug follow-up visit) will need to be completed prior to the 
GTED. A single Steering Committee (SC) and an Independent Data Monitoring Committee 
(IDMC) have been commissioned for this and the CANVAS 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. 
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Figure 1:
Diagram of Study Design
AHA=antihyperglycemic agent; CV=cardiovascular; HbA1c=hemoglobin A1c; GTED=global trial end date; R=randomization; 
T2DM=type 2 diabetes mellitus
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.
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In this study, duplicate urinary samples will be collected from 2 consecutive days (first morning 
void urine samples from the visit day and the day prior to the visit). The scheduled albumin 
creatinine ratio (ACR) measurements will be made on Day 1 (baseline), Week 26, Week 52, 
Week 78, Week 104, Week 156 and the last on-drug visit. 
1.2.
Randomization 
Central randomization was implemented in this study. Subjects were randomly assigned to 1 of 
2 treatment groups based on a computer-generated randomization schedule prepared by an 
external vendor based on the specification tested by the sponsor before the study. The 
randomization was balanced by using randomly permuted blocks; the randomization did not 
incorporate any stratification factors. 
1.3.
Trial Objectives
1.3.1.
Primary Objective
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at 
elevated risk of CV events, to assess the effect of canagliflozin compared to placebo on 
progression of albuminuria.
1.3.2.
Secondary Objectives 
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at 
elevated risk of CV events, to assess the effect of canagliflozin compared to placebo on:

The composite endpoint of death from CV causes or hospitalization for heart failure;

Death from CV causes.
1.3.3.
Exploratory Objectives
In subjects with T2DM receiving standard of care but with inadequate glycemic control and at 
elevated risk of CV events, to assess the effect of canagliflozin compared to placebo on:

Regression of albuminuria;

Change in estimated glomerular filtration rate (eGFR) from baseline to the last off-drug
value;

Urinary albumin/creatinine ratio (ACR);

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;
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
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;

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;

Changes in HbA1c;

Utilization of AHA therapy.
1.4.
Statistical Hypotheses 
The hypotheses in CANVAS-R are to support superiority claims of canagliflozin relative to 
placebo in reducing the following events:

Progression of albuminuria;

The composite endpoint of death from CV causes or hospitalization for heart failure;

Death from CV causes.
For each endpoint, the following statistical hypothesis on the hazard ratio (HR) of canagliflozin
over placebo will be tested:
H0: The hazard ratio 1.0, versus H1: The hazard ratio < 1.0
Canagliflozin will be claimed to be superior in the reduction of the target events as compared to 
placebo if the upper bound of 95% CIs of the hazard ratio is less than 1.0.
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 analysis (eg, adverse events [AEs]) and 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. The treatment 
groups referred in this SAP will be all canagliflozin and placebo. 
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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.
Table 1: 
Summary of Analysis Sets
Analysis Set
Analysis Population
Data Period
ITT
Randomized subjects
Day 1 to the last trial contact date (see Section 2.3.2) 
up to the GTED
On-Study
Treated subjects
Day 1 to the last trial contact date (see Section 2.3.2) 
up to GTED
On-Treatment
Treated subjects
Day 1 to the last dose date (see Section 2.3.2) plus Xa
days or the last trial contact date, whichever is earlier. 
a 
X is 2 days for laboratory (except ACR) and vital sign measurements, and 30 days for CV and mortality
endpoints, and adverse events (AEs).
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 (see 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 day 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.

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 adverse event (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.
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
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. For serum creatinine, the average of 
the last 2 pre-dose measurement will be used as baseline.
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 (see 
Table 1). Table 2 summarizes the analysis visit windows for laboratory, vital signs, and other key 
safety variables.
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 13
1c –137
92
Week 26
138–229
183
Week 52
230–456
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
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.
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3.
SUBJECT INFORMATION
3.1.
Baseline Anthropometric and Demographic Characteristics
Baseline anthropometric and demographic characteristics will be summarized by treatment group. 
Descriptive statistics (N, mean, standard deviation [SD], median, and range) will be provided by 
treatment group for the 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.
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), baseline 
eGFR, baseline 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 category: 

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;
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
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 
automatic 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. 
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 completed 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 had 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.
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The number of subjects with duration in each of the following categories (<13 weeks, 13 to 
<26 weeks, 26 to <52 weeks, 52 to <104 weeks, 104 to <156 weeks, ≥156 weeks) will also be 
presented by treatment group as well as overall. 
3.5.
Prior and Concomitant Medications
Concomitant medications of interest is collected on the eCRF at baseline and at each on-drug
visit. The number of subjects receiving medication in pre-specified categories, such as insulin, 
sulphonylurea, metformin, statin, anti-thrombotic, diuretic (loop, and non-loop), renin angiotensin 
aldosterone system (RAAS) inhibitor, will be presented by treatment group at baseline and during 
on-drug period. In addition, SGLT2 inhibitor use during the off-drug follow-up period will be 
summarized by treatment group. 
4.
EFFICACY
The analysis will be performed based on the ITT analysis set, if not otherwise specified.
All statistical tests, except those for the primary and secondary efficacy endpoints, will be 
considered nominal and reported with a 2-sided 95% confidence level.
Unless otherwise stated, all efficacy analyses and summaries will be performed using the 
treatment groups assigned by IWRS.
4.1.
Primary Efficacy Endpoint 
Subjects without baseline and/or post-baseline ACR measurements will be excluded from the 
primary efficacy analysis. Furthermore, subjects with macroalbuminuria at baseline (ACR 
>300 mg/g) will also be excluded from the analysis. 
4.1.1.
Definition
The primary efficacy endpoint is the time to the first occurrence of progression of albuminuria.
Urinary albumin creatinine ratio (ACR) is used to assess albuminuria. Subjects will be classified 
as having normoalbuminuria (ACR <30 mg/g), microalbuminuria (ACR 30 mg/g and 
≤300 mg/g), or macroalbuminuria (ACR of >300 mg/g]).2
Progression is 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.3
If the ACR at a visit meets the definition of progression as described, a confirmatory ACR 
collection approximately 1 to 2 months later (or sooner under unusual circumstances, eg, subject 
is stopping study drug) should be done. In cases where a confirmatory sample is not collected 
within 1 to 2 months, the next available set of ACR measurements can be used for confirmation. 
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The primary efficacy analysis will be based on results of ACR measurements from a single visit
whether confirmed or unconfirmed. The date of the progression/regression event will be defined 
as the visit date of the first urine sample for the potential progression/regression findings. A 
sensitivity analysis (see Section 4.1.4.2) will be based on results of ACR measurements from a 
single visit that were confirmed at a subsequent visit.
4.1.2.
Analysis Methods
At each visit, the geometric mean of the duplicate measurements will be computed and used for 
all subsequent analyses unless otherwise specified. For ACR values below the lower quantifiable 
limit, the lower quantifiable limit itself will be used in the geometric mean calculation. 
As the primary analysis for the primary efficacy endpoint, the time from Day 1 to first visit date 
observing progression (ie, using the visit date of the original sample collection and not using the 
visit date of the confirmatory sample collection) of albuminuria will be analyzed using a Cox 
proportional hazards regression model. The response variable in the model is time to progression 
and the model will include treatment and baseline albuminuria status as the explanatory variables. 
The hazard ratio of canagliflozin compared to placebo and its 95% CI will be estimated. 
Canagliflozin will be considered superior to placebo in the reduction of progression if the p-value 
of the test of significance, ie, the Wald test from the Cox model specified above, is ≤0.05 in the 
context of multiplicity adjustment described in Section 4.3.
For ITT analysis, endpoint events that occur during the data period (see Table 1) will be
considered as eligible events; otherwise subjects will be censored at the last ACR measurement 
up to GTED.
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 hazard ratio of canagliflozin (all canagliflozin group) compared to placebo and its 95% 
confidence interval will be estimated for each of the following subgroups:

Age group: <65, ≥65 years old;

Sex: Male, Female;
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
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;

Baseline albuminuria: Normoalbuminuria, Microalbuminuria;

Duration of diabetes ≥ 10 years: Yes/No;

History of CV disease: Yes/No;

Baseline use of Renin angiotensin aldosterone system (RAAS) inhibitor: Yes/No.
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-Treatment Analysis
For On-Treatment analysis, endpoint events that occur within the data period (see Table 1) will be 
eligible events; otherwise subjects will be censored at the earliest of the last ACR measurement
date, last study drug dose date + 30 days, or GTED.
The Cox model for primary analysis (as described in Section 4.1.2) will be repeated using the 
On-Treatment analysis set.
4.1.4.2.
Additional Supportive Analyses
Several Cox models analogous to the primary efficacy analysis model will also be performed for 
exploratory purposes:

The first Cox proportional hazards model involves the use of confirmed progression, plus the 
unconfirmed progression from the last ACR values;

Secondly, there will be an analysis that only excludes subjects with baseline nephrotic range 
macroalbuminuria (ie, ACR > 3000 mg/g). This analysis will evaluate time to first 
occurrence of 1 step progression in the following categories (ie, baseline normoalbuminuria, 
baseline microalbuminuria, baseline non-nephrotic range macroalbuminuria).
Additionally, the actual onset time of progression of albuminuria can be determined to occur
within an interval from a sequence of examination times (ie, data are interval censored). The 
accelerated failure time (AFT) model with log normal error structure will be implemented 
considering interval censoring excluding subjects with baseline macroalbuminuria.4 The 
dependent variable in the AFT model is the logarithm of time to progression of albuminuria, 
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expressed as time intervals. The model will include treatment group and baseline albuminuria 
status as the explanatory variables. 
The cumulative progression rate derived from Kaplan-Meier estimate will be displayed 
graphically to evaluate the timing of progression and the consistency of the treatment effect over 
time.
4.1.4.3.
Assessment of Missing Data
The potential impact of missing data in the interpretation of the primary efficacy analysis will be 
explored. The primary efficacy endpoint, progression of albuminuria was derived from urinary 
albumin/creatinine ratio (ACR) laboratory measurements which were generally collected 
biannually while subjects were on treatment (ie on treatment period) up to the global trial end date 
(GTED). For subjects who discontinue from treatment early before the development of 
progression of albuminuria, unobserved data of post-baseline ACR measurements at each 
scheduled visit up to the GTED will be considered missing and will be imputed. The multiple 
imputation procedure will apply to ACR data and the time to ACR progession data will then be 
generated based on the imputed data at the schedule visits.
Data for model development
Due to the staggered enrollment of the study, for those randomized at a later stage of the 
enrollment period, pseudo visits up to the max possible visit week prior to GTED, i.e. week 130, 
will be created according to the protocol schedule. In addition, multiple data points at each visit, 
e.g. confirmatory samples, will be aggregated using geometric mean according to the variability 
of ACR data. There is small proportion of subjects (less than 2.5%) with unscheduled visits which 
will be combined with the closest scheduled visit using the same approach.    
Imputation model
Assuming that after treatment discontinuation, subjects discontinued from the canagliflozin arm 
will exhibit a response similar to subjects in the placebo arm, the imputation model will be fit 
using the non-missing data in the placebo group and adjusted for covariates that may be related to 
the missing data mechanism and the risk of progression based on clinical judgment. The potential 
covariates include: 

Baseline ACR (continuous);

Baseline eGFR categories (30 to <60, 60 to <90, ≥90 mL/min/1.73m2);

Baseline blood pressure (SBP<140, DBP<90 mmHg): Yes/No;   

Baseline HbA1c ≥8%: Yes/No;

Age group: <65, ≥65 years old;

Race: White, Other;

Sex: Male, Female;
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In case of convergence issues, the covariates will be removed from the model in the descending 
order of the list (ie, starting from the bottom of the list).
Due to the highly skewed data of ACR, both baseline and post baseline ACR in the imputation 
model will be log transformed.  
Imputation Procedures
There are about 3% of subjects with intermittent missing in post-baseline ACR data. Those 
missing data will be imputed with data estimated from all observed data using the Markov Chain 
Monte Carlo procedure such that the missing data pattern is monotonic.  
The post-treatment ACR data increased gradually over time from the end-of-treatment data. 
Therefore, a “copy control” strategy will be applied and the imputation model will be fit 
sequentially at each visit using non-missing data in the placebo arm and any preceding visits 
(O’Kelly and Ratitch 2014, Section 7.4.2)5. The estimates of the model parameters are then used 
to parameterize a Bayesian posterior distribution. At each imputation, missing data in both active 
and placebo arms will be replaced with predicted values randomly drawn from the distribution. 
The imputed data will also be applied to the models of subsequent visits. For example, the 
imputation model at week 26 will be fit using baseline and covariate data (see Section of 
Imputation Model) and week 26 data of the placebo arm. The ACR data that are missing at 
week 26 in both active and treatment arms will be imputed in the same way. Similarly, the 
imputation model for week 52 will utilize observed data of control arm at week 52 and all the 
preceding data points, whether imputed or observed.
For subjects with missing data, the imputed data up to the earlier of death date or GTED will be 
combined with observed data. For subjects completing the treatment or developing progression, 
only data imputed for intermittent missing will be added back to the observed data.  
Re-construction of time to progression data 
The time to progression will be re-defined based on the imputed dataset where subjects with 
imputed or observed ACR that met the progression criteria will be considered having events at the 
corresponding visit. Subjects remaining event-free will be censored at the last scheduled visit 
before death date or GTED, whichever is earlier. 
Analysis summary
The imputed data will be re-analyzed using the same Cox model for the primary analysis (see 
Section 4.1.2). The imputation process will be repeated 1000 times and the multiple versions of 
analysis results will be combined into single inferential summary using Rubin’s rule.
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4.2.
Secondary Efficacy Endpoints
4.2.1.
Definition
There are 2 secondary efficacy endpoints specified in this study:

The composite endpoint of death from CV causesa or hospitalization for heart failure;

Death from CV causes (CV Death).
Analyses will be using adjudicated events and adjudication of these outcomes by the Endpoint 
Adjudication Committee (EAC) will be done in a blinded fashion.
4.2.2.
Analysis Methods
The analyses will be using the ITT analysis set.
4.2.2.1.
The Composite of CV Death or Hospitalization for Heart Failure
The analysis will be based on time to the first occurrence of the composite event using ITT 
analysis set. The hazard ratio of canagliflozin 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 history of CV disease (secondary and primary prevention) as the 
stratification factor. The p-value from the stratified log rank test for the treatment effect will also 
be reported.
The subgroup analysis will be conducted using the same approaches described in Section 4.1.3
and 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 <140 or 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;
                                                
a Undetermined death is considered CV death.
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
History of amputation: Yes/No;

Baseline use of statin;

Baseline use of anti-thrombotics;

Baseline use of RAAS inhibitor;

Baseline use of Beta blocker;

Baseline use of insulin;

Baseline use of diuretics. 
4.2.2.2.
CV Death
The analysis will be based on time to the first occurrence of CV death using ITT analysis set. The 
hazard ratio of canagliflozin 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 history of CV disease (secondary and primary prevention) as the stratification factor. The 
p-value from the stratified log rank test for the treatment effect will also be reported.
Subgroup analyses will be performed using the same subgroups and the analysis methods 
described in Section 4.2.2.1.
4.3.
Multiplicity Adjustment 
Per the SAP of the integrated summary of CANVAS and CANVAS-R studies, only one alpha 
family is proposed for the testing of the multiple hypotheses based on the integrated data and the 
CANVAS-R data. The Type I error for these tests will be strictly controlled via a gatekeeping 
procedure. If the MACE and the mortality endpoints in the integrated analysis succeed in 
rejecting the null hypotheses, all of the alpha for testing (ie, 5%) will pass to the CANVAS-R for 
testing of the primary and the secondary hypotheses of the study. Tests for CANVAS-R 
hypotheses will proceed sequentially conditional on the statistical significance of the hypothesis 
tests in the integrated summary at the 5% significant level.
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Figure 3:
Hypothesis Testing Sequence
Hypothesis
Superiority of Cana
in Albuminuria 
progression

Superiority of Cana
in composite of CV 
Death or hospitalization 
for heart failure

Superiority of Cana
in CV Death
4.4.
Exploratory Efficacy Endpoints
4.4.1.
Definition
The following exploratory endpoints will be analyzed:

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;

Regression of albuminuria;
Regression of albuminuria is 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 a decrease in the ACR value of greater 
than or equal to 30% from baseline. If the ACR at a visit meets the definition of potential 
regression described above, a confirmatory ACR collection approximately 1 to 2 months later 
                                                
a Non-CV death with a renal proximate cause is considered as renal death.
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(or sooner under unusual circumstances, eg, subject is stopping study drug), should be done. 
In cases where a confirmatory sample is not collected within 1 to 2 months, the next available 
set of ACR measurements can be used for confirmation. 

Change in urinary ACR over time;

Change in eGFR from baseline to the last off-drug measurement;

Estimated eGFR slopes using all on-drug measurements;

Changes in HbA1c.

AHA utilization
4.4.2.
Analysis Methods
4.4.2.1.
Renal Endpoints
4.4.2.1.1.
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 (see 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 the explanatory variables. The hazard ratio of 
canagliflozin compared to placebo and its 95% confidence interval will be estimated  from the 
model.
4.4.2.1.2.
Regression of Albuminuria
Regression of albuminuria will be analyzed in a similar fashion in modeling and censoring rule as 
the analysis for progression of albuminuria. The analysis will be using the ITT analysis set based 
on ACR measurements from a single visit whether confirmed or unconfirmed. Subjects with 
normal albuminuria at baseline will be excluded. The hazard ratio of canagliflozin compared to 
placebo and its 95% confidence interval will be estimated from the model. Additionally, analyses 
based on confirmed regression plus unconfirmed regression from the last ACR values will be 
performed in a similar fashion using ITT analysis set.
4.4.2.1.3.
Urinary ACR
Post-baseline ACR will be analyzed using mixed effect model repeat measurement (MMRM) and
the ITT analysis set. 
Since the distribution of ACR is highly skewed, the log transformed ACR values of all the post-
baseline and scheduled visits will be modeled, using a linear mixed effects model. The linear 
mixed effects model will be fit to the logarithm of ACR as a dependent variable, including 
treatment, logarithm of baseline ACR value, visit, treatment by visit interaction, and logarithm of 
baseline ACR value by visit interaction as fixed effects. The percentage of treatment difference, 
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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. An unstructured 
covariance will be used to model the within subject errors. 
4.4.2.1.4.
Change in eGFR
For change in eGFR from baseline to the last off-drug measurement will be analyzed in the ITT 
analysis set using an analysis of covariance (ANCOVA) model with treatment and the baseline 
eGFR value as covariates. The treatment difference of canagliflozin compared to placebo in the 
least-squares means and associated 95% CI will be estimated from the model. 
4.4.2.1.5.
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), and treatment by time interaction as fixed effects and intercept and time as 
random effects. The parameter of interest is the coefficient for treatment by time interaction term, 
which measures the slope difference between canagliflozin and placebo over time. 
4.4.2.2.
Changes in HbA1c
Change in HbA1c from baseline will be analyzed using MMRM and the ITT analysis set. The 
effect of canagliflozin relative to placebo on the changes in HbA1c from baseline over time will be 
assessed using MMRM. The analysis 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. 
4.4.2.3.
AHA Utilization
Summary of AHA utilization is described under Section 3.5.
5.
SAFETY
The safety analysis will be mainly based on the On-Treatment 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.
5.1.
Adjudicated MACE Events
The MACE is the composite of CV outcomes including CV death, non-fatal MIa, or non-fatal 
stroke. Adjudication of these outcomes by the EAC has been done in a blinded fashion.
                                                
a Silent MIs are excluded from the analysis.
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5.1.1.
Analysis Methods
The analysis will be based on the time to first occurrence of MACE using the ITT analysis set. 
The HR of all canagliflozin compared to placebo and its 95% CI will be estimated using a 
stratified Cox proportional hazards regression model with treatment (all canagliflozin and 
placebo) as the explanatory variable, and prior CV disease subgroup (secondary prevention and 
primary prevention) as the stratification factors. P-value of stratified log rank test for treatment 
effect will also be reported for the primary analysis.
5.1.2.
Supplementary Analysis
A prior post-hoc analysis performed by the FDA of the MACE-plus events occurring during the 
first 30 days post-randomization in CANVAS showed an imbalance in favor of placebo. In the 
PMR, FDA requested that the pattern of MACE events occurring in the first 30 days post 
randomization in CANVAS-R be explored. Additional examination of the MACE events in the 
first 60 and 90 days using the ITT analysis set will be made.
An excess of volume depletion AEs in the canagliflozin groups could provide a possible biologic 
basis for an imbalance in MACE events between canagliflozin and control. In the CANVAS 
study, the Kaplan-Meier (KM) time-to-event analysis comparing canagliflozin and placebo 
showed that the greatest separation in the curves for volume depletion AEs occurred during the 
first 90 days post-randomization.
To assess the potential association between MACE events and volume depletion AEs and fulfill 
the PMR request, hazard ratio will be estimated using the same stratified Cox model as in the 
main analysis (see Section 5.1.1) for events occurring within the first 30 days, and within the first 
90 days post-randomization. In addition, Kaplan-Meier plots including data within first 30 days 
and first 90 days will be presented.
Additionally, time to the first occurrence of each component of MACE as well as fatal/non-fatal 
MI and fatal/non-fatal stroke will be analyzied using the same Cox model described in 
Section 5.1.1. 
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 AE (TEAE) is defined as an AE with an onset after the initiation of double-
blind study drug and before the last study medication date plus 30 days. AEs with a start date 
prior to initiation of double-blind study drug which are subsequently reported to have either an 
increase in intensity or change in attribution in relationship to study drug (ie, attribution to 
possible, probably, very likely) after the initiation of double-blind study drug will also be 
considered as TEAEs.
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5.2.1.
Adverse Event Collection
The AE collection in CANVAS-R is streamlined to include serious adverse events (SAEs), AEs 
that lead to study drug discontinuation, and all AEs (serious and non-serious) for selected AEs of 
interest (Table 3, Section B). 
For selected AEs of interest, additional data will be collected on supplementary CRF pages 
mainly for the purposes of narrative description of certain events. Table 3 lists the AEs of interest. 
Table 3: 
Adverse Events of Interest 
Section A: For the AEs listed below, only serious AEs or AEs that led to 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 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
The AEs listed above will be identified using a MedDRA preferred term list (Appendix 1.3).
5.2.2.
Analysis Methods
The study duration of CANVAS-R is long relative to the rest of the canagliflozin Phase 3 
program. Accordingly, the incidences of AEs (ie, proportion of subjects reporting the AEs) 
derived from the study are not comparable to the incidences generated in the Phase 3 program. 
Therefore, the exposure-adjusted incidence rate will be reported in addition to the incidence. The 
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 
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up is included, the follow-up-adjusted incidence rate will be estimated. The rate is calculated as 
the total number of subjects with the AEs divided by the total follow-up time in subject-years. 
For general AEs and selected AEs of interest that are not routinely collected in CANVAS-R (refer
to Section A of Table 3), the main interest will be the serious AEs and the AEs leading to 
discontinuation of study medication.
5.2.2.1.
General Adverse Events
An overview summary table with the incidence and the exposure-adjusted incidence will be 
provided 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.
SAEs by system organ class and preferred term will be summarized by treatment group using the 
On-Treatment analysis set. The same summary will be provided for AE 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 which are reported in at least 4 or more subjects in any treatment 
group. Four (rule-of-4) was chosen based on the recommendation from the Safety, Planning, 
Evaluation, and Reporting Team (SPERT).6 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 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 may be 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, 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 1.3.
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5.2.2.2.
Male Mycotic Genital Infections
Balanitis and phimosis AEs will be identified using the MedDRA preferred terms listed in 
Appendix 1.3, and the analyses will be based on 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. 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 using the sponsor’s pharmacovigilance 
database and summarized by treatment group.
5.2.2.3.
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 1.3, 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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A summary of all malignancy events as reported in the malignancy supplementary page will be 
reported by treatment and primary site. For breast, bladder, or renal cancers, the risk factors for 
each cancer type captured in the supplementary page will be summarized by treatment.
5.2.2.4.
Photosensitivity
Photosensitivity AE will be identified using the MedDRA preferred terms listed in Appendix 1.3,
and the analyses will be based on 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.
5.2.2.5.
Venous Thromboembolic Events
Venous thromboembolic (VTE) events will be identified using the MedDRA preferred terms
listed in Appendix 1.3. 
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.
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 
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events were fractures and to determine fracture location (anatomic region) and type (low trauma 
or not). The main analyses of the adjudicated low trauma fracture AEs 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:

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.
Adjudicated AEs associated with fall will be summarized by treatment group.
A Kaplan-Meier plot for the time to the first occurrence of adjudicated fracture event will be 
provided by treatment group. The hazard ratio between canagliflozin (all canagliflozin) compared 
to placebo and its 95% confidence interval will be estimated from a Cox proportion hazards 
model with treatment as the explanatory variable.
A summary of all adjudicated fractures by anatomic location will be provided. The hazard ratio 
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 the adjudicated low trauma fractures.
5.2.2.7.
Amputation
The main analysis of lower extremity amputations as documented in the dedicated case report 
form page will be based on the On-Study analysis set. An overview summary table with the 
incidence and the follow-up-adjusted incidence will be generated 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.
For atraumatic lower limb amputation, a Kaplan-Meier plot for the time to the first occurrence of 
event will be provided by treatment group. 
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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 1.4:

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 group. 
5.2.2.8.
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) and related AEs will be identified using the list of MedDRA terms 
in Appendix 1.3. 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 and related events identified by the sponsor’s medical monitoring team and 
the subset of these events that went for adjudication will be provided.
5.2.2.9.
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 1.1. The 
percentage of subjects with specific treatment-emergent laboratory values meeting pre-defined 
limit of change (PDLC) criteria listed in Appendix 1.2 will be summarized. The 95% CI for the 
percentage difference between canagliflozin compared to placebo group will be provided for each 
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PDLC criterion which have 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 in Appendix 1.2. 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 medication.
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. 
5.5.
Electrocardiogram
Electrocardiogram was not be collected in this study.
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REFERENCES
1.
FDA Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Anti-diabetic 
Therapies to Treat Type 2 Diabetes, December 2008.
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.
Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 
2 Diabetes and Microalbuminuria Study Group.N Engl J Med. 2001 Sep 20;345(12):870-8. 
4.
Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan Bergamo Nephrologic Diabetes Complications 
Trial (BENEDICT) Investigators; Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004; 
351:1941–1951.
5.
O’Kelly M (2014), Ratitch B. Overview of the Imputation Methods. In: Clinical Trials with Missing Data. New 
York: John Wiley & Sons; 2014.
6.
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.
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APPENDIX
Appendix 1.1: 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)
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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 1.2: Criteria for Pre-defined Limit of Change (PDLC) and Abnormal Values
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: <LLN and decrease >25% from BL
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
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Appendix 1.3: 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
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Hepatic Injury
Hypoglycaemia
Male Mycotic Genital Infections
Cholestatic pruritus
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
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Hepatic Injury
Hypoglycaemia
Male Mycotic Genital Infections
Jaundice hepatocellular
Liver and small intestine transplant
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
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Malignancy Bladder Cancer
Malignancy Breast Cancer
Malignancy Phaeochromocytoma
Bladder squamous cell carcinoma 
recurrent
Breast sarcoma recurrent
Bladder squamous cell carcinoma stage 0
Contralateral breast cancer
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
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Renal Related
Severe Hypersensitivity/Cutaneous AEs
Upper UTI
Oculomucocutaneous syndrome
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
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UTI
Venous Thromboembolic events
Volume Depletion 
Ureteritis
Pulmonary thrombosis
Uretheritis
Renal vein embolism
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 1.4: Adverse Events with Potential Amputation Association
List of selected preferred terms included within the system organ classes 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
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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
Osteomyelitis
Localised infection
Bone abscess
Skin infection
Osteitis
Soft tissue infection
Osteomyelitis
Staphylococcal skin infection
Staphylococcal osteomyelitis
Subcutaneous abscess
Wound
Wound abscess
Wound dehiscence
Wound infection
NCT01989754