Clinical trial NCT02065791
Conditions: Diabetes Mellitus, Type 2 Diabetic Nephropathy
Keywords: Diabetes Mellitus, Type 2 Diabetic Nephropathies Canagliflozin JNJ-28431754 End-Stage Kidney Disease Chronic Kidney Disease Macroalbuminuria
Sponsor: Janssen Research & Development, LLC
Start date: 2014-02-17; Completion date: 2018-10-30
Enrollment: 4401 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to assess whether canagliflozin has a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in participants with type 2 diabetes mellitus (T2DM), Stage 2 or 3 chronic kidney disease (CKD) and macroalbuminuria, who are receiving standard of care including a maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

Detailed description:
This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), placebo-controlled (an inactive substance that is compared with a medication to test whether the medication has a real effect), parallel-group, multicenter study of the effects of canagliflozin on renal and cardiovascular outcomes in participants with type 2 diabetes mellitus (T2DM) and diabetic nephropathy, who are receiving standard of care including a maximum tolerated daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

The study will consist of a pretreatment phase (several weeks), and a double-blind treatment phase (up to approximately 66 months). During the pretreatment phase all participants will also receive diet/exercise counseling for lipid and blood pressure management as well as counseling on renal and cardiovascular (CV) risk factor medication. A post-treatment follow-up contact or visit will take place approximately 30 days after the last dose of study drug or the completion of the study. The total duration of the study is estimated to be about 5 to 5.5 years. Approximately 4,200 participants will be randomized in a 1:1 ratio to canagliflozin or matching placebo. Participants randomized to canagliflozin will receive a dose of 100 mg once daily. The overall safety and tolerability of canagliflozin will be evaluated by collecting information on adverse events, laboratory tests, vital signs (pulse, blood pressure), physical examination, and body weight.

Arms: arm 1: Each participant will receive 100 mg of canagliflozin once daily arm 2: Each participant will receive matching placebo once daily
Interventions: intervention 1: Canagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: One 100 mg over-encapsulated tablet orally once daily intervention 2: One matching placebo capsule orally (by mouth) once daily

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 06 September 2017
Janssen Research & Development*
Clinical Protocol
A Randomized, Double-blind, Event-driven, Placebo-controlled, Multicenter Study of the 
Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Subjects With Type 2 
Diabetes Mellitus and Diabetic Nephropathy
The CREDENCETM Trial 
(Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical 
Evaluation Trial)
Protocol 28431754DNE3001; Phase 3
AMENDMENT INT-6
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; Janssen Infectious Diseases BVBA; Janssen 
Sciences Ireland UC; 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).
EudraCT NUMBER: 2013-004494-28
Status:
Approved
Date:
06 September 2017
Prepared by:
Janssen Research & Development, LLC 
ERIS Number:
EDMS-ERI-67910946, 9.0
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.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 20
TIME AND EVENTS SCHEDULE .............................................................................................................. 26
ABBREVIATIONS ...................................................................................................................................... 31
1.
INTRODUCTION................................................................................................................................ 33
1.1.
Background .................................................................................................................................... 36
1.1.1.
Nonclinical Studies ..................................................................................................................... 36
1.1.2.
Clinical Studies ........................................................................................................................... 37
1.1.2.1.
Overview.................................................................................................................................. 37
1.1.2.2.
Pharmacokinetics .................................................................................................................... 38
1.1.2.3.
Pharmacodynamics................................................................................................................. 39
1.1.2.4.
Efficacy .................................................................................................................................... 39
1.1.2.4.1.
Glycemic Efficacy................................................................................................................. 40
1.1.2.4.2.
Weight Effects ...................................................................................................................... 40
1.1.2.4.3.
Blood Pressure Effects......................................................................................................... 41
1.1.2.5.
Safety....................................................................................................................................... 41
1.1.2.5.1.
Overall Safety....................................................................................................................... 41
1.1.2.5.2.
Safety Related to Renal Function ........................................................................................ 44
1.1.2.5.3.
Safety in Renal Impairment Population................................................................................ 44
1.1.2.5.3.1.
Safety in Moderate Renal Impairment .............................................................................. 44
1.1.2.5.3.2.
Findings in Subjects With eGFR <30 mL/min/1.73m2....................................................... 47
1.2.
Overall Rationale and Goals for the Study..................................................................................... 48
2.
OBJECTIVES AND HYPOTHESES.................................................................................................. 54
2.1.
Objectives ...................................................................................................................................... 54
2.2.
Hypotheses .................................................................................................................................... 55
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 55
3.1.
Overview of Study Design.............................................................................................................. 55
3.2.
Study Design Rationale.................................................................................................................. 60
4.
STUDY POPULATION ...................................................................................................................... 65
4.1.
General Considerations ................................................................................................................. 65
4.2.
Inclusion Criteria ............................................................................................................................ 65
4.3.
Exclusion Criteria ........................................................................................................................... 66
4.4.
Prohibitions and Restrictions ......................................................................................................... 68
4.5.
Repeat Testing and Subject Rescreening ..................................................................................... 69
5.
TREATMENT ALLOCATION ............................................................................................................ 69
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 71
6.1.
Study Drugs ................................................................................................................................... 71
6.2.
Concomitant Antihyperglycemic and Other Therapies .................................................................. 72
6.2.1.
Management of Glycemic Control .............................................................................................. 72
6.2.2.
Management of Renal and CV Risk Factors .............................................................................. 72
6.2.3.
Management of Medications that May Impact Serum Creatinine Levels ................................... 73
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Status: Approved, Date: 06 September 2017
7.
TREATMENT COMPLIANCE............................................................................................................ 73
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 73
9.
STUDY EVALUATIONS .................................................................................................................... 74
9.1.
Study Procedures........................................................................................................................... 74
9.1.1.
Overview..................................................................................................................................... 74
9.1.2.
Pretreatment Phase.................................................................................................................... 77
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 79
9.1.4.
Post-Treatment Follow-up .......................................................................................................... 79
9.1.5.
Post-Randomization Follow-up for Participants Unable to Attend Scheduled Visits.................. 80
9.2.
Reporting/Adjudication of Events in the Primary and Secondary Composite Endpoints 
and Other Events for Adjudication ................................................................................................. 80
9.3.
Study Management: Committees................................................................................................... 81
9.3.1.
Academic Research Organization .............................................................................................. 81
9.3.2.
Steering Committee.................................................................................................................... 81
9.3.3.
Medical Safety Review Committee............................................................................................. 81
9.3.4.
Independent Data Monitoring Committee................................................................................... 82
9.3.5.
Independent Endpoint Adjudication Committee ......................................................................... 82
9.4.
Efficacy Evaluations and Outcomes .............................................................................................. 82
9.4.1.
Measures of Efficacy .................................................................................................................. 82
9.4.2.
Efficacy Outcomes...................................................................................................................... 83
9.5.
Safety Evaluations and Outcomes................................................................................................. 84
9.5.1.
Safety Evaluation........................................................................................................................ 84
9.5.2.
Safety Outcomes ........................................................................................................................ 86
9.6.
Pharmacogenomic Evaluations ..................................................................................................... 86
9.7.
Exploratory Biomarker Evaluations................................................................................................ 87
10.
SUBJECT COMPLETION, PREMATURE DISCONTINUATION OF 
TREATMENTINTERVENTION, OR WITHDRAWAL FROM THE STUDY....................................... 87
10.1.
Subject Completion........................................................................................................................ 87
10.2.
Study Drug Treatment Premature Discontinuation and Reinstitution............................................ 87
10.2.1.
Study Drug Treatment Premature Discontinuation..................................................................... 87
10.2.2.
Reinstitution of Treatment With Study Drug That Has Been Interrupted ................................... 88
10.3.
Withdrawal From the Study............................................................................................................ 88
10.3.1.
Lost to Follow-up ........................................................................................................................ 89
10.3.2.
Withdrawal of Consent................................................................................................................ 89
10.4.
Circumstances for Reduced Follow-up.......................................................................................... 90
11.
STATISTICAL METHODS................................................................................................................. 91
11.1.
Analysis Sets.................................................................................................................................. 91
11.2.
Sample Size Determination ........................................................................................................... 91
11.3.
Efficacy Analyses ........................................................................................................................... 92
11.3.1.
Primary Efficacy Analysis ........................................................................................................... 92
11.3.2.
Secondary Efficacy Analyses ..................................................................................................... 92
11.3.3.
Exploratory Efficacy Analyses .................................................................................................... 93
11.3.4.
Multiplicity Adjustment ................................................................................................................ 93
11.3.5.
Interim Analysis .......................................................................................................................... 93
11.4.
Safety Analyses ............................................................................................................................. 94
12.
ADVERSE EVENT REPORTING ...................................................................................................... 94
12.1.
Adverse Events as Study Efficacy Endpoints ................................................................................ 95
12.2.
Definitions ...................................................................................................................................... 96
12.2.1.
Adverse Event Definitions and Classifications ........................................................................... 96
12.2.2.
Attribution Definitions.................................................................................................................. 98
12.2.3.
Severity Criteria .......................................................................................................................... 98
12.3.
Procedures..................................................................................................................................... 98
12.3.1.
All Adverse Events...................................................................................................................... 98
12.3.2.
Serious Adverse Events ........................................................................................................... 100
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Status: Approved, Date: 06 September 2017
12.3.3.
Pregnancy................................................................................................................................. 101
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 101
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 101
13.1.
Procedures................................................................................................................................... 102
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 102
14.
STUDY DRUG INFORMATION....................................................................................................... 102
14.1.
Physical Description of Study Drug(s) ......................................................................................... 102
14.2.
Packaging .................................................................................................................................... 102
14.3.
Labeling........................................................................................................................................ 102
14.4.
Preparation, Handling, and Storage............................................................................................. 102
14.5.
Drug Accountability ...................................................................................................................... 102
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 103
16.
ETHICAL ASPECTS ....................................................................................................................... 104
16.1.
Study-Specific Design Considerations......................................................................................... 104
16.2.
Regulatory Ethics Compliance..................................................................................................... 105
16.2.1.
Investigator Responsibilities ..................................................................................................... 105
16.2.2.
Independent Ethics Committee or Institutional Review Board (IEC/IRB)................................. 106
16.2.3.
Informed Consent ..................................................................................................................... 107
16.2.4.
Privacy of Personal Data .......................................................................................................... 108
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 109
16.2.6.
Country Selection ..................................................................................................................... 109
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 109
17.1.
Protocol Amendments.................................................................................................................. 109
17.2.
Regulatory Documentation .......................................................................................................... 110
17.2.1.
Regulatory Approval/Notification .............................................................................................. 110
17.2.2.
Required Prestudy Documentation........................................................................................... 110
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 111
17.4.
Source Documentation................................................................................................................. 111
17.5.
Case Report Form Completion .................................................................................................... 111
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 112
17.7.
Record Retention ......................................................................................................................... 112
17.8.
Monitoring .................................................................................................................................... 113
17.9.
Study Completion/Termination..................................................................................................... 113
17.9.1.
Study Completion ..................................................................................................................... 113
17.9.2.
Study Termination..................................................................................................................... 113
17.10.
On-Site Audits .............................................................................................................................. 114
17.11.
Use of Information and Publication.............................................................................................. 114
REFERENCES.......................................................................................................................................... 116
INVESTIGATOR AGREEMENT ............................................................................................................... 129
LIST OF ATTACHMENTS
Attachment 1:
Clinical Laboratory Tests.......................................................................................... 121
Attachment 2:
New York Heart Association Classification of Cardiac Disease............................... 123
Attachment 3:
Volume of Blood to be Collected From Each Subject During First Year.................. 124
Attachment 4:
Optional Specimens for Exploratory Research - Sample Collection and 
Handling.................................................................................................................... 125
Attachment 5:
Pharmacogenomic Sample Collection and Shipment Procedure ............................ 127
Attachment 6:
Modified Rankin Scale.............................................................................................. 128
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JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1: 
Reporting of Serious Unexpected and Related Events (Unless Otherwise Requested 
by Health Authorities or Ethics Committees) ............................................................................ 96
FIGURES
Figure 1:
Micro- and Macroalbuminuria: Change from Baseline in Albumin/Creatinine Ratio in 
CANVAS (28431754DIA3008) through 01 July 2012............................................................... 50
Figure 2:
eGFR (mL/min/1.73m2) (28431754DIA3008): Mean Change from Baseline Over Time 
(Safety) – Regardless of Rescue Medication – Within 2 Days After Last Study 
Medication................................................................................................................................. 52
Figure 3:
eGFR (mL/min/1.73m2) (28431754DIA3004): Mean Change from Baseline Over Time
(Safety) ..................................................................................................................................... 52
Figure 4:
eGFR (mL/min/1.73m2) (28431754DIA3009): Mean Change from Baseline Over Time 
(Safety) – Regardless of Rescue Medication – Within 2 Days After Last Study 
Medication................................................................................................................................. 53
Figure 5: 
Hypotheses Regarding the Effect of ACEi and ARBs on the Progression of Diabetic 
Nephropathy ............................................................................................................................. 54
Figure 6: 
Study Design Diagram.............................................................................................................. 56
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JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
10 December 2013
Amendment INT-1
12 June 2014
Amendment INT-2
03 February 2015
Amendment INT-3
29 September 2015
Amendment INT-4
19 January 2016
Amendment INT-5
Amendment INT-6
6 May 2016
06 September 2017
Amendments below are listed beginning with the most recent amendment.
Amendment INT-6 (06 September 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The primary reason for the amendment is to decrease the number of 
primary composite events required for the interim analysis from 540 to 405. In addition, 2 new secondary endpoints 
have been added and secondary endpoints have been reordered.
Applicable Section(s)
Description of Change(s)
Rationale: to provide clarity in the Time and Events Schedule regarding when plasma glucose monitoring is 
expected in accordance with the site laboratory manual and informed consent form. 
Time and Events
Schedule  
A row was added to the Time and Events Schedule specifying collection of fasting 
plasma glucose.  
Rationale: to add two new secondary endpoints and adjust the hierarchical order in which secondary endpoints 
will be tested.
Synopsis (Secondary 
Objective, Secondary 
Efficacy Outcomes, 
Secondary Efficacy 
Analyses);
2.1 Objectives 
(Secondary Objective);
9.4.1 Measures of 
Efficacy; 
9.4.2 Efficacy 
Outcomes (Secondary 
Efficacy Outcomes);
11.3.2 Secondary 
Efficacy Analyses
Two secondary endpoints were added, including the composite endpoint of 
cardiovascular (CV) death, non-fatal myocardial infarction (MI), and non-fatal stroke 
(ie, 3-point major adverse cardiac event [MACE]), and the stand-alone endpoint of 
hospitalized congestive heart failure. The order  in which secondary efficacy endpoints 
will be tested was adjusted to: 1) The composite endpoint of CV death and hospitalized 
congestive heart failure, 2) The composite endpoint of CV death, non-fatal MI, and 
non-fatal stroke (ie, 3-point MACE), 3) Hospitalized congestive heart failure, 4) The 
renal composite endpoint of end-stage kidney disease (ESKD), doubling of serum 
creatinine, and renal death, 5) CV death, 6) All-cause death, and 7) The CV composite 
endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive heart 
failure, and hospitalized unstable angina.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: based on internal and external data of the effects of sodium-glucose co-transporter 2 (SGLT2)
inhibitors on renal endpoints, the beneficial effects of canagliflozin on renal outcomes may be detected with 
fewer events in the primary composite endpoint. 
Synopsis (Statistical 
Methods: Interim 
Analysis); 9.3.4 
Independent Data 
Monitoring 
Committee; 11.3.5 
Interim Analysis;
16.1 Study-Specific 
Design Considerations
The interim analysis will be conducted when a fewer number of subjects meet the 
primary composite endpoint (ie, 405 vs 540). 
Rationale: to clarify when subjects should discontinue treatment due to chronic dialysis or renal transplant.
10.2.1 Study Drug
Treatment Premature 
Discontinuation
Text was clarified to instruct that study medication is to be discontinued when chronic 
dialysis or renal transplant is “initiated” rather than “required.”
Rationale: to accommodate subjects who start using a disallowed medication.
10.2.1 Study Drug 
Treatment Premature 
Discontinuation
Changed this bullet point: “The subject requires disallowed therapy (refer to Section 8, 
Prestudy and Concomitant Therapy)” 
to now read: “The subject is currently using disallowed therapy (refer to Section 8, 
Prestudy and Concomitant Therapy).”
Rationale: to clarify that restarting study medication should not be considered for certain subjects.
10.2.1 Study Drug 
Treatment Premature
Discontinuation
Added this sentence: Note: Double-blind study drug should be permanently 
discontinued for any subject who experiences a serious adverse event of biochemically-
confirmed DKA, has his/her treatment allocation formally unblinded by the 
investigator, or undergoes a renal transplant or initiates maintenance dialysis.     
Rationale: to inform investigators of additional safety reporting requirements associated with events of 
pancreatitis . 
12 Adverse Event 
Reporting 
As of October 2016, investigators were informed via an investigator letter that events 
of pancreatitis are designated as adverse events (AEs) of special interest to be reported 
to the sponsor within 24 hours of becoming aware of the event. In addition, all events 
of pancreatitis will require additional information to be recorded on a designated 
electronic case report form (eCRF) (including but not limited to fatal or 
hemorrhagic/necrotizing events). 
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: to clarify and further define adverse events of interest, and adverse events of special interest, 
including procedures requiring reporting within 24 hours.
12 Adverse Event 
Reporting
Added this heading: “Adverse Events of Interest”
Revised content as noted: 
For adverse events of interest, investigators will be asked to provide additional 
information. Adverse events of interest include all malignancies, [Deleted: 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 [Added: lower extremity events], and pregnancy.
Added this heading: “Adverse Events and Procedures Requiring Reporting Within 24 
Hours”
Revised content to now read: 
Ketone-related events (eg, DKA, ketoacidosis, metabolic acidosis, or acidosis) and 
pancreatitis events have been designated an adverse event of special interest and 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. Events with characteristics 
suggestive of DKA or pancreatitis will be adjudicated by an ad hoc adjudication 
committee, to verify whether or not the event meets a specified definition within the 
adjudication committee charters. These adverse events must be recorded on the 
supplemental Diabetic Ketoacidosis and Ketone-related Events or Pancreatitis eCRF to 
complement standard information collected on the eCRF AE/SAE page. 
In addition, all lower-extremity amputation procedures are considered adverse events 
of special interest and need to be reported to Janssen within 24 hours of becoming 
aware of the procedure. The underlying condition leading to the lower-extremity 
amputation must be recorded on the supplemental Lower-Extremity Event eCRF to 
complement standard information collected on the AE/SAE eCRF, and the details 
relating to the amputation procedure must be recorded on the Lower-Extremity 
Amputation eCRF.
Revised content as noted: 
Additional information and documentation will be requested from investigators to 
support a detailed assessment of all deaths. Investigators may also be asked to provide 
additional information on other adverse events, based upon review by the MSRC. 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. [Added: Some events will be subject to adjudication by an ad hoc 
adjudication committee to standardize the diagnosis.]
Rationale: to clarify the description of a statistical method used in the Interim Analysis.
Synopsis (Statistical 
Methods: Interim 
Analysis); 
9.3.4 Independent Data 
Monitoring 
Committee; 
11.3.5 Interim 
Analysis
Changed this sentence: “The Lan-DeMets alpha spending function approach will be 
used and the alpha spent in the interim analysis is 0.01.” 
to now read: “The alpha spending function will be used and the alpha spent in the 
interim analysis is 0.01.”
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: Minor errors were noted.
Throughout the 
protocol
Throughout the protocol
Amendment INT-5 (6 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: Clarify that all potential sustained doublings of serum creatinine values are derived from a 
baseline average determination rather than a single baseline value.
Synopsis (Primary Efficacy 
Outcomes);
3.2 Study Design rationale 
(Choice of Renal Efficacy 
Measures);
9.1.3 Double-Blind Treatment 
Phase;
9.2 Reporting/Adjudication of 
Events in the Primary and 
Secondary Composite 
Endpoints and Other Events 
for Adjudication;
9.4.2 Efficacy Outcomes;
11.3.1 Primary Efficacy 
Analysis
Added “average”, “baseline average values”, “average determination”, 
and “sustained” as appropriate.
Rationale: Include guidance regarding subject management surrounding the event of lower extremity 
amputations.
Time and Events Schedule 
footnote “c”’ “h”; “m”, ‘n”, 
“o”; 
12.3.1 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: Address a request from a Health Authority.
Time and Events Schedule 
(posttreatment); 
footnote “ee”
Added collection of concomitant medications, including AHAs, during 
the posttreatment period.
Rationale: Include new safety information and guidance regarding subject management surrounding the 
event of lower extremity amputations.
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JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
1.1.2.5.1 Overall Safety; 
6.1 Study Drug; 
12 Adverse Events Reporting; 
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 amputation.
Added a statement about additional AE of special interest “amputation”.
Rationale: Exclude subjects who may be at a higher risk for lower extremity amputation.
4.2 Exclusion criteria
Added criteria 16 to exclude history of atraumatic amputation within past 
12 months of screening, or an active skin ulcer, osteomyelitis, gangrene,
or critical ischemia of the lower extremity within 6 months of screening.
Rationale: Clarify therapy reporting for subjects who prematurely discontinue study drug.
8 Prestudy and Concomitant 
Therapy
Was clarified that therapies for all subjects will be recorded on the CRF, 
including those subjects who prematurely discontinue study drug.
Rationale: Clarify additional safety reporting requirements associated with diabetic ketoacidosis (DKA).
12 Adverse Events Reporting
Added a statement that 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: Minor errors were noted and/or corrected for clarity.
Throughout the protocol
Minor grammatical and formatting changes were made.
Amendment INT-4 (19 January 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: Due to slower than expected recruitment early in the study and to maintain 
the study timeline, the sample size is being expanded to increase the likelihood of accruing endpoints within the 
primary composite. In addition, the cap that limits enrollment of subjects with eGFR 60 to <90 mL/min/1.73m2 to 
approximately 25% was removed to allow more of these subjects to participate in the study. Furthermore, the 
number of events required for the interim analysis was increased from 420 to 540 to allow more time for renal 
endpoints to accrue. Two new secondary endpoints were added along with a reordering of other secondary 
endpoints. Lastly, if determined medically necessary, cautionary post-baseline use of mineralocorticoid antagonist 
(MRA) (according to local label) will be permitted to allow subjects requiring treatment with MRA to continue on 
double-blind study medication.
Applicable Section(s)
Description of Change(s)
Rationale: to add 2 secondary endpoints and adjust the hierarchical order in which secondary endpoints will be 
tested.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
11
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Synopsis (Secondary 
Objective, Secondary 
Efficacy Outcomes, 
Secondary Efficacy 
Analyses);
2.1 Objectives 
(Secondary Objective);
9.4.1 Measures of 
Efficacy; 
9.4.2 Efficacy 
Outcomes (Secondary 
Efficacy Outcomes);
11.3.2 Secondary 
Efficacy Analyses
Two secondary endpoints were added to test the composite endpoint of CV death and
hospitalized congestive heart failure and the stand alone endpoint of CV death. The order  
in which secondary efficacy endpoints will be tested was adjusted to 1) CV death and
hospitalized congestive heart failure, 2) CV death, 3) All-cause death, 4) Renal 
composite, and 5) CV composite.
Rationale: to allow participation of subjects who may benefit from treatment, but may have otherwise been 
excluded from the study due to eGFR cap and to maintain control over the proportion of subjects enrolled in the 
highest eGFR category.
Synopsis (Study 
Population);
3.1 Overview of Study 
Design (Screening to 
Randomization);
3.2 Study Design 
Rationale (Selection of 
Study Population); 
4.2 Inclusion Criteria
(Criterion #3); 
5 Treatment Allocation 
(Randomization and 
Blinding Procedures)
The global cap restricting no more than approximately 25% of subjects with eGFR ≥60 
to <90 mL/min/1.73m2 has been removed. Text was added to indicate capping may occur 
at the regional and/or site level should the ratio of 60%:40% for chronic kidney disease 
(CKD) Stage 3 (eGFR ≥30 to <60 mL/min/1.73m2; first category):CKD Stage 2 (eGFR 
≥60 to <90 mL/min/1.73m2; second category) drift substantially off target over the course 
of the recruitment period.
Rationale: due to slower than expected recruitment early in the study and to maintain the study timeline, the sample 
size is being expanded to increase the likelihood of accruing endpoints within the primary composite.
Synopsis (Overview of 
Study Design, Sample 
Size Determination); 
3.1 Overview of Study 
Design (Double-Blind 
Treatment Phase); 
Study Duration); 
9.1.1 Overview (Blood 
Collection); 
11.2 Sample Size 
Determination
The sample size was increased from 3,700 to 4,200 subjects. The projected study duration 
was adjusted from 5.5 years to 5 to 5.5 years to account for uncertainty in how the 
primary composite endpoint accrual rate will impact the study duration. In addition, 
assumptions regarding the duration of enrollment and overall duration of the study were 
updated to align with sample size calculations.
Rationale: if determined medically necessary, cautionary post-baseline use of MRA (according to local label) will 
be permitted, thus allowing subjects requiring treatment with MRA to continue on double-blind study medication.
4.4 Prohibition and 
Restrictions; 
8 Prestudy and 
Concomitant Therapy
Text was revised to list post-baseline use of MRAs as restricted rather than strictly 
prohibited.  Text was added to caution investigators of the increased risk of severe 
hyperkalemia associated with using the MRAs in this study population taking ACEi/ARB 
therapy and the need for more frequent monitoring of serum potassium and management 
of hyperkalemia according to local MRA labeling.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
12
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: based on external data, the beneficial effects of canagliflozin on renal outcomes would not be expected 
for at least 18 months. The timing of the existing interim analysis (ie, 420 events) would occur at a time point too 
early to demonstrate effects of canagliflozin on renal outcomes. 
Synopsis (Statistical 
Methods: Interim 
Analysis); 9.3.4 
Independent Data 
Monitoring 
Committee; 11.3.5 
Interim Analysis;
16.1 Study-Specific 
Design Considerations
The interim analysis will be conducted when a greater number of subjects meet the 
primary composite endpoint  (ie, 540 vs 420). In addition, the alpha spent on the interim 
analysis has been increased from 0.003 to 0.01.
Rationale: to clarify text, or reconcile inconsistencies
Throughout the protocol
Minor editorial changes were made
Amendment INT-3 (29 September 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The primary reason for the amendment is to inform investigators of 
additional safety reporting requirements associated with diabetic ketoacidosis (DKA), which is a newly identified 
adverse event of special interest. In addition, background information related to bone fracture and bone mineral 
density already described in detail in the Investigator Brochure is added for consistency across ongoing canagliflozin 
study protocols.
Applicable Section(s)
Description of Change(s)
Rationale: to inform investigators of additional safety reporting requirements associated with diabetic ketoacidosis 
(DKA), which is a newly identified adverse event of special interest.
1.1.2.5.1. Overall 
Safety; 5. Treatment 
Allocation; 10.2.1. 
Study Drug Treatment 
Premature 
Discontinuation; 12. 
Adverse Event 
Reporting; 12.3.1. All 
Adverse Events.
Added information, safety data and instructions on reporting related to diabetic 
ketoacidosis (DKA), ketoacidosis, metabolic acidosis, and acidosis.
Rationale: to exclude subjects who experience particular events outlined in Exclusion Criteria #7, #14 and #18
during the pre-treatment period prior to randomization.
4.3. Exclusion Criteria 
#7, #14, #18, 
Changed the event time frame from “prior to screening” to “prior to randomization” for
Exclusion Criteria #7 (myocardial infarction, unstable angina, revascularization procedure 
[eg, stent or bypass graft surgery], or cerebrovascular accident), #14 (major surgery) and 
#18 (current use of an SGLT2 inhibitor).
Rationale: to provide more background information, preclinical and clinical data related to bone fracture and 
decrease in bone mineral density.
1.1.2.5.1. Overall 
Safety.
Added more background information, preclinical and clinical data related to bone fracture 
and decrease in bone mineral density.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
13
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: to provide further clarifications.
1.1.2.5.1. Overall 
Safety; 3.2. Study 
Design Rationale. 
Relocate the text and data related to ACEi or ARB therapy from Section 1.1.2.5.1. 
Overall Safety to Section 3.2. Study Design Rationale. 
Time and Events 
Schedule (Footnote 
“v”); 3.1. Overview of 
Study Design; 3.2. 
Study Design 
Rationale; 4.3. 
Exclusion Criteria #9 
and general note; 4.5. 
Repeat Testing and 
Subject Rescreening; 
6.1. Study Drugs; 
9.1.2. Pretreatment 
Phase; 9.5.1. Safety 
Evaluation; 11.3.5. 
Interim Analysis; 12. 
Adverse Event 
Reporting; 12.3.1. All 
Adverse Events; 14.5. 
Drug Accountability; 
Attachment 3; 
Attachment 4.
Modified text for clarity.
Rationale: Minor errors were noted.
Throughout the 
protocol
Throughout the protocol
Amendment INT-2 (03 February 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To revise inclusion criteria to allow patients with higher baseline HbA1c
values who may benefit from the study treatment to participate in the study. In addition, changes to the prescreening 
assessment are intended to allow a wider range of measures to prescreen subjects for albuminuria/proteinuria, as 
well as to extend the duration of the prescreening assessment of the study. These changes should not impact the 
safety of subjects screened or randomized, as well as the event rates in this study.
Applicable Section(s)
Description of Change(s)
Rationale: To include subjects with higher baseline HbA1c who may be at increased risk for renal and 
cardiovascular events. Additionally, the higher threshold for HbA1c inclusion may help account for differences in 
Type 2 Diabetes Mellitus (T2DM) medical practice patterns that exist globally, and allow participation by subjects 
for whom available treatments are not able to achieve glycemic goals. As per Section 6.2.1 of the protocol, the 
background antihyperglycemic agent (AHA) regimen should be adjusted throughout the study to achieve glycemic 
goals, using standard local guidelines, as considered appropriate by the investigator for the individual subject. 
Investigators should not enroll subjects who may be considered non-compliant with study drug or who may have 
limited access to routine health care.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
14
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Synopsis (Study 
Population); 3.1 
Overview of Study 
Design (Figure 6 Study 
Design Diagram, 
Screening to 
Randomization); 4.2. 
Inclusion Criteria 
(Criterion #2);
Changed the upper limit of HbA1c level from “≤10.5%” to “≤12.0%” for the study entry.
Rationale: To provide a wider range of measures for prescreening subjects for evidence of albuminuria/proteinuria.
Synopsis (Overview of 
study design); 3.1. 
Overview of Study 
Design (Prescreening); 
9.1.2. Pretreatment
Phase (Prescreening)
Added the phrase “For the prescreening assessment where UACR is not routinely 
measured as per standard of care, it may be substituted by one of the following measures: 
albumin excretion rate >300 mg/24 hours, urine protein-to-creatinine ratio (PCR) 
>500 mg/g (>56.5 mg/mmol), or protein excretion rate >500 mg/24 hours.”
Time and Events 
Schedule (Footnote 
“u”)
Added the phrase “or other acceptable albuminuria/proteinuria measures if UACR values 
unavailable. For details of these additional measures refer to Section 9.1.2. Pretreatment 
Phase.”
3.1. Overview of Study 
Design (Prescreening); 
9.1.2. Pretreatment 
Phase (Prescreening)
Added guidance regarding the utility of reagent strip urinalysis (dipstick), if used as a tool 
for identifying subjects who may qualify prescreening criteria, that states “ Note: While 
positive reagent strip analysis (eg, dipstick ≥2+) may be suggestive of 
albuminuria/proteinuria that meet the prescreening criteria, any positive reagent strip 
findings must be accompanied by one of the specified albuminuria/proteinuria 
prescreening measures listed above prior to screening with central laboratory 
evaluations.”
Rationale: For prescreening assessments of albuminuria/proteinuria, there is no upper limit in order to allow 
subjects with a wider range of albuminuria/proteinuria measured at various local laboratories to continue on to a full 
screening visit where the UACR will be conducted by the central laboratory.
Synopsis (Overview of 
study design); 3.1. 
Overview of Study 
Design (Prescreening); 
9.1.2. Pretreatment 
Phase (Prescreening)
Removed the prescreening upper limit for UACR.
Rationale: To provide a longer timeframe in which local laboratory results may be used to prescreen subjects.
Synopsis (Overview of 
study design); 3.1. 
Overview of Study 
Design (Prescreening); 
9.1.2. Pretreatment 
Phase (Prescreening)
Revised text to indicate subjects will be prescreened on the basis of eGFR and UACR, or 
other acceptable albuminuria/proteinuria measurements by local laboratory within 
6 months prior to screening, rather than 3 months.
Rationale: To allow subjects who fail prescreening due to local laboratory UACR and/or eGFR values to be 
retested.
3.1. Overview of Study 
Design (Prescreening); 
9.1.2. Pretreatment 
Phase (Prescreening)
Added the sentence “Subjects who fail local laboratory pre-screening assessments are
allowed to repeat those laboratory tests.”
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
15
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: To provide clarification on management of background standard care medications
4.2 Inclusion Criteria 
(Criterion #5)
Added the word “stable” into the criterion, stating “All subjects must be on a stable, 
maximum tolerated labeled daily dose of ACEi or ARB for at least 4 weeks prior to 
randomization.”.
Synopsis (Overview of 
study design); 3.1. 
Overview of Study 
Design (Screening to 
Randomization); 6.2.3.
Management of 
Medications That May 
Impact Serum 
Creatinine Levels;
9.1.2. Pretreatment 
Phase;
Provided instruction that “Investigators are encouraged to keep other anti-hypertensive, 
lipid-lowering and antihyperglycemic therapies dose stable for approximately 4 weeks 
prior to randomization. In addition, investigators are encouraged to keep medications that 
are known to impact serum creatinine levels (eg, NSAIDs, trimethoprim, cimetidine, 
probenecid, aminoglycosides, amphotericin, ketoconazole, and clofibrate) stable during 
the screening period and for approximately 2 weeks before any serum chemistry
measurement during the course of the study.” 
Time and Events 
Schedule (Footnote 
“ff”); 8. Prestudy and 
Concomitant Therapy
Removed the content related to “AHAs taken within 12 months of screening will be 
recorded.”
Rationale: To provide additional instructions on eligibility of subjects for study enrollment.
4.3 Exclusion Criteria 
(Criterion #19)
Changed the sentence “Current or prior participation in another canagliflozin study” to 
“Current participation in another canagliflozin study or previously exposed to 
canagliflozin in a prior canagliflozin study.” to allow subjects who received placebo or 
non-canagliflozin active control treatment in previous canagliflozin study to participate in 
the CREDENCE study.
4.3. Exclusion Criteria 
(Criterion #17)
Added the sentence “Note: If deemed clinically appropriate at the discretion of the 
investigator, subjects may be removed from therapy with MRA or DRI during screening. 
Subjects who are off therapy with MRA or DRI for at least 8 weeks prior to 
randomization may be considered eligible for enrollment.”
Rationale: To provide clarification to study procedures
4.3. Exclusion Criteria 
(Criterion #14)
Removed example of major surgery to provide more discretion to investigators.
Major surgery (ie, requiring general anesthesia) within 12 weeks before screening, or has 
not fully recovered from surgery.
Note: Subjects with planned surgical procedures to be conducted under local anesthesia 
may participate.
Synopsis 
(Stratification, Primary 
efficacy analysis); 3. 
Study Design and 
Rationale; 5, Treatment 
Allocation; 9.1.3. 
Double-blind 
Treatment Phase 
(Day 1/Day of 
Randomization);11.3.1. 
Primary Efficacy 
Analysis
Clarified that stratification will be based on pretreatment eGFR value most proximate to 
the baseline visit (eg, screening, unscheduled, or Week -2), since, in addition to the 
screening eGFR value, other eGFR values may be obtained during the pretreatment phase 
of the study. 
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
16
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Synopsis (Overview of 
study design); 3.1. 
Overview of Study 
Design (Screening to 
Randomization); 9.1.2. 
Pretreatment Phase
Clarified the screening period extension process, stating “…the screening period may be 
extended, up to a total of 8 weeks (inclusive of the 2-week single-blind placebo run-in 
period); however, an additional 2 weeks of screening time may be allowed, if considered 
medically appropriate. Extension beyond this period of time would require concurrence 
with the sponsor’s medical monitor.”
3.1. Overview of Study 
Design (End of 
Treatment Visit); 9.14. 
Post-Treatment 
Follow-up; 10.1. 
Subject Completion;
Clarified the process of announcement of the predicted Global Trial End Date (GTED), 
end of treatment/final on-site visit, 30 day telephone follow-up contact and the actual 
GTED. 
Time and Events 
Schedule (Footnote 
“j”)
Modified footnote “j” to provide greater flexibility for the time frame when the Optional 
Exploratory Research Consent may be signed. 
6.1. Study Drugs 
(Two-week Single-
Blind Placebo Run-in 
Period following 
Screening); 9.1.2. 
Pretreatment Phase
Clarified that subjects should take the last dose of single-blind placebo study drug on the 
day prior to the Baseline (Day 1) visit. 
9.1.3. Double-Blind 
Treatment Phase
Removed “ESKD” from the list of events with which subjects will continue to receive 
double-blind study drug.
Rationale: To increase consistency, and be compliant with the current protocol template.
3.2. Study Design 
Rationale (Choice of 
Renal Efficacy 
Measures)
Deleted the last paragraph in sub-section “Choice of Renal Efficacy Measures” for 
consistency with Time and Events Schedule as well as other section of the protocol.
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 to monitor changes of UACR overtime. 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.
10.3.2. Withdrawal of 
Consent 
Modified text that describes reasons subjects may be discontinued from study medication 
to maintain consistency with the response options available in the eCRF.
12.2.1. Adverse Event 
Definitions and 
Classifications
Modified text under “Serious Adverse Event” to be complaint with the language in 
current protocol template. 
12.3.3. Pregnancy
Added examples for abnormal pregnancy outcomes considered as serious adverse events 
according to the current protocol template. 
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, spelling or formatting changes were made.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
17
Status: Approved, Date: 06 September 2017
Amendment INT-1 (12 June 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The primary reason for the amendment to the protocol is to reflect 
recommendations from the United States (US) Food and Drug Administration (FDA) for study 28431754DNE3001. 
Applicable Section(s)
Description of Change(s)
Rationale:
To further reinforce standards of care for glycemic, blood pressure and lipid goals in both treatment 
arms. 
6.2.1. Management of 
Glycemic Control; 6.2.2. 
Management of Renal and 
CV Risk Factors; 15. Study 
Specific Materials
Added text to inform study sites about the individualized metrics reports for glycemic, 
blood pressure and lipids control that will be prepared for the sites approximately 
biannually and about the independent data monitoring committee (IDMC) monitoring of 
the same data in unblinded fashion by the treatment group.
Added text stating that investigators will be provided American Diabetes Association 
(ADA) guidance as a reference for standards of care in the management glycemic, blood 
pressure and lipids control, but are encouraged to use similar local guidelines if they exist.
Rationale:
To refine the specific definition of the endpoint event of renal death.
Synopsis, Primary Efficacy 
Outcomes; 3.2. Study 
Design Rationale; 9.4.2.
Efficacy Outcomes
The definition of renal death was clarified as death in subjects who have reached end-stage 
kidney disease (ESKD), die without initiating renal replacement therapy, and no other 
cause of death is determined via adjudication.
Rationale:
To clarify the time frame in laboratory measurements for endpoint events.
11.3.1. Primary Efficacy 
Analysis;
Synopsis, Primary Efficacy 
Outcomes; 3.2. Study 
Design Rationale; 9.4.2 
Efficacy Outcomes
The date of confirmed doubling of serum creatinine was clarified as being the date when 
the first doubling from baseline is detected from local or central laboratory determinations.
Additionally, clarifications were added to indicate the endpoint of doubling of serum 
creatinine may be triggered by a central or local laboratory results.
The time window for confirmation of the initial estimated glomerular filtration rate 
(eGFR) value and doubling of serum creatinine via the central laboratory was clarified as 
being 30 days and preferably within 60 days of the initial value.
Rationale:
To clarify the definition of and the procedure for baseline serum creatinine.
11.3.1. Primary Efficacy 
Analysis;
T&E Schedule, footnote 
“v”;
9.1.2. Pretreatment Phase
Additional details were added to instruct that the baseline serum creatinine will be 
determined using the average of 2 pre-treatment measures up to 4 weeks apart. 
To instruct that an additional serum chemistry collection for serum creatinine will be made
at the run-in visit (Week -2) for subjects who have an extended screening period 
(ie, >2 weeks between the screening visit and run-in (Week -2) visit.
Rationale:
To include an assessment of stroke disability to evaluate stroke outcomes.
9.5.2. Study Outcomes; 
Attachment 6
Text was added instructing study sites that for subjects who experience a stroke during the 
study, a modified Rankin Scale (mRS) assessment will be conducted, and the mRS 
assessment form is provided in Attachment 6 of the protocol.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
18
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
Rationale:
To use general standards for management of hyperkalemia in place of specific hyperkalemia 
management guidance, since there is no evidence of excess risk for hyperkalemia associated with the 
canagliflozin 100 mg dose used in this study.
8. Prestudy and 
Concomitant Therapy; 9.5.1. 
Safety Evaluation; 15. Study 
Specific Materials
References to the specific hyperkalemia management guidance were removed.
Rationale:
To clarify prescreening.
T&E Schedule, footnote 
“k”; 9.1.2. Pretreatment 
Phase;
T&E Schedule, footnote 
“i”; 9.1.2. Pretreatment 
Phase; 16.2.3. Informed 
Consent:
Added details regarding the collection of the latest 3 pre-study local laboratory serum 
creatinine values if available.
Added an optional separate abbreviated prescreening-specific informed consent form 
to allow study sites to conduct the prescreening assessments of urinary 
albumin-to-creatinine ratio (UACR) and eGFR.
Rationale:
To provide more clarity.
Synopsis, Sample Size 
Determination; 
11.2. Sample Size 
Determination;
T&E Schedule, footnote 
“n”; 9.5.1. Safety 
Evaluation;
4.1. General 
Considerations; 
4.2. Inclusion Criteria; 
4.3. Exclusion Criteria; 
4.5. Repeat Testing and 
Subject Rescreening; 
5. Treatment Allocation; 
9.2.Reporting/Adjudication 
of Events in the Primary 
and Secondary Composite 
Endpoints and Other 
Events for Adjudication;
Sample size calculation was clarified to account for the effect of treatment 
discontinuation.
Added clarification regarding the frequency of the focused physical examination.
Added clarification regarding repeat laboratory measures.
Added clarification to definition of tubal occlusion to Inclusion Criterion# 6.
Added clarification regarding reassessment of blood pressure in Exclusion 
Criterion#5. Removed previous history of hyperkalemia from Exclusion Criterion#6.  
Clarified instructions for repeating blood pressure and laboratory result, as well as 
procedures for rescreening subjects.
Clarified that urine glucose results will not be reported by central laboratories and that 
investigators avoid performing local urinalysis with dipstick.
Clarified circumstance for recording local serum creatinine laboratory results.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
19
Status: Approved, Date: 06 September 2017
Applicable Section(s)
Description of Change(s)
10.1. Subject Completion; 
10.2.1. Study Drug 
Treatment Premature 
Discontinuation
Throughout the protocol
Clarified study completion date.
Clarified when study drug should be discontinued as result of endpoint being reached.
Added SI units for UACR. Minor grammatical, spelling or formatting changes were 
made.
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
20
Status: Approved, Date: 06 September 2017
SYNOPSIS
A Randomized, Double-blind, Event-driven, Placebo-controlled, Multicenter Study of the Effects of 
Canagliflozin on Renal and Cardiovascular Outcomes in Subjects With Type 2 Diabetes Mellitus 
and Diabetic Nephropathy
EUDRACT number: 2013-004494-28
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). Canagliflozin has been approved by several Health Authorities including the 
United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA) as an 
adjunct to diet and exercise to improve glycemic control in adults with T2DM. The goal of this study is to 
assess whether canagliflozin has a renal and vascular protective effect in reducing the progression of renal 
impairment relative to placebo in subjects with T2DM, Stage 2 or 3 chronic kidney disease (CKD) and 
macroalbuminuria, who are receiving standard of care including a maximum tolerated labeled daily dose 
of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). 
OBJECTIVES AND HYPOTHESES
Primary Objective
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of care, to
assess the efficacy of canagliflozin relative to placebo in reducing:

The composite endpoint of end-stage kidney disease (ESKD), doubling of serum creatinine, and 
renal or cardiovascular (CV) death
Secondary Objectives
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of care, to 
assess the efficacy of canagliflozin relative to placebo in reducing:

The composite endpoint of CV death and hospitalized congestive heart failure

The composite endpoint of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke 
(ie, 3-point major adverse cardiac event [MACE]) 

Hospitalized congestive heart failure

The renal composite endpoint of ESKD, doubling of serum creatinine, and renal death

CV death

All-cause death

The CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive 
heart failure, and hospitalized unstable angina
Exploratory Objectives
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of care, to 
assess the efficacy of canagliflozin relative to placebo in reducing:

The composite endpoint of ESKD and renal or CV death

Individual components of the renal and cardiovascular composite endpoints (ESKD, doubling of
serum creatinine, renal death, CV death, fatal or non-fatal MI, fatal or non-fatal stroke, hospitalized 
congestive heart failure, hospitalized unstable angina)
NCT02065791


JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
21
Status: Approved, Date: 06 September 2017
and to assess the impact of canagliflozin relative to placebo on:

Changes in estimated glomerular filtration rate (eGFR) over time (as calculated by the Chronic 
Kidney Disease-Epidemiology Collaboration [CKD-EPI] equation)

Changes in albuminuria over time
Safety Objectives
To assess the overall safety and tolerability of canagliflozin.
Hypotheses
Canagliflozin reduces the risk of the composite endpoint of ESKD, doubling of serum creatinine, and 
renal or CV death, relative to placebo, in subjects with T2DM, Stage 2 or 3 CKD, and macroalbuminuria 
who are receiving standard of care including a maximum tolerated labeled daily dose of an ACEi or ARB.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, parallel-group, 2-arm, multicenter study that will 
include a total of approximately 4,200 subjects. The study will have a pretreatment phase, consisting of a 
prescreening assessment and a screening period (up to 8 weeks), inclusive of a 2-week single-blind 
placebo run-in period. Subjects will be prescreened on the basis of eGFR, and urinary albumin-to-
creatinine ratio (UACR). Only subjects with an eGFR of 30 to <90 mL/min/1.73m2 and a UACR of 
level >300 mg/g (>33.9 mg/mmol), as confirmed by a local laboratory within 6 months prior to screening 
will be eligible for screening by the central laboratory. For the prescreening assessment where UACR is 
not routinely measured as per standard of care, it may be substituted by one of the following measures:
albumin excretion rate >300 mg/24 hours, urine protein-to-creatinine ratio (PCR) >500 mg/g 
(>56.5 mg/mmol), or protein excretion rate >500 mg/24 hours.
Subjects must be on a stable maximum tolerated labeled daily dose of an ACEi or ARB for a period of at 
least 4 weeks prior to randomization. To reach this requirement, the screening period may be extended up 
to a total of 8 weeks (inclusive of the 2-week single-blind placebo run-in period); however. An additional 
2 weeks of screening time may be allowed, if considered medically appropriate. Extension beyond this 
period of time would require concurrence of the sponsor’s medical monitor. Investigators are encouraged 
to keep other anti-hypertensive, lipid-lowering and antihyperglycemic therapies dose stable for 
approximately 4 weeks prior to randomization. In addition, investigators are encouraged to keep 
medications that are known to impact serum creatinine levels stable during the screening period and for 
approximately 2 weeks before any serum chemistry measurement during the course of the study.
Qualified subjects will enter the single-blind placebo run-in phase at Week -2. During this phase, subjects 
will be instructed to take one capsule daily in order to assess their compliance with study drug. Subjects 
who are compliant during the single-blind placebo run-in period will be randomly assigned in a 1:1 ratio 
to canagliflozin or matching placebo group and will enter the double-blind treatment phase at the 
randomization visit (Day 1). Subjects randomized to canagliflozin will receive 100 mg canagliflozin, to 
be taken once daily (QD). 
After randomization, subjects will return to the clinic at Week 3, Week 13, Week 26, and every 26 weeks 
thereafter for laboratory assessments, concomitant medication review, adverse event collection and 
determination of clinical endpoints. At Week 39 and at the midpoint between office visits after Week 52, 
telephone contact will be made to check the subject status, including discussing study diary entries, 
concomitant medication use, adverse events, and determining clinical endpoints. All subjects treated by 
the investigator will be managed to reach their glycemic, blood pressure and lipid goals according to 
established local and regional guidelines, with medical therapies used according to approved local labels. 
A post-treatment follow-up contact will take place following the treatment phase. Subjects who 
discontinue study medication prematurely should continue to attend all subsequent study visits and be 
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Status: Approved, Date: 06 September 2017
followed to the global trial end date (GTED). This event-driven study is estimated to have a total duration 
of approximately 5 to 5.5 years.
DOSAGE SELECTION RATIONALE
The 100 mg dose of canagliflozin was chosen for this study based on the clinical effect of canagliflozin 
100 mg in reducing macroalbuminuria and a favorable benefit to risk ratio for subjects who had a baseline 
eGFR of 30 to <90 mL/min/1.73m2 and macroalbuminuria in the Phase 3 development program. This 
included an examination of expected reductions in blood pressure and UACR as well as safety 
considerations (eg, volume depletion adverse events, adverse events leading to discontinuation, and lab 
findings suggestive of hyperkalemia) where the balance favored canagliflozin 100 mg over 300 mg in the 
population of subjects with renal impairment.
STUDY POPULATION
Subjects who are 30 years of age and diagnosed with T2DM with the following laboratory values (as 
determined by the central laboratory at the screening visit): an HbA1c level 6.5% to 12.0%, an eGFR of 
30 to <90 mL/min/1.73m2, and a UACR of >300 mg/g to 5000 mg/g (>33.9 mg/mmol to 
565.6 mg/mmol), who are receiving standard of care including a stable maximum tolerated labeled daily 
dose of an ACEi or ARB for at least 4 weeks and who meet all other enrollment criteria will be eligible 
for randomization. 
An overall global target ratio for randomized cohort of approximately 60%:40% for CKD Stage 3 
(eGFR 30 to <60 mL/min/1.73m2; first category):CKD Stage 2 (eGFR 60 to <90 mL/min/1.73m2; 
second category) will be monitored centrally. In an effort to limit exposure to investigational product and 
to ensure sufficient experiences in subjects with Stage 3 CKD, the entry of subjects with Stage 2 CKD 
(ie, eGFR 60 to <90 mL/min/1.73m2) may be restricted on a regional and/or site basis should the  ratio 
drift substantially off target over the course of the recruitment period. 
STRATIFICATION
Eligible subjects will be stratified according to their pretreatment eGFR value most proximate to the 
baseline visit (eg, screening, unscheduled, or Week -2) and will be randomized within the following 
3 strata: 1) 30 to <45 mL/min/1.73m2, 2) 45 to <60 mL/min/1.73m2, 3) 60 to <90 mL/min/1.73m2.
DOSAGE AND ADMINISTRATION 
Study Drugs
Upon successful completion of screening, eligible subjects will enter a 2-week run-in period, during 
which they will receive single-blind placebo capsules (one capsule to be taken once daily before the first 
meal of the day) to assess compliance with study drug.
Subjects who are compliant during the single-blind placebo run-in period will be randomly assigned in a 
1:1 ratio to canagliflozin 100 mg or matching placebo to be taken once daily, before the first meal of the 
day. All study drug after randomization will be provided in a double-blind manner.
EFFICACY OUTCOME/DEFINITIONS/EVALUATION
Primary Efficacy Outcomes
The primary efficacy outcome is reduction in a composite endpoint of the first occurrence of ESKD, 
doubling of serum creatinine, and renal or CV death.
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Status: Approved, Date: 06 September 2017
Definitions for each component of the primary composite endpoint are:

ESKD: Initiation of maintenance dialysis for at least 1 month, or renal transplantation, or a sustained 
eGFR of <15 mL/min/1.73m2 (by CKD-EPI formula and confirmed by repeat central laboratory
measure 30 days and preferably within 60 days)

Doubling of serum creatinine: from the baseline average determination (sustained and confirmed by 
repeat central laboratory measure 30 days and preferably within 60 days)

Renal death: death in subjects who have reached ESKD, die without initiating renal replacement 
therapy, and no other cause of death is determined via adjudication

CV death: death due to MI, stroke, heart failure, sudden death, death during a CV procedure or as a 
result of procedure-related complications, presumed sudden CV death, death of unknown cause, or 
death resulting from a documented CV cause other than those listed above (eg, aneurysm, peripheral 
vascular disease [PVD]) 
Confirmatory data for all potential study endpoints will be collected from study investigators and will be
adjudicated by a blinded Independent Endpoint Adjudication Committee.
Secondary Efficacy Outcomes
The secondary efficacy outcomes are reduction in the composite endpoint of CV death and 
hospitalized congestive heart failure; the composite endpoint of CV death, non-fatal MI, and non-
fatal stroke (ie, 3-point MACE); hospitalized congestive heart failure; the renal composite endpoint 
of ESKD, doubling of serum creatinine and renal death; CV death; all-cause death; and the CV 
composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive heart 
failure, and hospitalized unstable angina.
The definitions for each component of the CV composite endpoint are defined in the endpoint 
adjudication charter.
Confirmatory data for the CV composite endpoint will be collected from study investigators and will be 
adjudicated by a blinded Independent Endpoint Adjudication Committee.
Exploratory Efficacy Outcomes
The exploratory efficacy outcomes are reduction in the composite endpoint of ESKD and renal or CV 
death, reductions in the individual components of the renal and CV composite endpoints (ESKD, 
doubling of serum creatinine, renal death, CV death, fatal or non-fatal MI, fatal or non-fatal stroke, 
hospitalized congestive heart failure, hospitalized unstable angina), as well as changes in eGFR and 
albuminuria over time.
SAFETY OUTCOMES/EVALUATION
The safety outcomes include the overall safety and tolerability of canagliflozin. The safety evaluations 
include the collection of adverse events, laboratory tests, vital signs (pulse, blood pressure), physical 
examination, and body weight.
PHARMACOGENOMIC AND BIOMARKER EVALUATIONS
A pharmacogenomic blood sample and plasma, serum, and urine archive samples will be collected (where 
local regulations permit) to allow for pharmacogenomic and biomarker analyses that could help to further 
explain and examine the efficacy and safety findings in this study.
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Status: Approved, Date: 06 September 2017
STATISTICAL METHODS
Analysis Sets
The intent-to-treat (ITT) analysis set includes all randomized subjects. The assessment of the primary and 
secondary endpoints will be based upon this analysis set. 
Sample Size Determination
This is an event driven study. A total of approximately 4,200 subjects will be randomized to either 
canagliflozin 100 mg or matching placebo in a 1:1 ratio. The study aims to observe the occurrence of the 
primary efficacy events in 844 unique randomized subjects, on or before the GTED, to have 90% power 
to detect a 20% relative risk reduction (RRR, defined as one minus hazard ratio) accounting for the effect 
of treatment discontinuation on the primary endpoint at a 5%, 2-sided significance level. 
The above sample size is estimated based on the following additional assumptions:

Event rate for the composite endpoint in the placebo arm: 6.5% per year

Premature treatment discontinuation rate: 6% per year

Overall lost-to-follow-up: 1% 

Duration of enrollment period: 27 months  

Duration of study (from first subject randomized to last end of study visit): estimated to be 
60 months.
Primary Efficacy Analysis
The primary efficacy measure will be the time from randomization to the first occurrence of ESKD, 
doubling of serum creatinine, and renal or CV death. The comparison of the treatment groups will be 
assessed by means of a stratified Cox proportional hazard model with terms of treatment and strata 
defined by pretreatment eGFR (30 to <45, 45 to <60, 60 to <90 mL/min/1.73m2). The primary 
analysis will be based on the ITT analysis set up to GTED. Subjects will be analyzed according to the 
treatment group that they are randomized, regardless of actual treatment received.
Estimates of RRR, hazard ratio and the corresponding 95% CI will be derived from the model. 
Kaplan-Meier estimates for the event curve will be provided for the 2 treatment groups. 
In addition, ratios of cause-specific hazards between the treatment groups will be obtained for each 
component of the primary efficacy composite endpoint (ESKD, doubling of serum creatinine, renal death, 
or CV death), with stratification of the baseline hazard by pretreatment eGFR group as in the analysis of 
the primary efficacy composite endpoint. Sensitivity analysis using a stratified log-rank test will be 
conducted to assess the robustness of the primary efficacy analysis. 
Secondary Efficacy Analyses
The time from randomization to the first occurrence of the secondary endpoint events will be analyzed 
separately in a similar fashion as the primary analysis. If superiority of canagliflozin 100 mg over placebo 
in reducing the risk of the primary efficacy endpoint is established, the treatment effects in secondary 
endpoints will be tested subsequently in the following hierarchical order:

The composite endpoint of CV death and hospitalized congestive heart failure

The composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE) 

Hospitalized congestive heart failure

Renal composite endpoint of ESKD, doubling of serum creatinine, and renal death
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Status: Approved, Date: 06 September 2017

CV death

All-cause death

CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive heart 
failure, and hospitalized unstable angina
Statistical significance is required before testing the next hypothesis in the hierarchical test procedure.
Exploratory Efficacy Analyses
The time from randomization to the first occurrence of composite endpoint events of ESKD and CV death 
or renal death will be analyzed similar to the primary efficacy analysis. 
For on-treatment eGFR measurements, a linear mixed effects model will be fitted to eGFR as a dependent 
variable, including treatment, stratification factor, 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.
Similar modeling analysis will be performed for UACR. Since the distribution of UACR value is highly 
skewed, log transformation of UACR values will be made prior to the modeling.
When the trial is fully recruited, the baseline characteristics of the subjects (including those which may be 
imbalanced) will be examined and can be considered in exploratory analyses. A more detailed description 
of the analyses for all outcomes will be pre-specified in the Statistical Analysis Plan (SAP) for this study.
Safety Analyses
Subjects in the safety analysis set will be included in the denominators for the summaries of adverse 
event, exposure, and concomitant medication data. 
Multiplicity Adjustment
A closed testing procedure will be implemented to control the overall type I error rate at 5% for primary 
and secondary endpoints. 
Interim Analysis
An interim analysis will be conducted when the primary efficacy events have been observed in 
approximately 405 subjects. The analysis method for primary efficacy endpoint will be used for the 
interim analysis. The assumptions behind the sample size calculation of the study will be examined and 
the study duration may be prolonged in order to attain the target number of events. In addition, if the 
conditional power (based on the assumption that the hazard ratio in the remaining study is 0.80) is 10% or 
lower, the study may be stopped for futility. The alpha spending function will be used and the alpha spent 
in the interim analysis is 0.01. Detailed stopping guidelines will be specified in the charter of Independent 
Data Monitoring Committee (IDMC). 
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JNJ-28431754 (canagliflozin)
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Status: Approved, Date: 06 September 2017
TIME AND EVENTS SCHEDULE
Protocol Activitya
Pretreatmenta
Double-Blind Treatmenta
Posttreatmenta
Pre-
Screening Screening
Run-Inb
Baseline
Treatment
End of 
Treatment
Pre-
Screening
Week -10
to -3
Week -2
Day 1
Week 3
Week 13
Week 26
Week 39 
(TC) c
Week 52 
and at 52-
week 
intervals 
thereafterd
Week 65 
and at 26-
week 
intervals 
thereafter 
(TC)e c
Week 78 
and at 52-
week 
intervals 
thereafterf
EOT, EOS 
or EWg
Follow-Up 
Contacth
Screening/Administrative
Informed Consenti
X
X
Informed Consent 
for optional 
samplesj i
X
Inclusion/Exclusion 
Criteria
X
X
X
Medical history and 
demographics
X
Assess compliance 
with single-blind 
placebo run-in
X
Record pre-study 
serum creatinine
Xk
Randomization
X
Pretreatment Procedures
Study Drug
Dispense single-
blind placebo
X
Administer/dispense 
double-blind study 
drugl
X
X
X
Xl
Xl
Procedures
Initial physical 
examination/Vitals
and weight, foot 
examination
Xm
Follow-Up /Vitals, 
foot examinationn
X
X
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JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
Protocol Activitya
Pretreatmenta
Double-Blind Treatmenta
Posttreatmenta
Pre-
Screening Screening
Run-Inb
Baseline
Treatment
End of 
Treatment
Pre-
Screening
Week -10
to -3
Week -2
Day 1
Week 3
Week 13
Week 26
Week 39 
(TC) c
Week 52 
and at 52-
week 
intervals 
thereafterd
Week 65 
and at 26-
week 
intervals 
thereafter 
(TC)e c
Week 78 
and at 52-
week 
intervals 
thereafterf
EOT, EOS 
or EWg
Follow-Up 
Contacth
Brief Visit w/vitals, 
weight, foot 
examinationo
Xp
X
X
X
X
X
Height
X
12-lead 
electrocardiogramq
X
Clinical Laboratory Assessments
Follicle stimulating 
hormone, if 
necessary per 
inclusion criteria)
X
Hemogram (CBC) 
w/ Plate & Auto 
Diffr
X
X
X
X
Urinalysisr
X
X
X
X
Serum chemistrys t r
Xu
X
Xv
X
X
X
X
Xs
Xs
X
Fasting plasma 
glucoser
X
X
X
X
Xii
X
X
Glycated Hemoglobin 
(HbA1c)s
X
X
X
X
Xs
Xs
X
Fasting lipid 
profilew r
X
X
X
X
First morning void for 
albumin/creatinine 
ratios x r
Xu
X
X
X
Xs
Xs
X
Archived samples 
(plasma, serum, and 
urine samples) for 
exploratory 
analysisr
X
X
X
Pharmacogenomic 
specimeny
X
Urine Pregnancy 
Test, Qualitativez
X
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JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DNE3001 - Amendment INT-6
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Status: Approved, Date: 06 September 2017
Protocol Activitya
Pretreatmenta
Double-Blind Treatmenta
Posttreatmenta
Pre-
Screening Screening
Run-Inb
Baseline
Treatment
End of 
Treatment
Pre-
Screening
Week -10
to -3
Week -2
Day 1
Week 3
Week 13
Week 26
Week 39 
(TC) c
Week 52 
and at 52-
week 
intervals 
thereafterd
Week 65 
and at 26-
week 
intervals 
thereafter 
(TC)e c
Week 78 
and at 52-
week 
intervals 
thereafterf
EOT, EOS 
or EWg
Follow-Up 
Contacth
Subject Counseling and Assessments
Diet and exercise 
counselingaa
X
Dispense glucose 
testing supplies and 
first study diarybb cc
X
Xbb
Xbb
Xbb
Review/discuss 
subject diary and 
SMBG resultsdd
X
X
X
X
X
X
X
X
X
X
Review 
Concomitant 
Medications ee
Xff
Xff
X
X
X
X
X
X
X
X
X
X
Endpoints and 
Adverse Events 
Assessmentgg
X
X
X
X
X
X
X
X
X
X
X
Xhh
a
EOS = end-of-study; EOT = end-of-treatment; EW=early withdrawal; HbA1c =hemoglobin A1c; CBC = complete blood count; SMBG = self-monitored blood glucose; 
TC = telephone contact.
b
Subjects who fail protocol-specified screening criteria for study entry may be rescreened at the discretion of the investigator as described in Section 4.5, Repeat Testing and Subject 
Rescreening.
c
At Week 39 and at the midpoint between office visits after Week 52, telephone contact will be made to check the subject’s status, including discussing the subject’s diary entries, 
concomitant medications, and adverse events, including those events in the primary composite endpoint and those included in the secondary endpoints. In addition, investigators
should ask subjects about any foot problems and remind all subjects about routine preventative foot care and early intervention for foot problems (see Section 12.3.1 All Adverse 
Events for further detail).
d
This visit will occur at Week 52, 104, 156, 208, and 260.
e
This telephone contact will occur at Week 39, 65, 91, 117, 143, 169, 195, 221, 247, and 273.
f
This visit will occur at Week 26, 78, 130, 182, 234 and 286.
g
End-of-treatment/end-of-study/early withdrawal evaluations will be performed when the double-blind treatment phase of the study is ended or at the time the subject discontinues the 
double-blind study drug or is withdrawn from the study. Evaluations will be performed as soon as possible after stopping the study drug. Subjects who discontinue double-blind 
treatment for any reason should attend all subsequent visits and will be continually monitored according to the Time and Events Schedule for the duration of the study, until 
completion of the study (ie, the global trial end date [GTED]).
h
A telephone follow-up contact (or optional study visit, at the discretion of the investigator) will be conducted for all subjects approximately 30 days (+/- 12 days) after the last dose of 
study drug. If a telephone contact or study visit is not possible, follow-up information may be collected via email or other electronic means. At this telephone contact, investigators 
should ask subjects about any foot problems and remind them about routine preventative foot care and early intervention for foot problems.
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Status: Approved, Date: 06 September 2017
i
For subjects who require additional local laboratory assessment solely for the purpose of prescreening, either the optional prescreening-specific or full informed consent must be 
obtained before collecting UACR and eGFR values. If an optional prescreening-specific informed consent is obtained, and the subject is eligible to enter the screening period, the 
full informed consent must be obtained before screening is initiated. See Section 16.2.3, Informed Consent, for details.
j
Subject participation in the pharmacogenomics and exploratory biomarker research is optional. The Optional Exploratory Research Consent may be obtained after signing the full 
consent and at any point prior to collecting the sample, including after randomization.
k
The latest 3 pre-study serum creatinine values, when available, collected within a year prior to screening in an outpatient setting, and at least 30 days apart, will be recorded in the 
eCRF.
l
Study drug is dispensed every 26 weeks after the first year.
m
Full physical examination will include a full review of body systems (vital signs, as below, head and neck, eyes, chest and lungs, breast, CV, extremities and back, abdomen, and 
neurological examination). A pelvic/genitourinary system examination (ie, prostate, rectal, and gynecologic examinations) should be performed if considered clinically appropriate by 
the investigator. 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 12.3.1 All Adverse Events for further detail).
n
Focused physical examination will be performed at the follow-up visits occurring at Week 52, and every 52 weeks thereafter, and will include targeted examinations based on the 
subject’s specific complaints, signs or symptoms of a disease. 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 12.3.1 All Adverse Events for further detail).
o
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 eCRF. 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 12.3.1 All Adverse 
Events for further detail).
p
Please refer to Section 9.5.1. Safety Evaluation.
q
Electrocardiograms will be conducted at the local investigator site or affiliated facility.
r
Specific details about specimen collection, storage, packaging, and shipping will be provided in Attachment 4. For fasting plasma glucose and lipids, subjects must be fasting for at 
least 8 hours before blood sample collection, except for the screening visit when nonfasting blood samples may be collected. The first morning void specimens will be used to 
measure albumin and creatinine. A set of plasma, serum, and urine samples for subjects who consent to the optional exploratory analysis will be collected at each specified time
point. The urine collections for routine urinalyses and exploratory specimens should be obtained from a spot urine specimen in the clinic.
s
The test is performed every 26 weeks after the first year.
t
For serum creatinine and eGFR values to be considered as a component of composite endpoint, the results need to be confirmed by central laboratory repeat test 30 days and 
preferably within 60 days.
u
Prescreening local laboratory test will be performed and does not require a first morning void sample. These tests include eGFR and UACR, or other acceptable 
albuminuria/proteinuria measures if UACR values unavailable. For details of these additional measures refer to Section 9.1.2. Pretreatment Phase. 
v
A serum chemistry determination should be made at the Week -2 visit ONLY for subjects who have an extended screening period (ie, >2 weeks between the screening visit and the 
run-in visit) or who do not have a central serum chemistry value determined within the 2 weeks prior to the Week -2 visit. For subjects no longer meeting entry criteria for serum 
creatinine or eGFR based on this extra serum chemistry determination, an extension of the 2-week single-blind placebo run-in period may be required to accommodate a one-time 
repeat at the discretion of the investigator (see Section 4.5, Repeat Testing and Subject Rescreening).
w
If the subject is fasting at the screening visit, the lipid profile can be obtained at that time point; otherwise, fasting lipid profile should be obtained at the Week -2 visit.
x
The subject will provide a urine specimen from the first morning void on the morning of the clinic visit. If the subject does not provide the morning void collection on the day of the 
visit, the subject may bring a first morning void specimen to the investigational site during the subsequent week. For subjects working a night shift, or who otherwise have atypical 
sleep patterns, the collection should be made at the end of the subject’s usual sleep period.
y
A 10-mL blood sample will be collected only from subjects who give informed consent for the pharmacogenomics component of the study to allow for pharmacogenomic research, as 
necessary (where local regulations permit). A sample may be collected at any point after randomization if not obtained at baseline. Specific details about DNA samples collection, 
storage, packaging, and shipping will be provided in Attachment 5.
z
Urine pregnancy testing will be performed by local laboratories for all women unless they are surgically sterile or unless there is a documented history of their postmenopausal status. 
Additional serum or urine 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 or continue in the study.
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aa
Subjects should be counseled to maintain a diet and exercise regimen consistent with those outlined in treatment guidelines for T2DM (eg, the American Diabetes Association 
guideline).
bb
The supplies are dispensed every 26 weeks after randomization.
cc
Subjects will be provided with and instructed on the use of a home blood glucose monitoring system. In addition, a diary and glucose testing supplies will also be provided as 
necessary.
dd
See Section 9.1.1, Overview, for diary procedures.
ee
Concomitant therapy consists of all medications, including AHAs, taken after the initiation of double-blind study medication (Day 1).
ff
Record as prestudy therapy any medications taken from 30 days before screening.
gg
This review will also include subjects' blood glucose level, lipid profile and blood pressure as well as the use of blood pressure medications. Assessments on adverse events and study 
endpoints will also be performed.
hh
Serious adverse events and potential endpoint events will be assessed (refer to Section 9.1.4. Post-Treatment Follow-up).
ii
Only at Week 52.
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ABBREVIATIONS
ACEi
angiotensin-converting enzyme inhibitor
ADA
American Diabetes Association
ADR
adverse drug reaction
AE
adverse event
AHA
antihyperglycemic agent
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
ARO
Academic Research Organization
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BID
twice daily
BMD
bone mineral density
BMI
body mass index
BP
blood pressure
CI
confidence interval
CKD
chronic kidney disease
Cmax
maximum concentration (during a dosing interval)
CV
cardiovascular
DBP
diastolic blood pressure
DCCT
Diabetes Control and Complications Trial
DKA
diabetic ketoacidosis
DM
diabetes mellitus
DRI
direct renin inhibitor
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOT
end of treatment
ESKD
end-stage kidney disease
FDA
Food and Drug Administration
FPG
fasting plasma glucose
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GTED
global trial end date
HbA1c
hemoglobin A1c
HDL-C
high-density lipoprotein cholesterol
IB
Investigator Brochure
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
IDMC
Independent Data Monitoring Committee
IEAC
Independent Endpoint Adjudication Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web response system
LDL-C
low-density lipoprotein cholesterol
LS
least squares
MACE
major adverse cardiac event
MI
myocardial infarction
MRA
mineralocorticoid receptor antagonist
MSRC
Medical Safety Review Committee
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
PCR
protein-to-creatinine ratio
PDLC
predefined limit of change
Pgp
P glycoprotein
PG
plasma glucose
PK
pharmacokinetics
PPAR
peroxisome proliferator activated receptor
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PQC
Product Quality Complaint
RRR
relative risk reduction
QD
once daily
RTG
renal threshold for glucose
SAP
statistical analysis plan
SBP
systolic blood pressure
SGLT1/SGLT2
sodium-glucose co-transporter 1/sodium-glucose co-transporter 2
SMBG
self-monitored blood glucose
SNGFR
single nephron glomerular filtration rate
SU
sulphonylurea
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TGF
tubuloglomerular feedback
tmax
time to reach the maximum plasma concentration
UACR
urinary albumin/creatinine ratio
UGE
urinary glucose excretion
ULN
upper limit of normal
US
United States
UTI
urinary tract infection
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1.
INTRODUCTION 
The incidence of type 2 diabetes mellitus (T2DM) has been rapidly rising over the past decades 
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. Diabetic nephropathy is 
one of the microvascular complications of diabetes mellitus (DM) and is characterized by 
persistent albuminuria and a progressive decline in renal function. 
The prevalence of diabetic nephropathy (microalbuminuria or worse) in patients with T2DM was 
28% by 15 years after diagnosis, with a projected prevalence of 38% by 25 years after diagnosis 
(UKPDS 1998); for macroalbuminuria or worse, the prevalence was 7% after 15 years and 12% 
after 25 years (Adler 2003). Approximately 20% of subjects with T2DM and nephropathy will 
have progressed to end-stage kidney disease (ESKD) after 20 years (ADA 2004). Once ESKD
has developed in these patients, the 5-year survival rate for patients on dialysis is 36% 
(NKUDIC 2012). Long-term dialysis or kidney transplantation for ESKD is associated with a 
high cost of care, which was estimated to be about 17 billion dollars in the United States (US) or 
0.77 billion pounds in the United Kingdom (UK) for managing diabetic nephropathy in patients 
with DM in 2004 (Gordois 2004).
The clinical progression of diabetic nephropathy is well characterized (Mogensen 1998). 
Initially, hyperfiltration is accompanied by increases in glomerular filtration rate (GFR) and 
increased renal plasma flow. A meta-analysis found that the presence of hyperfiltration in 
patients with type 1 diabetes mellitus (T1DM) more than doubled the risk of developing micro-
or macroalbuminuria (Magee 2009). This phase is followed by reductions in GFR and the 
development of microalbuminuria (defined as urinary albumin excretion of 30 mg/day or 
20 g/min and 300 mg/24 h or 200 g/min), which may be accompanied by increases in blood 
pressure, later progresses to further GFR decline, overt proteinuria (ie, macroalbuminuria, 
defined as urinary albumin excretion of >300 mg/day or >200 g/min) and associated with 
worsening hypertension, continually leads to ESKD with a possible need for renal replacement 
therapy, and eventually to a renal death, or cardiovascular (CV) death. 
Hyperglycemia is an important contributor to the onset and progression of diabetic nephropathy. 
A significant relationship was seen between hemoglobin A1c (HbA1c) levels and risk of 
developing and progression of diabetic nephropathy in patients with T1DM (DCCT 1995; 
DCCT 2000; Lachin 2007). Similarly, intensive control of blood glucose reduced the risk of the 
development and progression of diabetic nephropathy in patients with T2DM (UKPDS 1998;
ADVANCE 2008; Perkovic 2013). The relationship between hyperglycemia and risk of diabetic 
nephropathy was also confirmed in a recent meta-analysis (Coca 2012).
In addition, inhibition of the renin-angiotensin pathway by angiotensin receptor blocker (ARB) 
or by angiotensin-converting enzyme inhibitor (ACEi) has been demonstrated to reduce the 
progression of diabetic nephropathy in subjects with T2DM (Parving 2001; Lewis 2001;
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HOPE 2000; Viberti 2002) and T1DM (Bjorck 1990; Lewis 1993). The renal-protective effects 
by ACEi or ARB appear to be beyond those that can be attributed to blood pressure lowering. 
Thus, agents acting by a unique hemodynamic mechanism in addition to the renin-angiotensin 
system may exert further renal protection and possibly reduce adverse CV outcomes in diabetic 
nephropathy.
Canagliflozin is an orally active inhibitor of sodium-glucose co-transporter 2 (SGLT2) that is 
being developed as an oral antihyperglycemic agent (AHA) for the treatment of patients with 
T2DM. 
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). In patients with T2DM, the 
RTG is elevated, leading to increased glucose reabsorption despite hyperglycemia, which likely 
contributes to sustained elevation in serum glucose concentrations (DeFronzo 2009). 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 
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.
In patients with T2DM, the clinical progression of diabetic nephropathy is variable, primarily 
due to the multiple renal insults, including not only hyperglycemia, but also hypertension and 
vascular pathology resulting in ischemic renal injury. However, hyperfiltration at the level of the 
single nephron, proximal tubular glycotoxicity and a stimulus for tubular cell growth as a result 
of enhanced sodium coupled glucose transport into tubular cells are common features in patients 
with T2DM.
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In streptozotocin-treated diabetic rats, single nephron GFR (SNGFR), glomerular plasma flow 
and mean glomerular transcapillary pressure were elevated and preceded the onset of diabetic 
nephropathy (Zatz 1985). The increase in glomerular capillary pressure is a consequence of 
decreased resistance of the afferent glomerular arteriole and increased resistance of the efferent 
glomerular arteriole (Hostetter 1995). Brenner and coworkers (1996) demonstrated in animal 
models that as nephrons are progressively destroyed, glomerular filtration and nephron size 
increases in a compensatory manner in the remaining nephrons (increase in SNGFR, however 
decrease in total GFR). The increases in glomerular filtration eventually result in glomerular 
damage and focal sclerosis (O’Bryan 1997).
Augmentation of proximal tubular sodium reabsorption stimulates increased filtration via 
systemic volume expansion, as well as decreased tubuloglomerular feedback (Bank 1990;
Ditzel 1983; Vallon 1999). Given the coupling between glucose and sodium transport by SGLT2 
in the proximal tubule, increases in glucose filtered at the glomerulus will increase sodium 
reabsorption in the proximal tubule causing salt and water retention, and volume expansion. The
increased proximal tubule reabsorption reduces the delivery of sodium to the distal tubule. The 
macula densa responds to reduced sodium in the distal tubule by decreasing afferent glomerular 
arteriole tone, which increases filtration until distal salt delivery is restored. Thus in 
hyperglycemic states, the increase in GFR may, in part, be a consequence of reduced 
tubuloglomerular feedback (TGF), a mechanism coupling tubular reabsorption of sodium and 
fluid with glomerular filtration (Thomson 2012; Gilbert 2013).
SGLT2 inhibitors, such as canagliflozin, increase the delivery of sodium to the distal tubule by 
blocking SGLT2-dependent glucose reabsorption thereby increasing tubuloglomerular feedback, 
which is associated with a decrease in hyperfiltration in preclinical models of diabetes and 
clinical studies (Cherney 2013; Thomson 2012). 
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 CV disease. The extensive Phase 3 clinical development program studied 
approximately 10,285 subjects with T2DM and including nearly 6,650 subjects treated with 
100 mg or 300 mg doses of canagliflozin. A 1,090 subject-year exposure through 
31 December 2012 was reported with median duration of follow-up experience (safety, efficacy 
and serial chemistry measurements) of 93 weeks. Across all of the studies, clinically meaningful 
reductions in 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 some 
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 
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and insulin secretory demand, were also seen with canagliflozin treatment. Canagliflozin has 
been approved by several Health Authorities including the US Food and Drug Administration 
(FDA) and European Medicines Agency (EMA) as an adjunct to diet and exercise to improve 
glycemic control in adults with T2DM. 
In the Phase 3 program, a pooled population of 1,085 subjects with a baseline eGFR 30 to 
<60 mL/min/1.73m2 was defined as moderate renal impairment and analyzed separately. This 
population also included all 272 subjects in a Phase 3 study (28431754DIA3004) that only 
enrolled subjects with T2DM and renal impairment with a baseline eGFR 30 to 
<50 mL/min/1.73m2. Among all 1,085 subjects with renal impairment, 703 subjects were treated 
with 100 mg or 300 mg doses of canagliflozin. Results of analyses showed that canagliflozin 
reduced HbA1c, body weight, and blood pressure relative to placebo in this pooled population. 
Furthermore, there were 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. In addition, the safety profile of 
canagliflozin appeared to be acceptable in this population. 
The goal of this study is to assess whether canagliflozin has a renal protective effect in reducing 
the progression of diabetic nephropathy relative to placebo in subjects with T2DM, Stage 2 or 3 
Chronic Kidney Disease (CKD) and macroalbuminuria, who are receiving standard of care, as 
defined in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
(KDOQI) consensus guidelines (NKF 2007; NKF 2012), including a maximum tolerated labeled 
daily dose of ACEi or ARB. 
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 
(IB) 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. Results of alterations in renal injury 
and function with SGLT2 inhibitors in preclinical models of diabetic nephropathy are described 
below. 
After 12 weeks, diabetic db/db mice treated with a selective SGLT2 inhibitor, JNJ-39933673, 
other than canagliflozin, improved glycemic control and reduced urinary ACR (2075 mg/g in 
treated group versus 74536 mg/g in control group, p<0.001). JNJ-39933673 treatment also 
reduced histologic changes characteristic of diabetic nephropathy such as mesangial expansion, 
accumulation of fibronectin and type IV collagen, podocyte loss as well as prevented renal 
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accumulation of macrophages and renal neutral lipid accumulation (Qiu 2013). Similar 
reductions in blood glucose levels and urinary albumin excretion were seen with another 
selective SGLT2 inhibitor (T-1095) in another rodent model of diabetes (streptozotocin treated 
rats) (Adachi 2000). It should be noted that improved glycemic control in these rodent models 
will also reduce the decline in renal function. Thus, in these studies it was not possible to dissect
the impact of improved glycemic control from that of a hemodynamic effect on renal outcomes.
Several publications have reported results of nonclinical renal studies with SGLT2 inhibitors. 
The effects of luseogliflozin, a novel SGLT2 inhibitor, lisinopril (an ACEi) and the combination 
of lisinopril and luseogliflozin, or vehicle were examined in diabetic rat model of diabetic 
nephropathy. Rats treated with vehicle exhibited progressive proteinuria, a decline in GFR, focal 
glomerulosclerosis, renal fibrosis, and tubular necrosis. Lisinopril, as well as luseogliflozin when 
administered alone, prevented the fall in GFR and reduced the degree of glomerular injury, renal 
fibrosis, and tubular necrosis. In contrast, treatment with insulin had no effect on the progression 
of renal disease in T2DM rats. Combination therapy reduced the degree of glomerular injury, 
renal fibrosis, and tubular necrosis to a greater extent than administration of either drug alone. 
These results suggest that SGLT2 inhibition slows the progression of diabetic nephropathy more 
than that seen with insulin, and combination therapy with an SGLT2 inhibitor and an ACEi is 
more renoprotective than administration of either compound alone (Kojima 2013).
A renal micropuncture study in diabetic Wistar rats was conducted to assess the hemodynamic 
effects of dapagliflozin, a selective SGLT2 inhibitor, on early diabetic nephropathy. 
Dapagliflozin treatment increased the delivery of sodium to the distal tubule and reduced the 
diabetes-related increases in SNGFR (eg, reduced hyperfiltration) (Thomson 2012).
Although the mechanisms have yet to be elucidated, results from these rodent studies suggest 
that SGLT2 inhibition may reduce glomerular hyperfiltration and delay the onset and reduce the 
progression of diabetic nephropathy.
1.1.2.
Clinical Studies
1.1.2.1.
Overview
As of 01 May 2013, approximately 1,840 subjects (including healthy subjects, non-diabetic 
subjects with specific diseases [eg, renal or hepatic disease], and subjects with T2DM) have 
completed studies in the Phase 1 program conducted by the sponsor. In addition, 1,106 subjects 
in 3 Phase 2 studies and 10,961 subjects in 10 Phase 3 studies have completed or are 
participating in clinical studies conducted by the sponsor.
This included a total of 1,085 subjects with T2DM and moderate renal impairment in the Phase 3 
program. Two-hundred seventy-two (272) of these subjects were from a Phase 3 study 
(28431754DIA3004) that only enrolled subjects with T2DM and renal impairment (ie, baseline 
eGFR of 30 to <50 mL/min/1.73m2). The total exposure through 31 December 2012 for 
subjects with moderate renal impairment was 1090 subject-years with a median duration of 
follow-up experience (safety, efficacy and serial chemistry measurements) of 93 weeks. 
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1.1.2.2.
Pharmacokinetics
Canagliflozin exhibits similar PK in healthy subjects and subjects with T2DM. The mean 
absolute oral bioavailability of canagliflozin was 65% following single-dose administration of 
the canagliflozin 300 mg tablet in healthy subjects. In healthy subjects (25 to 1,600 mg once 
daily [QD]) and subjects with T2DM (50 mg to 300 mg QD and 300 mg twice-daily [BID]), after 
oral administration of single and multiple doses, mean canagliflozin AUC0-increased in an 
approximately dose-proportional manner whereas mean maximum plasma concentration (Cmax) 
increased in an approximately dose-proportional manner up to 1,200 mg. Following oral 
administration of canagliflozin, the median time to reach maximum plasma concentration (tmax) 
was approximately 1 to 2 hours. The mean terminal plasma elimination half-life (t1/2) of 
canagliflozin was 10 and 13 hours with canagliflozin doses of 100 and 300 mg, respectively. The 
tmax was independent of dose. After repeated dosing with 50 to 300 mg canagliflozin, steady state 
was reached by 4 to 5 days. Minimal accumulation of canagliflozin was observed at steady-state 
across 50, 100, and 300 mg doses with mean accumulation ratios ranging from 1.3 to 1.4 in 
subjects with T2DM. Bioavailability of canagliflozin was not affected after co-administration of 
canagliflozin 300 mg with food in healthy subjects indicating that the canagliflozin tablet 
formulation may be taken without regard to meals.
O-glucuronidation is the major metabolic elimination pathway for canagliflozin in humans. In 
human plasma, 2 non-pharmacologically active O-glucuronide conjugates of unchanged drug, 
M5 (formed by UGT2B4) and M7 (formed by UGT1A9), were present. Enzyme inducers (such 
as St. John’s wort [Hypericum perforatum], rifampicin, barbiturates, phenytoin, carbamazepine, 
ritonavir, efavirenz) may give rise to decreased exposure of canagliflozin. Following co 
administration of canagliflozin with rifampicin (an inducer of various active transporters and 
drug metabolizing enzymes), 51% and 28% decreases in canagliflozin systemic exposure (AUC) 
and peak concentration (Cmax) were observed. These decreases in exposure to canagliflozin may 
decrease efficacy. For patients who are tolerating 100 mg canagliflozin the dose should be 
increased to 300 mg canagliflozin if therapy with a UGT enzyme inducer is initiated.
Canagliflozin is transported by P glycoprotein (Pgp) and Breast cancer Resistance Protein. 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 effect of 
concomitant administration of canagliflozin (a weak Pgp inhibitor) on dabigatran etexilate (a Pgp 
substrate) has not been studied. As dabigatran concentrations may be increased in the presence of 
canagliflozin, monitoring (looking for signs of bleeding or anemia) should be exercised when 
dabigatran is combined with canagliflozin. Cholestyramine may potentially reduce canagliflozin 
exposure. Dosing of canagliflozin should occur at least 1 hour before or 4 to 6 hours after 
administration of a bile acid sequestrant to minimize possible interference with their absorption.
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. 
A single-dose Phase 1 study (28431754DIA1003) with canagliflozin in non-diabetic subjects 
with various degrees of renal function (including ESKD on hemodialysis) was performed. 
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Median tmax values for canagliflozin were similar across all renal function groups. Exposure 
(AUCand Cmax) of canagliflozin was higher in subject groups with impaired renal function 
ranging from mild to severe impairment. In subjects with mild, moderate, and severe renal 
impairment, Cmax values were approximately 13%, 29%, and 29% higher while AUCvalues 
were approximately 17%, 63%, and 50% higher, respectively, compared with subjects with 
normal renal function. Mean renal clearance for canagliflozin was lower in subjects with reduced 
renal function, while mean half-life was slightly prolonged for the renally impaired groups 
compared with subjects with normal renal function. Increases in canagliflozin AUC of the 
magnitude seen with renal impairment are not deemed to be clinically relevant.
In subjects with ESKD (pre-dialysis and after a 4-hour hemodialysis session [post-dialysis]), the 
systemic exposure of canagliflozin was similar to that in subjects with normal renal function. 
Similar systemic exposure in subjects with ESKD compared with subjects with normal renal 
function has previously been reported for other drugs for which the PK was altered in proportion 
to the degree of renal impairment (De Martin 2006; Shi 2004). It was speculated that this may be 
due to the removal of uremic substances by dialysis that might decrease the drug’s intrinsic 
clearance by inhibiting metabolic enzymes and transporters (Nolin 2008; Zhang 2009). Mean 
arterial canagliflozin concentrations were similar to venous concentrations at each time point 
during hemodialysis. Only a small fraction of administered dose (<1% of canagliflozin and 
<1.2% of metabolites [M5 and M7]) was removed in the dialysate fluid following a 4-hour 
hemodialysis session. These results indicate that hemodialysis has a minimal effect on plasma 
concentrations and the PK of canagliflozin, and that the metabolites were negligibly dialyzable.
1.1.2.3.
Pharmacodynamics
In subjects with T2DM following single and multiple oral doses (30 to 600 mg QD and 300 mg 
BID), canagliflozin treatment dose dependently increased UGE0-24h, with mean UGE0-24h of 
approximately 100 g/day typically observed with doses of 100 mg/day or higher. 
In subjects with T2DM, canagliflozin treatment with 100 mg and 300 mg once daily lowered 
RTG to approximately 70 to 90 mg/dL (3.9 to 5.0 mmol/L), respectively. Because RTG remains 
above plasma glucose (PG) levels associated with hypoglycemia and because very little UGE 
occurs whenever PG is below the RTG, canagliflozin, itself, is not expected to pose a risk for 
hypoglycemia.
1.1.2.4.
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 (PPAR) 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: ie, subjects with renal impairment (eGFR of 30 to 
<50 mL/min/1.73m2); subjects with or at high risk for CV complications; and older subjects. 
The dose of canagliflozin in the Phase 3 program is 100 mg and 300 mg. The 100 mg dose of 
canagliflozin was chosen for this study based on the clinical efficacy and safety information 
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available in the moderate renal impairment group of subjects who participated in the Phase 3 
development program (see Section 3.2, Study Design Rationale). The efficacy section below will 
be focused on the results of 100 mg canagliflozin in 3 sets of subjects with T2DM: those
involved in 9 completed Phase 3 studies, those included in a pooled population with moderate 
renal impairment, and those who participated in a 52-week Phase 3 study (28431754DIA3004) 
with moderate renal impairment (eGFR of 30 to <50 mL/min/1.73m2). 
1.1.2.4.1.
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 in combination therapy. In 
the monotherapy study, an HbA1c reduction of -0.91% was observed for canagliflozin 100 mg 
relative to placebo. 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 canagliflozin 100 mg (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 
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% on canagliflozin 100 mg. A total of 24% of subjects achieved a target 
HbA1c <7% at the end of treatment on canagliflozin 100 mg relative to 17% of subjects on 
placebo.
In a 52-week Phase 3 study in 272 adult subjects with T2DM who were inadequately controlled 
on their current diabetes treatment regimen (ie, HbA1c of 7.0% and 10.5%) and had renal 
impairment (eGFR 30 and <50 mL/min/1.73m2), the mean, placebo-subtracted reduction in 
HbA1c was -0.27% on canagliflozin 100 mg (with the 95% CI for the between-group difference 
for the canagliflozin 100 mg and placebo including “0”). Results at Week 26 were similar to 
those observed at Week 52 (28431754DIA3004).
1.1.2.4.2.
Weight Effects 
In addition to the observed glycemic improvements, treatment with canagliflozin resulted in 
consistent, statistically significant reductions in total body weight relative to placebo, with -1.4% 
to -2.7% reductions observed with canagliflozin 100 mg relative to placebo. 
In the pooled moderate renal impairment population, as observed for HbA1c-lowering response, 
and anticipated based upon canagliflozin mechanism of action, the placebo-subtracted least 
squares (LS) mean percent change from baseline to the primary assessment timepoint in body 
weight was somewhat attenuated for the canagliflozin 100 mg dose (-1.6%) relative to subjects 
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with higher baseline eGFRs, but the same (-1.6%) to those seen in the study of subjects with 
renal impairment (ie, baseline eGFR of 30 to <50 mL/min/1.73m2).
In the Phase 3 study in subjects with T2DM and moderate renal impairment 
(28431754DIA3004), body weight was meaningfully reduced over the 52-week study with 
canagliflozin (placebo-subtracted change from baseline difference of -1.5% for the canagliflozin 
100 mg dose)
1.1.2.4.3.
Blood Pressure Effects
Reductions in SBP were observed with canagliflozin in Phase 3 studies (ranging from -2.2 
to -5.7 mm Hg of SBP with the canagliflozin 100 mg dose relative to placebo, in placebo-
controlled 26-week studies), and were generally statistically significantly greater relative to 
placebo, and also greater relative to comparator agents (glimepiride and sitagliptin).
In a pooled analysis of subjects with moderate renal impairment in the Phase 3 program, the LS 
mean reduction from baseline in SBP with canagliflozin 100 mg was -4.4 mmHg and a slightly 
lesser reduction from baseline in DBP (-1.8 mmHg) was observed at Week 26. In the placebo 
group, smaller decreases from baseline SBP and DBP were observed at Week 26 (-1.6 mmHg 
and -1.1 mmHg, respectively). Results were generally similar regardless of concomitant use of 
ACEi/ARB or diuretics
In the Phase 3 study in subjects with T2DM and moderate renal impairment 
(28431754DIA3004), SBP was reduced over the 52-week study with canagliflozin 100 mg, with 
a placebo-subtracted change from baseline difference of -5.49 mmHg observed.
1.1.2.5.
Safety 
1.1.2.5.1.
Overall Safety
Based on PK data showing higher exposure of canagliflozin in subject groups with mild to 
severe renal impairment, a robust summary of safety data, including data from both the 100 mg 
and 300 mg dose of canagliflozin studied in the Phase 3 program is provided below. 
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 well tolerated overall. 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. 
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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. 
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 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. 
In preclinical studies in rats, hyperostosis (increased trabecular bone) was observed; mechanistic 
toxicology studies demonstrated that hyperostosis, like the tumors discussed above, related to 
carbohydrate malabsorption in rats treated with canagliflozin, with consequent marked 
hypercalciuria (which is not seen in human). A detailed analysis of bone safety was conducted in 
the Phase 3 program, including an assessment using DXA in a dedicated Phase 3 study (a study 
conducted in older subjects [ages 55 and 80 years] with T2DM) and a cross-program 
assessment of fracture incidence. Bone mineral density (BMD) was examined at 4 sites: at the 
lumbar spine, total hip, distal radius, and femoral neck.  Minimal changes in BMD from baseline 
to Week 104 were seen in the lumbar spine (a cancellous bone region), femoral neck (a mixed 
cancellous and cortical bone region), and distal forearm. A decrease in BMD from baseline to 
Week 104 in the total hip, a site comprised of mixed cortical and cancellous bone (like the 
femoral neck), was observed for both canagliflozin treatment groups (-0.9% and -1.2% in the 
canagliflozin 100 mg and 300 mg groups, respectively, placebo adjusted). In a cardiovascular 
study of 4,327 subjects with known or at high risk for cardiovascular disease (Study DIA3008), 
the incidence rates of bone fracture were 1.6, 1.6, and 1.1 per 100 subject years of exposure to 
canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, with the fracture 
imbalance initially occurring within the first 26 weeks of therapy. In other T2DM studies with 
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canagliflozin, which enrolled a general diabetes population of approximately 5,800 subjects, no 
difference in fracture risk was observed relative to control.
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 apolipoprotein B, non-HDL-C, and LDL particle number were 
approximately half as large as the rise in LDL-C. In subjects with moderate renal impairment, 
the degree of increase in LDL-C was smaller than that seen in subjects with mildly impaired or 
normal renal function. 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 
triglycerides were also observed with canagliflozin.
As of 11 May 2015, in the T2DM clinical development program, incidence rates of unblinded 
serious adverse events of diabetic ketoacidosis (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 an ongoing Phase 3 study, the 
Independent Data Monitoring Committee observed a non-dose-dependent increase in the 
incidence of non-traumatic, lower-extremity amputations (mostly of the toes) in the canagliflozin 
100 mg and 300 mg groups  compared to placebo. With a mean duration of follow-up in 
CANVAS of approximately 4.5 years, the annualized incidence of lower-extremity amputation 
was 0.73, 0.54, and 0.30 events per 100 patient-years in the canagliflozin 100 mg, canagliflozin 
300 mg, and placebo groups, respectively. Overall, treatment with canagliflozin was associated 
with an approximately 2-fold increase in amputation event rates (relative risk [RR] 2.15; 95% 
CI: 1.3 - 3.5). The Phase 3 study Independent Data Monitoring Committee (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 
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associated with the greatest risk for amputation included prior amputation, peripheral vascular 
disease, and neuropathy.
1.1.2.5.2.
Safety Related to Renal Function
Canagliflozin safety information related to general renal function in the clinical program can be 
found in the IB (IB Section 4.6.2.5, Effect of Canagliflozin on Renal Function). Effects of 
canagliflozin on albuminuria and eGFR in the Phase 3 program are also summarized in this 
protocol Section 1.2, Overall Rationale and Goals for the Study.
In summary, treatment with canagliflozin leads to small reductions from baseline in eGFR that 
were generally stable or improved with continued treatment. Analyses of eGFR 
post-discontinuation showed reversibility of the initial reductions seen on canagliflozin. The 
biomarker of renal injury, the UACR, did not increase in subjects treated with canagliflozin who 
were normoalbuminuric at baseline, and decreased in subjects with baseline albuminuria (either 
micro- or macroalbuminuria). The incidence of renal-related serious adverse events was similar 
across treatment groups. Data from clinical studies with canagliflozin does not suggest an 
increased risk of renal injury.
1.1.2.5.3.
Safety in Renal Impairment Population
1.1.2.5.3.1.
Safety in Moderate Renal Impairment
A total of 1,085 subjects from the pooled analysis of subjects with moderate renal impairment 
(eGFR 30 to <60 mL/min/1.73m2) were included and analyzed in the Moderate Renal 
Impairment Dataset. Overall, the exposure for this dataset was 503 patient-years, and 16% of 
subjects discontinued before the primary study endpoint, with a numerically higher proportion in 
the placebo group (19%) compared with the combined canagliflozin group (15%).
Baseline demographic characteristics were generally similar across treatment groups. The 
median age of subjects was 67 years, with 38% of subjects between the ages of 35 to 64 years, 
45% between the ages of 65 and 74 years, and 17% older than 75 years. Men comprised 58% of 
the subjects. Consistent with the regions of the world in which subjects were recruited, 78% of 
the subjects were white, 13% of subjects were Asian, and 3% of subjects were black or 
African-American. The mean BMI was 32.5 kg/m2 and more than half of the subjects (64%) 
were obese (BMI 30 kg/m2).
Baseline diabetes characteristics were generally similar across treatment groups. The median 
eGFR was 50.0 mL/min/1.73m2, the mean was 48.2 mL/min/1.73m2, and the range was 30.0 to 
59.9 mL/min/1.73m2. Approximately one-third of subjects had an eGFR <45 mL/min/1.73m2. 
Most subjects had mild to moderate hyperglycemia at baseline (baseline mean HbA1c of 
8.0-8.1%), with 18% of total subjects poorly controlled (HbA1c 9%). The median duration of 
diabetes was 15.0 years in the combined canagliflozin group and 13.6 years in the placebo group. 
Overall, 59% of subjects had a history of 1 or more microvascular complications, a substantial 
proportion having 2 complications (21%). Microvascular complications included neuropathy 
(37%), nephropathy (35%), and retinopathy (25%).
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The incidence of subjects who experienced any adverse event, prior to use of rescue medication, 
was higher in the canagliflozin 100 mg and 300 mg groups (73.1% and 74.5%, respectively) 
compared with the placebo group (68.3%). The incidence of subjects who experienced adverse 
events leading to discontinuation was higher in the canagliflozin 300 mg group (7.4%) relative to
the canagliflozin 100 mg (4.7%) and placebo groups (5.0%). Overall, most adverse events were 
reported by the investigators as mild or moderate in intensity.
The incidence of serious adverse events, including results after initiation of glycemic rescue 
therapy, was 19.6%, 13.3% and 14.8% in placebo, canagliflozin 100 mg and canagliflozin 
300 mg groups, respectively. The incidence of subjects with serious adverse events that led to 
discontinuation was low, with similar incidences in the combined canagliflozin group and the 
placebo group (3.0% and 3.7%, respectively). The incidence of subjects with serious adverse 
events that were considered related to study drug was also low, with similar incidences in the 
combined canagliflozin and placebo groups (1.3% and 1.6%, respectively). The incidence of 
events occurring in any particular specific adverse event term was low, with no particular 
specific adverse event having an incidence of more than 1.1% (>4 subjects) in either 
canagliflozin group and most reported in only 1 subject (0.3%).
The incidence of adverse events that led to discontinuation of study drug, including results after 
initiation of glycemic rescue therapy, was slightly higher in the canagliflozin 300 mg group 
(7.7%) compared with the canagliflozin 100 mg group (5.6%) and the placebo group (5.8%). The 
majority of specific adverse events that led to discontinuation resulted in the discontinuation of 
only 1 subject. Adverse events of renal failure acute, renal impairment, and blood creatinine 
increased each resulted in discontinuation of 2 (0.3%), 4 (0.6%), and 3 (0.4%) subjects, 
respectively, in the combined canagliflozin group and 0, 3 (0.8%), and 2 (0.5%) subjects, 
respectively, in the placebo group.
Fourteen subjects died, with deaths occurring in 3 (0.9%) subjects and 5 (1.4%) subjects in the 
canagliflozin 100 mg and 300 mg groups, respectively, and 6 (1.6%) subjects in the placebo 
group. None of the deaths was considered related to study drug by the investigator. No deaths 
related to an adverse event in the Renal and urinary disorders SOC were reported.
Selected Adverse Events 
The incidence of volume depletion adverse events was higher in the combined canagliflozin 
group (6.8%) relative to the placebo group (2.6%). The incidence was higher in the canagliflozin 
300 mg group (8.5%) relative to the canagliflozin 100 mg group (5.0%). Volume 
depletion-related adverse events were serious in 4 (0.6%) subjects in the combined canagliflozin 
group and 5 (1.3%) subjects in the placebo group, and led to discontinuation in 3 (0.4%) subjects 
in the canagliflozin groups and no subjects in the placebo group. Relative to the placebo and 
canagliflozin 100 mg groups, volume depletion adverse events in the canagliflozin 300 mg group 
tended to occur earlier in the studies, as indicated by a greater proportion of subjects with events 
in the first 30 days.
The incidence of osmotic diuresis-related adverse events was higher in the combined 
canagliflozin group (4.0%) relative to placebo (3.7%). The specific adverse event terms most 
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commonly reported with canagliflozin were adverse events of pollakiuria (2.3%) and thirst 
(1.0%). There were no adverse events related to osmotic diuresis that led to study discontinuation 
in any treatment group and none of the events was serious.
The incidence of UTI adverse events was higher in the canagliflozin 300 mg group (7.4%) 
relative to the placebo group (6.0%), whereas the incidence in the canagliflozin 100 mg group 
(6.2%) was similar to the placebo group. The incidence of discontinuations due to UTI adverse 
events was 0.5% (2 subjects) and 0.3% (1 subject) in the placebo and 100 mg canagliflozin 
groups, respectively. No subjects discontinued due to a UTI adverse event in the 300 mg 
canagliflozin group. Serious UTI adverse events occurred in 3 (0.8%) subjects (preferred terms: 
urinary tract infection [2 subjects] and urosepsis [1 subject]) and 1 (0.3%) subject (preferred 
term: urinary tract infection) in placebo and 100 mg canagliflozin groups, respectively. No 
serious UTI adverse events occurred in the 300 mg canagliflozin group.
The incidence of documented hypoglycemic episodes in subjects receiving a sulphonylurea 
and/or insulin was moderately higher in the canagliflozin 100 mg (41.9%) and the canagliflozin 
300 mg group (43.8%) relative to the placebo group (29.2%). The incidence rate per subject-year 
exposure was similar in the canagliflozin 100 mg and 300 mg groups (1.13 and 1.19, 
respectively), and higher relative to the placebo group (0.83). The incidence of subjects 
experiencing severe hypoglycemic episodes was higher in the pooled canagliflozin group (2.6%), 
with no dose relationship, relative to the placebo group (1.2%). The hypoglycemia event rates 
per subject-year exposure in subjects not receiving background AHA associated were similar in 
canagliflozin 100 mg and placebo groups (0.47 and 0.45, respectively) and greater relative to the 
canagliflozin 300 mg group (0.06).
The incidence of acute renal failure (by SMQ) adverse events was higher in the canagliflozin 
100 mg group (3.8%) and canagliflozin 300 mg group (3.0%) relative to the placebo group 
(2.1%). The incidence of events that led to discontinuation of study drug or were considered 
related to study drug by the investigator was higher in the canagliflozin 300 mg group relative to
the canagliflozin 100 mg and placebo groups. The incidence of serious events was similar in all 
groups.
Selected Laboratory Findings
As part of an outlier analysis of all Phase 3 studies in subjects with moderate renal impairment, 
the incidence of subjects who met the eGFR predefined limit of change (PDLC) criterion of 
<80 mL/min/1.73m2 and a decrease >30% from baseline to “any” post-baseline value was higher 
in the canagliflozin 100 mg and 300 mg groups (9.3% and 12.2%, respectively) relative to the 
placebo group (4.9%). In contrast, the incidence of subjects meeting this PDLC criterion to the 
last value measured while on study drug was similar in the canagliflozin 100 mg and placebo 
groups (3.0% and 3.3%, respectively) and was 4.0% in the canagliflozin 300 mg group. 
The incidence of subjects with any serum potassium value meeting PDLC criteria (>ULN and 
>15% increase from baseline) was similar in the canagliflozin 100 mg and placebo groups, 7.2% 
and 7.9%, respectively, and higher in the canagliflozin 300 mg group, 12.0%. Potassium 
elevations were transient, with no notable difference in the incidence of subjects meeting the 
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PDLC criteria across groups at the last value. In patients with moderate renal impairment, 
increases in potassium were more commonly seen in those with elevated potassium at baseline 
and in those using medications that reduce potassium excretion, such as potassium-sparing 
diuretics, medications that interfere with the renin-angiotensin-aldosterone system, angiotensin-
converting-enzyme inhibitors, and angiotensin receptor blockers. Adverse events of 
hyperkalemia occurred with a similar incidence across treatment groups: 1.5% and 2.2% in the 
canagliflozin 100 mg and 300 mg groups, respectively, and 1.6% in the placebo group. These 
events were considered as serious adverse events in 3 subjects (1 subject in the canagliflozin 100 
mg and 2 subjects in the canagliflozin 300 mg group, and led to discontinuation in 2 subjects (in 
the canagliflozin 300 mg group). The adverse event of blood potassium increased was reported 
in 0.9% and 1.1% of subjects in the canagliflozin 100 mg and 300 mg groups, respectively, and 
not reported in the placebo group. None of the adverse events of blood potassium increase were 
considered as drug-related, and none were serious or led to discontinuation.
For low serum bicarbonate, the incidence of subjects meeting PDLC criteria (value <16 mmol/L) 
at any time was 7.2% in the combined canagliflozin group, without notable dose dependent 
differences, and 2.7% in the placebo group. For the last value, the incidences of subjects meeting 
the PDLC criterion were 1.6% and 0.3%, in the combined canagliflozin group and non 
canagliflozin group, respectively
For increases in serum magnesium, the incidence of subjects with any post-baseline value 
meeting PDLC criteria (>ULN and >25% increase from baseline) was 1.5% and 2.3% in the 
canagliflozin 100 mg and 300 mg groups, respectively, and not observed in the placebo group. A 
lower incidence of subjects meeting PDLC criteria for the “last” value was seen: 0.6% and 1.4% 
of subjects in the canagliflozin 100 mg and 300 mg groups, respectively. Increases in serum 
magnesium meeting the PDLC criteria were generally mild, with modest increases from baseline, 
and with no values reaching the range considered to reflect hypermagnesemia (ie, >1.5 mmol/L).
For increases in serum phosphate, the incidence of subjects with any value meeting PDLC 
criteria (>ULN and >25% increase from baseline) was 2.7% and 5.1% in the canagliflozin 
100 mg and 300 mg groups, respectively, and 0.3% in the placebo group. A lower incidence of 
subjects met the PDLC criteria for the last value: 0.6% and 1.4%, in the canagliflozin 100 mg 
and 300 mg groups, respectively, with no subjects in the placebo group meeting the criterion. No 
adverse events of hyperphosphatemia or increased blood phosphate were reported in the 
canagliflozin groups, suggesting that these transient, mild increases in serum phosphate. No 
subject required treatment for increases in phosphate.
A higher proportion of subjects in the canagliflozin groups relative to the placebo group met the 
PDLC criteria for increases in serum sodium: 4.5% and 4.8% of subjects in the canagliflozin 
100 mg and 300 mg groups, respectively, and 2.2% of subjects in the placebo group.
1.1.2.5.3.2.
Findings in Subjects With eGFR <30 mL/min/1.73m2
In the CANagliflozin cardioVascular Assessment Study (CANVAS), subjects were eligible for 
randomization if their eGFR was 30 mL/min/1.73m2 and were discontinued from the study if 
their eGFR decreased to <15 mL/min/1.73m2; thus safety information, albeit limited, is available 
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for 149 subjects in this population with severe renal impairment. SBP decreases were noted in 
the population of subjects treated with canagliflozin who had an eGFR <30 mL/min/1.73m2 at 
any time while on study drug, with SBP changes of -7.7 mmHg and -7.5 mmHg in the 
canagliflozin 100 mg and 300 mg treatment groups, respectively, relative to a mean change 
of -3.1 in the comparator group noted after eGFR dropped below 30 mL/min/1.73m2.
While only a limited number of subjects experienced a reduction at some point in the study to an 
eGFR <30 mL/min/1.73m2, no notable differences were seen between canagliflozin and 
non-canagliflozin groups in adverse event reporting. Due to the limited ability of canagliflozin to 
increase urinary glucose excretion in subjects with an eGFR of less than 30 mL/min/1.73m2 (due 
to the severe decrease in functioning nephrons), it may have been expected that adverse events 
related to increased urinary glucose excretion (eg, osmotic diuresis, decreases in intravascular 
volume) would be minimal in this population.
While in subjects with an eGFR <45 mL/min/1.73m2 minimal to no improvement in blood 
glucose control will be expected, the safety profile of canagliflozin as assessed by adverse event 
reporting appears to be acceptable with no clinically important differences seen relative to the 
non-canagliflozin group. It should be noted that the ability of canagliflozin to increase delivery 
of sodium to the distal tubule and enhance tubuloglomerular feedback in the remaining nephrons 
in these subjects should be intact, allowing these subjects to potentially benefit in terms of 
reducing progression of diabetic nephropathy in response to canagliflozin treatment.
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 
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 (DeFronzo 2009). 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; 
Gilbert 2013). Increases in glomerular pressure are believed to be an important factor in the onset 
and progression of diabetic nephropathy (Anderson 1986; ADA 2004). ACEi and ARB decrease 
glomerular pressure by stimulating efferent glomerular arteriole vasodilation and reduce 
albuminuria and the progression of diabetic nephropathy (IDNT Study, Lewis 2001; RENAAL
Study, de Zeeuw 2004).
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In preclinical diabetic rodent models, SGLT2 inhibition increases tubuloglomerular feedback and 
reduces SNGFR, 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/1.73m2), an 8-week treatment with empagliflozin, 
a 
selective 
SGLT2 
inhibitor, 
significantly 
reduced 
glomerular 
hyperfiltration 
(eGFR 139 mL/min/1.73m2) (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 canagliflozin Phase 3 program, albuminuria (measured as first morning void urinary 
albumin/creatinine ratio) was assessed in several studies. After 52 weeks of treatment in the 
CANVAS study, reductions in albuminuria were seen with canagliflozin treatment in subjects 
with micro- and macroalbuminuria at baseline (Figure 1).
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Figure 1:
Micro- and Macroalbuminuria: Change from Baseline in Albumin/Creatinine Ratio in 
CANVAS (28431754DIA3008) through 01 July 2012
A. Microalbuminuria:
B. Macroalbuminuria: 
BL
WK 12
WK 52
-60
-50
-40
-30
-20
-10
0
Study Week
Number of Subjects
Median ACR(ug/mg) % Change
With 95% CI
288
283
222
Placebo
320
311
269
CANA 100
288
281
234
CANA 300
Placebo
CANA 100
CANA 300
Base Median
65 (ug/mg)
71 (ug/mg)
73 (ug/mg)
BL
WK 12
WK 52
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
Study Week
Number of Subjects
Median ACR(ug/mg) % Change
With 95% CI
96
94
76
Placebo
72
70
63
CANA 100
83
78
70
CANA 300
Placebo
CANA 100
CANA 300
Base Median
688 (ug/mg)
624 (ug/mg)
720 (ug/mg)
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In subjects with macroalbuminuria in CANVAS, the median percent change from baseline in 
UACR at Week 52 was -3.6% in the placebo group, -58.6% in the canagliflozin 100 mg group, 
and -53.3% in the canagliflozin 300 mg group. Notably this effect was seen on the background of 
ACEi and ARB use (82% of subjects in CANVAS were taking ACEis or ARBs at baseline). In a 
52-week study (28431754DIA3004) in subjects with moderate renal impairment (ie, baseline 
eGFR 30 to <50 mL/min/1.73m2), median percent reductions in albuminuria were also 
observed in subjects treated with canagliflozin 100 mg and 300 mg (-16.4% and -28%, 
respectively) relative to an increase in placebo (19.7%).
The categorical 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]) according to the categorizations defined in the National Kidney Foundation 
KDOQI Guideline 1 (NKF 2007) was assessed. The definition of microalbuminuria is a UACR
30 to 300 mg/g and the definition of macroalbuminuria is a UACR >300 mg/g. In a post-hoc 
analysis in CANVAS, 253/1390 (18.2%) placebo-treated subjects showed albuminuria 
progression (defined by albuminuria status change and 30% increase in UACR from baseline) 
relative to baseline versus 221/1406 (15.7%) with canagliflozin 100 mg, 191/1397 (13.7%) with 
canagliflozin 300 mg, and 412/2803 (14.7%) with canagliflozin overall. Relative to placebo, the 
hazard ratio was 0.81 (95% CI: 0.68 to 0.97) for canagliflozin 100 mg and 0.71 (95% CI: 0.59 to 
0.85) for canagliflozin 300 mg.
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 52 weeks 
in CANVAS (28431754DIA3008, Figure 2), over a 52-week study in subjects with moderate 
renal impairment (28431754DIA3004, Figure 3), as well as over a 104-week period in an active 
comparator study (28431754DIA3009, add-on to metformin, Figure 4) are shown below. These 
acute, modest declines in eGFR that do not progress and may attenuate over time are consistent 
with a hemodynamically mediated effect somewhat not unlike the effects seen with ACEi and 
ARB therapy (Holtkamp 2011).
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Figure 2:
eGFR (mL/min/1.73m2) (28431754DIA3008): Mean Change from Baseline Over Time (Safety) –
Regardless of Rescue Medication – Within 2 Days After Last Study Medication
(Study 28431754DIA3008: Safety Analysis Set)
Figure 3:
eGFR (mL/min/1.73m2) (28431754DIA3004): Mean Change from Baseline Over Time (Safety)
(Study 28431754DIA3004: Safety Analysis Set)
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Figure 4:
eGFR (mL/min/1.73m2) (28431754DIA3009): Mean Change from Baseline Over Time (Safety) –
Regardless of Rescue Medication – Within 2 Days After Last Study Medication
(Study 28431754DIA3009: Safety Analysis Set)
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 5.
BLWK 4
WK 12
WK 26
WK 36
WK 44 WK 52
WK 64
WK 78
WK 88
WK 104
WK 104 LOCF
-8
-6
-4
-2
0
Study Week
Number of Subjects
Mean eGFR(mL/min/1.73m2) Change
With SE
472 463
447
424
415
402
394
385
369
359
339
472
CANA 100
469 458
439
419
405
386
377
367
346
334
319
469
CANA 300
468 458
445
418
404
386
385
367
343
328
311
468
Glimepiride
CANA 100
CANA 300
Glimepiride
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Figure 5: 
Hypotheses Regarding the Effect of ACEi and ARBs on the Progression of Diabetic 
Nephropathy
The present study is intended to determine whether canagliflozin treatment has a renal protective 
effect in subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria, who are receiving 
standard of care, as defined in KDOQI consensus guidelines (NKF 2007; NKF 2012) and 
treatment with an ACEi or ARB. The renal protective effect of canagliflozin relative to placebo 
is measured by the reduction in progression to ESKD, doubling of serum creatinine, and renal or 
CV death. The study will also assess the effects of canagliflozin on reducing renal events 
(ESKD, doubling of serum creatinine and renal death), or CV events (CV death, non-fatal MI, 
non-fatal stroke, hospitalized unstable angina, and hospitalized congestive heart failure), and all-
cause death. Additionally, the study will explore the clinically important renal and CV events 
(ESKD and renal or CV death), each component of the primary and secondary composite 
endpoints, as well as changes in eGFR and albuminuria over time.
2.
OBJECTIVES AND HYPOTHESES
2.1.
Objectives
Primary Objective
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of 
care, to assess the efficacy of canagliflozin relative to placebo in reducing:

The composite endpoint of ESKD, doubling of serum creatinine, and renal or CV death
Secondary Objectives
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of 
care, to assess the efficacy of canagliflozin relative to placebo in reducing:

The composite endpoint of CV death and hospitalized congestive heart failure
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
The composite endpoint of CV death, non-fatal myocardial infarction (MI), and non-fatal 
stroke (ie, 3-point MACE)

Hospitalized congestive heart failure

The renal composite endpoint of ESKD, doubling of serum creatinine, and renal death

CV death

All-cause death

The CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized 
congestive heart failure, and hospitalized unstable angina
Exploratory Objectives
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of 
care, to assess efficacy of canagliflozin relative to placebo in reducing:

The composite endpoint of ESKD, renal or CV death

Individual components of the renal and cardiovascular composite endpoints (ESKD, 
doubling of serum creatinine, renal death, CV death, fatal or non-fatal MI, fatal or non-
fatal stroke, hospitalized congestive heart failure, hospitalized unstable angina)
and to assess the impact of canagliflozin relative to placebo on:

Changes in eGFR over time

Changes in albuminuria over time
Safety Objective
To assess the overall safety and tolerability of canagliflozin.
2.2.
Hypotheses
Canagliflozin reduces the risk of the composite endpoint of ESKD, doubling of serum creatinine, 
and renal or CV death, relative to placebo, in subjects with T2DM, Stage 2 or 3 CKD and 
macroalbuminuria who are receiving standard of care including a maximum tolerated labeled 
daily dose of an ACEi or ARB.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, event-driven, placebo-controlled, parallel-group, 2-arm, 
multicenter study to evaluate the effects of canagliflozin relative to placebo on progression to 
ESKD, doubling of serum creatinine, renal or CV death in subjects with T2DM, Stage 2 or 3 
CKD and macroalbuminuria, who are receiving standard of care including a maximum tolerated 
labeled daily dose of an ACEi or ARB. 
The following section provides an overview of subject management including screening, run-in, 
and double-blind treatment. 
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An overview of the study design is illustrated in Figure 6.
Figure 6: 
Study Design Diagram
ACEi= angiotensin-converting enzyme inhibitor; UACR = urinary albumin-to-creatinine ratio; AHA = antihyperglycemic agent; 
ARB = angiotensin receptor blocker; BP =. blood pressure; eGFR = estimated glomerular filtration rate; 
HbA1c = hemoglobin A1c; R = randomization; T2DM= type 2 diabetes mellitus; Wk=week.
Prescreening 
Subjects will be prescreened on the basis of eGFR and UACR. Only subjects with an eGFR 
30 to <90 mL/min/1.73m2 and a UACR >300 mg/g (>33.9 mg/mmol), as confirmed by a local 
laboratory within 6 months prior to screening, will be eligible for screening by the central 
laboratory. For the prescreening assessment where UACR is not routinely measured as per 
standard of care, it may be substituted by one of the following measures: albumin excretion rate 
>300 mg/24 hours, urine protein-to-creatinine ratio (PCR) >500 mg/g (>56.5 mg/mmol), or 
protein excretion rate >500 mg/24 hours. Subjects who fail local laboratory pre-screening 
assessments are allowed to repeat those laboratory tests.
Note: While positive reagent strip analysis (eg, dipstick 2+) may be suggestive of 
albuminuria/proteinuria that meet the prescreening criteria, any positive reagent strip findings 
must be accompanied by one of the specified albuminuria/proteinuria prescreening measures 
listed above prior to screening with central laboratory evaluations.
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Information related to the management of subjects’ blood pressure, including the use of an ACEi 
or ARB, will also be collected to ensure it meets the study’s requirement (ie, dose stable for at 
least 4 weeks prior to randomization).
Screening to Randomization (up to 8-10 weeks, inclusive of the 2-week single-blind placebo 
run-in period)
Subjects will undergo a screening visit for a preliminary determination of eligibility between 
Week -8 and Week -3. Men or women 30 years of age, diagnosed with T2DM with HbA1c
level 6.5% to 12.0% at screening are eligible to enroll. Eligible subjects must have an eGFR 
of 30 to <90 mL/min/1.73m2 and UACR of >300 mg/g to 5,000 mg/g (>33.9 mg/mmol to 
565.6 mg/mmol).
Subjects who meet inclusion criteria in the screening period must be on the stable maximum 
tolerated labeled daily dose of an ACEi or ARB for a period of at least 4 weeks prior to 
randomization. To reach this requirement, the screening period may be extended up to a total of 
8 weeks (inclusive of the 2-week single-blind placebo run-in period); however, an additional 
2 weeks of screening time may be allowed, if considered medically appropriate. Extension 
beyond this period of time would require concurrence of the sponsor’s medical monitor.
Investigators
are 
encouraged 
to 
keep 
other 
anti-hypertensive, 
lipid-lowering 
and 
antihyperglycemic therapies dose stable for approximately 4 weeks prior to randomization. In 
addition, investigators are encouraged to keep medications that are known to impact serum 
creatinine levels stable during the screening period (for details see Section 6.2.3, Management of 
Medications That May Impact Serum Creatinine Levels).
Qualified subjects will enter the single-blind placebo run-in phase at Week -2. During this phase, 
subjects will be instructed to take one capsule daily in order to assess their compliance with 
study drug. The study site staff should not disclose to the subject that during the single-blind 
placebo run-in period subjects will receive placebo capsules. At the Week -2 visit, subjects 
should also be counseled to perform self-monitored blood glucose (SMBG) determinations, 
according to standard guidelines. The frequency of SMBG determinations will be at 
investigator’s discretion based on individualized standard of care. Subjects will also receive 
diet/exercise counseling and instructions on hypoglycemia recognition and management, as well 
as counseling on renal and CV risk factor medication. This counseling may be reinforced as 
needed throughout the study.
Double-Blind Treatment Phase
Subjects who complete the 2-week single-blind placebo run-in period with 80% compliance (by 
pill count), will be stratified according to their pretreatment eGFR value most proximate to the 
baseline visit (eg, screening, unscheduled, or Week -2) and will be randomized within the 
following 3 strata: 1) 30 to <45 mL/min/1.73m2, 2) 45 to <60 mL/min/1.73m2, 3) 60 to 
<90 mL/min/1.73m2. They will be randomly allocated to treatment with canagliflozin 100 mg or 
matching placebo (in a 1:1 ratio). Double-blind study drug will be administered once daily
(ie, one capsule taken before the morning meal). A total of approximately 4,200 subjects will be 
randomized. 
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Office visits will occur 3 times during the first 13 weeks (ie, Day 1 [randomization], Week 3, and 
Week 13]). Subjects will then be seen at Week 26 and then every 26 weeks thereafter for an 
office visit with laboratory assessment, concomitant medication review, adverse event collection 
and determination of clinical endpoints. Study drug will be dispensed on Day 1 and at Week 13 
and Week 26, and every 26 weeks thereafter. Telephone contact will be made at Week 39 and at 
the midpoint between office visits after Week 52, to check the subject’s status, including 
discussing the subject’s diary entries, concomitant medications, and adverse events, including 
those events in the primary and secondary outcomes. Clinical evaluations and laboratory tests 
using local laboratory facilities may be performed more frequently, as clinically appropriate, and 
abnormalities determined by the investigator to be clinically important should be recorded on the 
local laboratory eCRF.
Blood pressure, lipid, and glucose control should be managed according to local standard of care 
guidelines (such as National Kidney Foundation) in this population. Local laboratory findings
that prompt adjustment to medical treatment, require protocol-specified monitoring 
(ie, potassium), or are associated with adverse events should be documented in the specified 
eCRF. 
End of Treatment Visit
The study has an end of treatment (EOT) visit as soon as possible after the sponsor announces
the projected GTED. Subjects are expected to remain in the double-blind treatment phase until 
the sponsor-announced GTED. The date is based on study site local time. The study sites will be 
notified of the projected GTED, at which time subjects will be scheduled to return to the study 
site for the EOT visit. Subjects should remain on double-blind study drug up until their EOT 
visit. Efficacy and safety outcomes will be collected at the EOT visit.
Subjects who permanently discontinue the study drug before the announcement of the projected 
GTED will complete the EOT/Early Withdrawal (EW) visit as soon as possible after the last 
dose of study drug (or when it is known the subject will be permanently discontinuing study 
drug). In addition, these subjects will return for all scheduled visits in the same way as the 
subjects still on study drug treatment. If these subjects refuse office visits, the investigator is 
asked to encourage the subjects to allow regular contact until study end, according to the Time 
and Events Schedule, either with them, or with a legally acceptable representative, a close friend 
or relative, or their primary care physician to determine vital status and if an efficacy or safety 
outcome event has occurred.
Vital status will be collected for all subjects who permanently discontinue study drug early, 
withdraw from study, or are lost to follow-up at the EOT visit either by telephone or in person, or 
if applicable, by a review of subject’s medical or public records unless this contact is not allowed 
by local regulations.
A Steering Committee, a Medical Safety Review Committee (MSRC), an Independent Data 
Monitoring Committee (IDMC), and an Independent Endpoint Adjudication Committee (IEAC) 
will be commissioned for this study. Refer to Section 9.3, Study Management Committee, for 
details. 
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Study Duration 
Assuming the study endpoints occur as planned, the total study duration is estimated to be 5 to 
5.5 years, including a subject accrual phase of approximately 2 to 2.5 years. Subjects are 
expected to be followed for approximately 4.5 years on average, with the last visit for the last 
subject targeted to occur when all subjects have at least 3 to 3.5 years of follow-up. All study 
sites will be notified of the projected GTED (projected to occur in the fourth quarter of 2019). 
Immediately after the projected GTED notification is sent, for subjects who remain on double-
blind study drug, study sites will be required to schedule the last on treatment visits.
Collection of Data Related to Renal and Cardiovascular Safety Outcomes
Investigators will be required to report any renal or CV event that they consider could possibly 
be an endpoint or a component of the primary or secondary composite endpoint, (refer to 
Section 9.2, Reporting/Adjudication of Events in the Primary and Secondary Composite 
Endpoints and Other Events for Adjudication), as well as all deaths. Additional information and 
documentation will be requested from investigators for all such events to support a detailed 
assessment of these outcomes by the IEAC.
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 Time and Events Schedule. After early 
discontinuation of randomized treatment, subjects will continue to be followed in the same way 
as those who are on study drug treatment.
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 continue to be followed for the full duration of their
originally scheduled study visits. The follow-up regimen for these individuals will be the same as 
those individuals who continue with randomized therapy, ie, requiring study site visits every 
26 weeks with phone/e-mail contact occurring at the midpoint between study site visits (refer to 
Section 9.1.4, Post-Treatment Follow-up, and Section 9.1.5, Post-Randomization Follow-up for 
Participants Unable to Attend Scheduled Visits, for collection of information on renal and CV 
events and other assessments). The investigator will make every effort to ascertain the vital 
status of all subjects at the end of the study (GTED), including using all reasonable means to 
contact the subject, family members, the subject’s physicians and medical records, and the use of 
locator agencies and checking public records, as allowed by local law (see Section 10.4, 
Circumstances for Reduced Follow-up).
Safety Evaluations 
Safety evaluations will include the monitoring of all adverse events, clinical laboratory tests, 
physical examination, vital sign measurements, and measurement of body weight. Further details 
can be found in Section 9.5.1, Safety Evaluation. For adverse events of interest, investigators 
will be asked to provide additional information on separate electronic case report forms (eCRFs). 
The detailed information on collection and reporting of all adverse events is also described in 
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Section 9.5.1, Safety Evaluation. Investigators may also be asked to provide additional 
information on other adverse events, based upon review by the MSRC, IEAC or 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.
Pharmacogenomic Blood Sample
A pharmacogenomic blood sample should be collected on Day 1 (or at a subsequent visit if not 
collected on Day 1) from subjects who consent separately to the pharmacogenomic component 
of the study to allow for pharmacogenomic research, as necessary (where local regulations 
permit). Subject participation in pharmacogenomic research is optional. Refusal to consent for 
this component does not exclude a subject from participation in the clinical study.
Biomarker Research Sample
Plasma, serum, and urine archive samples will be collected (where local regulations permit and 
in subjects who consent to provide these samples) annually as described in the Time and Events 
Schedule to allow for exploratory biomarkers analyses that could help to further explain and 
examine the efficacy and safety findings in this study. Subject participation in the exploratory 
biomarker research is optional. Refusal to consent for this component does not exclude a subject 
from participation in the clinical study.
3.2.
Study Design Rationale
Overall Design, Blinding, Control, Study Phases/Periods, Treatment Groups
This study was designed based on the guidelines for the identification and management of kidney 
disease (NICE 2008; NKF 2012), in general accordance with the US FDA and EMA guidance on 
the development of medications and clinical investigations for the treatment and prevention of 
diabetes mellitus (FDA 2008; EMEA 2012), and in consultation with Health Authorities.
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment, improving the precision of the 
assessments of both efficacy and safety. Since canagliflozin has blood glucose- and blood 
pressure lowering effects and can alter lipids, all subjects are required to be under standard care 
including anti-hypertensive, lipid lowering and antihyperglycemic therapies. Antihyperglycemic, 
lipid lowering and anti-hypertensive therapies can be adjusted any time during the study as 
needed.
The pretreatment phase allows sufficient time for study-related procedures to be performed and 
for determining subject eligibility based on the study entry criteria and test results. During the 
pretreatment phase, adjustment of therapy to reach the stable maximum tolerated labeled daily 
dose of an ACEi or ARB before at least 4 weeks prior to randomization may be performed. 
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The 2-week single-blind placebo run-in period will allow sufficient time for investigators to 
assess whether subjects demonstrate compliance with study procedures, including compliance 
with administration of study drug.
Eligible subjects will be stratified according to their pretreatment eGFR value most proximate to 
the baseline visit (eg, screening, unscheduled, or Week -2) and will be randomized within the 
following 3 strata: 1) 30 to <45 mL/min/1.73m2, 2) 45 to <60 mL/min/1.73m2, 3) 60 to 
<90 mL/min/1.73m2. The cut-off threshold for eGFR strata was based on the potential 
differences in the primary event rate and in the relative contribution of the components of the 
composite primary endpoint between the three eGFR strata.
Randomization and blinding will be used to minimize bias in the assignment of subjects to 
treatment groups, to increase the likelihood that known and unknown subject attributes 
(eg, demographic and baseline characteristics) are evenly balanced across treatment groups. 
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints, and to maximize the likelihood that the study precisely and reliably addresses 
the questions it is designed to answer.
Selection of Study Population 
The study population is selected to ensure a sufficiently high rate of deterioration of renal 
function occurring in the study, which will allow the study to reach the primary aim in a 
reasonable amount of time. 
This study includes subjects with T2DM on a variety of different AHAs with a range of different 
levels of baseline glycemic control.
To be eligible for enrollment, subjects must also have Stage 2 or 3 CKD with an eGFR 30 to 
<90 mL/min/1.73m2 (as determined by CKD-EPI equation) and macroalbuminuria with a UACR
>300 mg/g to 5000 mg/g (>33.9 mg/mmol to 565.6 mg/mmol).
An overall global target ratio for randomized cohort of approximately 60%:40% for CKD 
Stage 3 (ie, eGFR ≥30 to <60 mL/min/1.73m2; first category):CKD Stage 2 (ie, eGFR ≥60 to 
<90 mL/min/1.73m2; second category) will be monitored centrally. In an effort to limit exposure 
to investigational product and to ensure sufficient experiences in subjects with Stage 3 CKD, 
entry of subjects with Stage 2 CKD (ie, eGFR ≥60 to <90 mL/min/1.73m2) may be restricted on 
a regional and/or site basis should the ratio drift substantially off target over the course of the 
recruitment period. 
Use of ACEi or ARB 
All subjects are also required to be receiving the maximum tolerated labeled daily dose of ACEi 
or ARB. This requirement is aligned with current guidelines which recommend the use of ACEi 
or ARB for patients with CKD and diabetes (KDIGO 2013). The rationale for this requirement is 
based on the observation that inhibition of the renin-angiotensin pathway by ACEi or ARB 
reduces the progression of diabetic nephropathy in subjects with T2DM (see Section 1, 
Introduction) and the hypothesis that canagliflozin may exert its renal protective effect through a 
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unique hemodynamic mechanism different from that by ACEi or ARB (see Section 1, 
Introduction). Thus, this requirement will allow the study to address whether canagliflozin can 
provide further renal protection in diabetic nephropathy in addition to standard of care ACEi or 
ARB therapy. 
Combination therapy with an ACEi and an ARB was associated with an increased risk of adverse 
events among patients with diabetic nephropathy (Fried 2013). Therefore, combination use of 
ACEi and ARB, use of mineralocorticoid receptor antagonists or direct renin inhibitors are 
prohibited during this study.
In the canagliflozin Phase 3 program, it was not common for subjects on ACEi or ARBs to 
down-titrate doses or discontinue the ACEi or ARB therapy. There were a total of 236 subjects 
with baseline eGFR 30 to <90 mL/min/1.73m2 and UACR >300 mg/g in the Phase 3 program 
who were treated with ACEi or ARBs at baseline. The number of subjects who permanently 
discontinued therapy with ACEi or ARB before the end of the study was 6 of 65 (9.2%), 6 of 77 
(7.8%), and 3 of 94 (3.2%) in the canagliflozin 100 mg, 300 mg and comparator groups, 
respectively.
Dosage Selection, Route of Administration, Dose Interval, Treatment Period
Canagliflozin has been filed with health agencies for marketing approval based on the results of 
the clinical program, and has been approved for marketing in some countries. As per the US
Package Insert (USPI) and EU Summary of Product Characteristics (SmPC), the recommended 
starting dose of canagliflozin is 100 mg. Canagliflozin should be taken once daily before the first 
meal of the day.
The 100 mg dose of canagliflozin was chosen for this study in subjects with T2DM, Stage 2 or 3 
CKD and macroalbuminuria who are receiving standard of care, mainly based on a favorable 
benefit to risk ratio and clinical data available in the moderate renal impairment group of 
subjects (ie, with baseline eGFR 30 to <60 mL/min/1.73m2) who participated in the Phase 3 
development program. This included an examination of expected reductions in blood pressure 
(the mean reduction from baseline in SBP for placebo, canagliflozin 100 mg and 300 mg groups 
was -1.6 mmHg, -4.4 mmHg and -6.0 mmHg, respectively) and UACR (ie, in subjects with 
macroalbuminuria in CANVAS study [28431754DIA3008], the median percent change from 
baseline in UACR at Week 52 for placebo, canagliflozin 100 mg and 300 mg groups 
was -3.6%, -58.6%, and -53.3% respectively) as well as safety considerations in the pooled 
population with moderate renal impairment (eg, volume depletion adverse events [incidence 
rates for placebo, canagliflozin 100 mg and 300 mg groups were 2.6%, 5.0% and 8.5%, 
respectively], adverse events leading to discontinuation [incidence rates for placebo, 
canagliflozin 100 mg and 300 mg groups were 5.0%, 4.7% and 7.4%, respectively], and lab 
findings of hyperkalemia [incidence rates for placebo, canagliflozin 100 mg and 300 mg groups 
were 7.9%, 7.2% and 12.0%, respectively]) where the balance favored canagliflozin 100 mg over 
300 mg in the population of subjects with moderate renal impairment.
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Choice of Renal Efficacy Measures
The development and progression of renal disease in people with diabetes follows a clearly 
defined pathway: Initially, hyperfiltration (elevated GFR) significantly increases the risk for 
development of microalbuminuria, which progresses to macroalbuminuria, associated with 
reduction in renal function (lower glomerular filtration rate), which eventually leads to renal 
failure with the need for dialysis or transplantation, and finally to death (Mogensen 1998; 
Magee 2009).
The renal components in the composite endpoint (ESKD, doubling of serum creatinine, and renal 
death) are all clinically meaningful and represent different manifestations of the same underlying 
pathophysiologic process. They are widely accepted endpoints indicative of severity of renal 
impairment and have been used in other renal-related outcome trials (Ninomiya 2009;
Parving 2012; de Zeeuw 2013). Diabetic nephropathy increases the risk of CV disease and leads 
to a poorer prognosis (Aso 2008). In addition, CV death is included in the primary composite 
because it is an important competing risk in this patient population (Amin 2013). These endpoint 
events can be clearly defined (definitions are provided in the protocol Section 9.4, Efficacy 
Evaluations and Outcomes) and quantitatively measured. To further ensure the study objectivity, 
all the major efficacy endpoint events will be adjudicated by a blinded IEAC.
Sustained doubling of baseline average serum creatinine values will be confirmed by central 
laboratory repeat test 30 days and preferably within 60 days from the index event. Doubling of 
serum creatinine as a marker of a significant progression of renal disease has been shown to be 
an appropriate parameter in the assessment of renal outcomes and disease progression that 
correlated positively with important CV and renal outcomes in a large outcomes studies (IDNT, 
RENAAL) in patients with T2DM (Lewis 2001; Brenner 2001). Not unlike the effects seen with 
ACEi and ARB therapy (Holtkamp 2011), the hemodynamically mediated effects of 
canagliflozin are associated with acute, modest declines in renal filtration with a concomitant 
increase in serum creatinine that do not progress over time and attenuate with cessation of
treatment.
ESKD is defined as initiation of maintenance dialysis (confirmed by continued need for dialysis 
for at least one month), renal transplantation, or an eGFR <15 mL/min/1.73m2 (determined by 
the central laboratory using the CDK-EPI formula and confirmed by repeat central laboratory 
measure 30 days and preferably within 60 days). 
Renal death is defined as death in subjects who have reached ESKD, die without initiating renal 
replacement therapy, and no other cause of death is determined via adjudication. The endpoint of 
“renal death” in the composite is to capture and account for any subjects who died with renal 
failure but did not have renal replacement therapy applied (because of medical or social reasons). 
This component of the composite endpoint has been used in other renal-related outcome studies
(Parving 2012; de Zeeuw 2013). These renal death events will be adjudicated by a blinded IEAC.
As exploratory endpoints, changes in eGFR and albuminuria over time will be monitored. The 
slope of the eGFR decline is strongly correlated with adverse clinical endpoints including ESKD 
and all-cause mortality (Turin 2012; 2013). The CKD-EPI equation was chosen for estimating 
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GFR in this study. The CKD-EPI equation has been found to be generally more accurate than the 
Modification of Diet in Renal Disease Study (MDRD) equation and is preferred in the most 
recent clinical practice guidelines (KDIGO 2013). An analysis using pooled data sets with 
measured GFR across multiple studies (including subjects with diabetes) found the CKD-EPI 
equation to be superior to the MDRD study equation across a wide range of GFRs and patient 
types (Levey 2009). The CKD-EPI equation has also been shown to be superior to MDRD in 
elderly subjects (Kilbride 2013) and can better categorize subjects as to long-term clinical risk 
than the MDRD study equation (Matsushita 2010).
Choice of Cardiovascular Efficacy Measures
Patients with T2DM with reduced eGFR and albuminuria are at increased risk of CV death and 
adverse renal outcomes (Amin 2013). Therefore, an intervention that would be expected to 
reduce the progression of diabetic nephropathy might reduce the incidence of CV death. In 
addition, CV death also serves as a competing risk for renal-related endpoints. CV deaths would 
be expected to account for approximately two thirds of the deaths in this subject population 
(Packham 2012), and this component of the composite endpoint has also been used in other 
renal-related outcome studies (Parving 2012; de Zeeuw 2013). Other causes of death (such as 
malignancy, infection, or injuries) would not be expected to be influenced by changes in 
nephropathy progression. In addition to CV death, other clinically important CV events are also 
monitored in this study, including non-fatal MI, non-fatal stroke, hospitalized CHF, or 
hospitalized unstable angina. These events are clearly defined in the charter of the IEAC and will 
be adjudicated by an IEAC.
Archive Samples for Exploratory Research and Specimens for Biomarker Assessment
Numerous biomarkers have been studied as potentially important surrogate measures of renal or 
CV events and overall health in subjects with T2DM (Ridker 2004). Fasting plasma, serum, and 
urine samples will be collected (where local regulations permit) and archived to allow for the 
analysis of important biomarkers (not prespecified) and could help to further explain and 
examine the efficacy and safety findings in this study. Details are provided in Section 9.7, 
Exploratory Biomarker Evaluations.
Pharmacogenomic (DNA) Samples Collection
It is recognized that genetic variation can be an important contributory factor to inter-individual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis (Parsa 2013). Pharmacogenomic research may help to explain 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of collecting DNA samples in this study is to allow the 
identification of genetic factors that may influence the efficacy of canagliflozin in the study 
population. Details are provided in Section 9.6, Pharmacogenomic Evaluations. 
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4.
STUDY POPULATION
4.1.
General Considerations
The study will include subjects with a diagnosis of T2DM with Stage 2 or 3 CKD and 
macroalbuminuria. 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 study representative before enrolling 
the subject in the study. 
Note: For laboratory test values, a one-time repeat measurement is allowed, at the discretion of 
the investigator, if the screening value is not consistent with prior values and the repeat is 
considered clinically appropriate. For more information, refer to Section 4.5. Repeat Testing and 
Subject Rescreening.
4.2.
Inclusion Criteria
Potential subjects must satisfy all of the following criteria to be enrolled in the study:
Inclusion Criteria at Screening Visit
1.
Man or woman 30 years-old with a clinical diagnosis of T2DM
2.
HbA1c 6.5% to 12.0%
3.
eGFR 30 to <90 mL/min/1.73m2 (as determined using the CKD-EPI equation)
Note: An overall global target ratio for randomized cohort of approximately 60%:40% for 
CKD Stage 3 (ie, eGFR ≥30 to <60 mL/min/1.73m2; first category):CKD Stage 2
(ie, eGFR ≥60 to <90 mL/min/1.73m2; second category) will be monitored centrally. In an 
effort to limit exposure to investigational product and to ensure sufficient experiences in 
subjects with Stage 3 CKD, entry of subjects with Stage 2 CKD (ie, eGFR ≥60 to 
<90 mL/min/1.73m2) may be restricted on a regional and/or site basis should the ratio drift 
substantially off target over the course of the recruitment period. 
4.
Urinary albumin-to-creatinine ratio >300 mg/g to 5,000 mg/g (>33.9 mg/mmol to 
565.6 mg/mmol).
5.
All subjects must be on a stable maximum tolerated labeled daily dose of ACEi or ARB for 
at least 4 weeks prior to randomization.
Note: A maximum tolerated labeled daily dose of an ACEi or ARB is defined as the 
maximum approved labeled dose for diabetic nephropathy (for agents with an approved 
indication for diabetic nephropathy in patients with T2DM, ie, losartan and irbesartan) or the 
maximum approved dose for hypertension (for agents without an approved indication for 
diabetic nephropathy), unless side effects or adverse events limit the use of the maximum 
approved dose. For subjects who are not on a maximum labeled daily dose of an ACEi or 
ARB, investigators will be required to document why a higher dose should not be used. 
6.
Women must be:

postmenopausal, defined as
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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 <18 months and a 
serum follicle stimulating hormone (FSH) level >40 IU/L, or

surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal occlusion
[which includes tubal ligation procedures as consistent with local regulations]), 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, and consistent with local regulations regarding use of birth control 
methods for subjects participating in clinical studies, 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.
7.
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.  
8.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol 
9.
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. Each subject must also sign a separate informed consent form if he or she agrees to 
provide an optional DNA sample for research (where local regulations permit). Refusal to 
give consent for the optional DNA research sample does not exclude a subject from 
participation in the study.
Inclusion Criterion for Randomization
10. Subjects must have 80% compliance (by pill count) with single-blind placebo.
4.3.
Exclusion Criteria
Potential subjects who meet any of the following criteria will be excluded from participating in 
the study:
Diabetes-Related/Metabolic
1.
History of diabetic ketoacidosis or T1DM. 
2.
History of hereditary glucose-galactose malabsorption or primary renal glucosuria.
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Renal/Cardiovascular
3.
Known medical history or clinical evidence suggesting non-diabetic renal disease
4.
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.
5.
Uncontrolled hypertension (systolic BP 180 and/or diastolic BP 100 mmHg) by Week -2.
Note: Subjects not fulfilling blood pressure criteria at the initial screening visit may have 
their blood pressure lowering medication regimen adjusted, followed by re-evaluation up to 
the Week -2 run-in period (the ACEi or ARB regimen must be stable for at least 4 weeks 
before Day 1 to be eligible).
6.
Blood potassium level >5.5 mmol/L during screening.
Note: Subjects in whom hyperkalemia was associated with the use of nonsteroidal 
anti-inflammatory drugs (NSAIDs), beta-blockers, or mineralocorticoid receptor antagonists 
(eg, spironolactone or eplerenone), who have been withdrawn from these drugs, and in 
whom usage of these drugs is not indicated in the view of the treating physician, may be 
included in the study.
7.
Myocardial infarction, unstable angina, revascularization procedure (eg, stent or bypass graft 
surgery), or cerebrovascular accident within 12 weeks before randomization, or a
revascularization procedure is planned during the trial.
8.
Current or history of heart failure of New York Heart Association (NYHA) Class IV cardiac 
disease (The Criteria Committee of the New York Heart Association). See Attachment 2.
9.
ECG findings within 12 weeks before randomization that would require urgent diagnostic 
evaluation or intervention (eg, new clinically important arrhythmia or conduction 
disturbance).
Gastrointestinal
10. Known significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis).
Laboratory
11. Alanine aminotransferase (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.
Other conditions
12. 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). 
13. History of human immunodeficiency virus antibody positive.
14. Major surgery within 12 weeks before randomization, or has not fully recovered from 
surgery.
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15. Any condition that in the opinion of the investigator or sponsor’s medical monitor would 
make participation not in the best interest of the subject, or could prevent, limit, or confound 
the protocol-specified assessments.
16. History of atraumatic amputation within past 12 months of screening, or an active skin ulcer, 
osteomyelitis, gangrene, or critical ischemia of the lower extremity within 6 months of 
screening.
Medications/ Therapies
17. Combination use of ACEi and ARB. 
18. Use of mineralocorticoid receptor antagonists (MRA) or a direct renin inhibitor (DRI).
Note: If deemed clinically appropriate at the discretion of the investigator, subjects may be 
removed from therapy with MRA or DRI during screening. Subjects who are off therapy
with MRA or DRI for at least 8 weeks prior to randomization may be considered eligible for 
enrollment.
19. Current use of an SGLT2 inhibitor (within 12 weeks prior to randomization).
20. Current participation in another canagliflozin study, or previously exposed to canagliflozin 
in a prior canagliflozin study.
21. Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients (refer to 
Section 14.1, Physical Description of Study Drug[s]).
22. Received an active investigational drug (including vaccines) other than a placebo agent, or 
used an investigational medical device within 12 weeks before Day 1/baseline.
General
23. Pregnant or breast-feeding or planning to become pregnant or breast-feed during the study.
24. 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 ensure that all study enrollment criteria have been met and 
determine that the subject has not had any interval change in clinical status since the time of 
the initial screening visit. Before randomization, subjects whose clinical status changes after 
screening such that they now meet an exclusion criterion, should be excluded from 
participation.
4.4.
Prohibitions and Restrictions
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). 

Combination use of ACEi and ARB will not be permitted. 
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
Use of direct renin inhibitors (DRIs) will not be permitted.

If determined medically necessary, cautionary post-baseline use of MRA is permitted. As 
per labeling of MRA therapy, concomitant use of an MRA with ACEi (or ARB) therapy 
may significantly increase the risk of hyperkalemia. Thus, enhanced potassium monitoring 
must be carefully considered if starting an MRA post-randomization. Contraindications, 
Warnings, and Precautions specified in local product labeling of MRAs must be strictly 
adhered to, such as avoiding use of an MRA in subjects treated with other potassium-
conserving diuretics and in subjects with acute renal insufficiency, with significantly 
compromised renal function, or subjects with heart failure and proteinuria.

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. 

Strenuous exercise may affect safety laboratory results; for this reason, strenuous exercise 
should be avoided within 72 hours before planned study visits. 
4.5.
Repeat Testing and Subject Rescreening
During the screening period, a disqualifying blood pressure measurement or laboratory test may 
be repeated one time at the discretion of the investigator and where there is a clinical reason to 
do so. In subjects for whom a one-time repeat measure is deemed clinically appropriate, the 
repeat measure should be assessed within the screening period and prior to recording the subject 
as having failed screening. 
Subjects who do not satisfy entry criteria based on a physical or laboratory measurement either 
during the initial screening assessment or following an allowable one-time repeat assessment will 
be reported as having failed screening and may, at the discretion of the investigator and with 
concurrence of the sponsor’s medical monitor, be rescreened after appropriate clinical 
management. Rescreening will require that all screening parameters be repeated, including the 
signing of a new informed consent form and the completion of a full screening visit with a 
comprehensive central laboratory review. Rescreened subjects must meet all entry criteria to be 
considered eligible for the study. Generally, a subject may only be rescreened once, but one
additional rescreening may be allowed with concurrence of the sponsor’s medical monitor.
5.
TREATMENT ALLOCATION
Stratification
Eligible subjects will be stratified according to their pretreatment eGFR value most proximate to 
the baseline visit (eg, screening, unscheduled, or Week -2) and will be randomized within the 
following 3 strata: 1) 30 to <45 mL/min/1.73m2, 2) 45 to <60 mL/min/1.73m2, and 3) 60 to 
<90 mL/min/1.73m2.
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 
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randomly permuted blocks and will be stratified by pretreatment eGFR (30 to <45, 45 to <60, 
60 to <90 mL/min/1.73m2). 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, medication numbers, and 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 user 
identification (ID) and personal identification number 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. 
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. However, the treatment blind may be broken to provide 
unblinded information to the study site only if specific emergency treatment/course of action 
would be dictated by knowing the treatment status of the subject. In such cases, the investigator 
may in an emergency determine the identity of the treatment through the 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 
the 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 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. 
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. For the purpose of the interim analysis, the randomization codes and, 
if required, the translation of randomization codes into treatment and control groups will be 
disclosed to those authorized and only for those subjects included in the interim analysis.
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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. 
Unless required for urgent medical management, investigators should obtain all post-baseline 
urinalyses through the central laboratory and not by a local laboratory. Urine glucose results will 
not be reported by the central laboratory. Investigators will be counseled to avoid performing 
local urinalysis with dipstick unless required for urgent medical management (eg, DKA or other 
safety concerns). 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 eligible subjects will receive single-blind placebo 
capsules and will be instructed to take one capsule prior to the first meal of the day for a total of 
2-weeks to assess compliance. 
Subjects will take the last dose of single-blind placebo study drug on the day prior to the 
Baseline (Day 1) visit. The investigational site staff should avoid disclosing to the subject that 
the run-in period drug is placebo.
Double-Blind Study Medication
On Day 1, subjects will be randomly assigned in a 1:1 ratio to canagliflozin 100 mg or matching 
placebo.
On Day 1, the first dose of double-blind study drug will be administered at the study site after
all baseline procedures have been completed. 
After Day 1, subjects will be counseled to take one capsule of canagliflozin 100 mg or matching 
placebo once daily, before the first meal of the day, for the duration of the study or until early 
discontinuation.
The study drug must be swallowed whole with liquid and not chewed, divided, dissolved, or 
crushed. 
If a subject does not take a dose of study drug within 12 hours after its scheduled time (ie, before 
the first meal of the day), the dose of study drug should be skipped for that day, and the subjects 
should be instructed to take their usual dose of study drug on the following morning at its 
regularly scheduled time.
Study drug treatment may be interrupted ,eg, for safety and/or tolerability reasons such as 
hospitalizations for major surgical procedure or serious medical illness. Study drug treatment 
interruptions, occurring for any reason and lasting 7 days or longer, will be documented on the 
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eCRF. Study drug should be reinstituted once the subject has recovered and the safety and/or 
tolerability concern is no longer present.
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol.
For subjects who develop conditions that are associated with 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 study drug 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
Subjects will receive diet/exercise counseling at the single-blind placebo run-in visit (Week -2)
for their glycemic control. During this visit, subjects should also be counseled to perform fasting 
SMBG determinations, according to standard local guidelines, and to enter results into the 
protocol-specified study diary that will be provided to each subject, as described in Section 9.1.1.
The background AHA regimen may be adjusted at any time during the study to achieve glycemic 
goals, using standard local guidelines, and as considered appropriate by the investigator for the 
individual subject. As a reference of one possible standards of care guidance that study sites can 
use, the current American Diabetes Association (ADA) Standards of Medical Care in Diabetes 
will be provided to the sites (Section 15, Study Specific Materials). Adjustment to the AHA 
regimen should be carefully implemented so as to avoid events of hypoglycemia.
For optimization of glycemic control among the study participants, study sites will be informed,
approximately biannually, about the proportion of subjects in their Country and/or Region who 
are meeting treatment targets, along with a benchmark of other Countries/Regions and the global
on-average performances for the CREDENCE™ study sites worldwide.
To monitor whether additional measures are needed to ensure that treatment targets are being 
reached in both treatment arms, the IDMC will review unblinded glycemic data by treatment 
group.
6.2.2.
Management of Renal and CV Risk Factors
Subjects will receive counseling at the single-blind placebo run-in visit (Week -2) for their renal 
and CV risk factor medication. 
Before randomization and throughout the study, investigators should carefully consider the 
management of hyperlipidemia and hypertension based upon standard local guidelines for the 
care of subjects with T2DM. As a reference of one possible standards of care guidance that study 
sites can use, the current ADA Standards of Medical Care in Diabetes will be provided to the 
sites (Section 15, Study Specific Materials).
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In line with monitoring for the glycemic parameters described in Section 6.2.1, an individual site 
report will include metrics on the proportion of subjects reaching treatment targets for systolic 
blood pressure as well as the proportion of subjects being treated with HMG-CoA reductase 
inhibitors (statin). The IDMC will review unblinded blood pressure and lipid management data 
by treatment group.
6.2.3.
Management of Medications that May Impact Serum Creatinine Levels
Investigators are encouraged to keep medications that are known to impact serum creatinine 
levels (eg, NSAIDs, trimethoprim, cimetidine, probenecid, aminoglycosides, amphotericin, 
ketoconazole, and clofibrate) stable during the screening period and for approximately 2 weeks 
before any serum chemistry measurement during the course of the study.
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 
responsible for providing additional instructions to reeducate any subject who is not compliant 
with taking the study drug or with making required clinic visits. The initial compliance will be 
assessed during the 2-week single-blind placebo run-in period.
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 and throughout the study. 
Prestudy therapies taken from 30 days before screening and up to the time of the first dose of 
double-blind study drug must be recorded on the eCRF. 
All therapies (prescriptions or over-the-counter medications, including vitamins and herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded as prestudy therapy 
(before the first dose of double-blind study drug) or concomitant therapy (after first dose of 
double-blind study drug) on the eCRF, including in subjects who prematurely discontinue study 
drug.
Concomitant therapies will not be provided by the sponsor. 
For subjects requiring a downward adjustment of blood pressure medication, other background 
therapy (eg, diuretics) should be modified prior to adjusting the dose of ACEi or ARB, and prior 
to interruption/discontinuation of study drug. 
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Subjects who experience a volume depletion adverse event or a meaningful change in eGFR 
should have concomitant medications reviewed by the investigator with adjustments made as 
clinically appropriate. Guidance for the management of volume depletion adverse events or 
eGFR changes will be provided in a separate document (see Section 15, Study Specific 
Materials). 
There is no evidence of excess risk for hyperkalemia associated with the canagliflozin 100 mg 
dose used in this study (see Section 3.2, Study Design Rationale). Therefore, general standards 
for management of hyperkalemia should be applied in case of an elevation in serum potassium. 
Prohibited and Restricted Post-Baseline Therapies
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited and restricted post-baseline therapies are administered. In addition, prohibited 
medication must be immediately recorded in RAVE.
Prohibited therapies include:

Other SGLT2 inhibitors (including concurrent use of canagliflozin)
Note: 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.

Combination use of ACEi and ARB

Direct renin inhibitors
Restricted therapy includes:

Mineralocorticoid receptor antagonists 
Note: if post-baseline treatment with an MRA is determined medically necessary over the 
course of the double-blind treatment period, more frequent monitoring of serum potassium 
and more aggressive medication management should occur as per the local label. For 
example, if spironolactone is prescribed and the potassium values exceed 5.0 mEq/L
(mmol/L) (as per US label for spironolactone), consideration should be made to first 
discontinue or interrupt treatment with spironolactone, followed by other medications that 
may be suspected to have contributed to hyperkalemia  (eg, ACEi/ARB, double-blind study 
drug). 
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. 
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Visit Schedules and Visit Windows
A screening visit should occur 1 to 8 weeks before the single-blind placebo run-in visit
(Week -2). The single-blind placebo run-in period should be 2 weeks in length, with a 
recommended visit window of 4 days. 
During the post-randomization period, subsequent scheduled study visits during the first year of 
the study should occur at Day 1 (baseline, the day of randomization) and Weeks 3, 13, 26, and 
52. A telephone contact will be conducted at Week 39 to collect information related to subjects’ 
concomitant medications, adverse events and events in the primary and secondary composite 
endpoints. After the first year, scheduled in-clinic study visits should occur at 26-week intervals
with telephone contacts approximately midway between in-clinic visits. 
For the visits at Weeks 3, 13 and 26, the recommended visit window is 7 days. After Week 26, 
the recommended visit window is 14 days.
A telephone follow-up contact (or optional study visit, at the discretion of the investigator) will 
be conducted for all subjects approximately 30 days (and no more than 42 days) after the last 
dose of study drug. If a telephone contact or study visit is not possible, follow-up information 
may be collected via email or other electronic means.
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 continue double-blind study drug through the time of study site notification of 
the projected GTED, it will be important for study 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, study sites will be required to follow up on 
subsequent scheduled visits, and 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
A negative pregnancy test is required at baseline. 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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Subject Diary: Collection of Self-Monitoring of Blood Glucose and Possible Hypoglycemic 
Event Information
A standard, protocol-specified study diary will be provided to each subject. Routine self-
monitored blood glucose (SMBG) measurements may be recorded in the diary, and all episodes 
of possible hypoglycemia should be documented as well as associated fingerstick glucose 
measurements, if available.
The study diary may also be used to keep track of medications and/or medication changes at the 
investigator’s discretion. In addition, the study diary should be used for the subject to record 
health-care provider visits (other than protocol-specified study visits), emergency care, and 
hospital visits. 
The study diary should be reviewed by study research staff at each scheduled visit.
Collection of Optional Specimens for Exploratory Research
A set of fasting plasma, serum, and urine samples will be collected at the time points specified in 
the Time and Events Schedule from subjects who consent to this component of the study to allow 
for exploratory research related to canagliflozin and biomarker analyses that may provide further 
understanding regarding the diagnosis and treatment of T2DM or diabetic nephropathy (where 
local regulations permit). Subject participation in this component of the study is optional. 
Refusal to consent for this component does not exclude a subject from participation in the 
clinical study. Refer to Section 9.7, Exploratory Biomarker Evaluations, for further details. Refer 
to Attachment 4, Optional Specimens for Exploratory Research - Sample Collection and 
Handling, for further information regarding the collection and handling of exploratory blood and 
urine samples.
Pharmacogenomic Testing
A blood sample will be collected on Day 1 (or any time after Day 1 if the specimen is 
inadvertently missed on Day 1) from subjects who have consented to participate in the 
pharmacogenomic component of the study. Subject participation in this component of the study 
is optional. Refusal to consent for this component does not exclude a subject from participation 
in the clinical study. Refer to Section 9.6, Pharmacogenomic Evaluations, for further details. 
Refer to Attachment 5, Pharmacogenomic Sample Collection and Shipment Procedures, for 
details on collecting and handling blood samples for pharmacogenomic research. 
Blood Collection
The estimated total blood volume that will be collected for a subject who completes the study 
(including all procedures outlined in the pretreatment and double-blind treatment phases over 
approximately 5 to 5.5 years) will be approximately 340 mL with the maximum amount 
collected in a single visit being approximately 40 mL. For details please see Attachment 3.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
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9.1.2.
Pretreatment Phase
Prescreening Assessment
Potential subjects will sign an informed consent form before any study-related procedures are 
performed. 
Subjects will be prescreened on the basis of eGFR and UACR. Only subjects with an eGFR 
30 to <90 mL/min/1.73m2 and a UACR >300 mg/g (>33.9 mg/mmol), as confirmed by a local 
laboratory within 6 months prior to screening, will be eligible to proceed to a full screening visit 
including central laboratory assessments. For the prescreening assessment where UACR is not 
routinely measured as per standard of care, it may be substituted by one of the following 
measures: albumin excretion rate >300 mg/24 hours, urine protein-to-creatinine ratio (PCR) 
>500 mg/g (>56.5 mg/mmol), or protein excretion rate >500 mg/24 hours. Subjects who fail 
local laboratory pre-screening assessments are allowed to repeat those laboratory tests. 
Note: While positive reagent strip analysis (eg, dipstick 2+) may be suggestive of 
albuminuria/proteinuria that meet the prescreening criteria, any positive reagent strip findings 
must be accompanied by one of the specified albuminuria/proteinuria prescreening measures 
listed above prior to screening with central laboratory evaluations.
In addition, when available, the latest 3 pre-study serum creatinine values collected within a year 
prior to screening in an outpatient setting, and at least 1 month apart, will be recorded in the 
eCRF.
For subjects who require additional local laboratory assessment solely for the purpose of 
prescreening, either the optional prescreening-specific or full informed consent must be obtained. 
For detailed description of the informed consent forms see Section 16.2.3. Informed Consent.
During the prescreening assessment, a focused review and initial assessment of subjects’ use of 
an ACEi or ARB will be performed to ensure that all subjects assessed for enrollment have been 
(or will be) on a stable, maximum tolerated labeled daily dose of ACEi or ARB for at least
4 weeks prior to randomization.
Screening Visit (Week -10 to Week -3)
If an optional prescreening-specific informed consent is obtained, and the subject is eligible to 
enter the screening period, the full informed consent must be obtained before screening is 
initiated.
At the screening visit, a focused medical history and initial screening assessment of 
inclusion/exclusion criteria will be performed and samples for required central laboratory tests 
will be collected. Laboratory specimens will be obtained as described in the Time and Events 
Schedule. Vital signs and weight will be measured and prestudy medicines will be reviewed. An 
operations manual will be provided to describe collection, processing, and shipping procedures 
for the duration of the study. 
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During the screening period, the investigator should adjust/optimize the subject’s medications as 
necessary according to local standard guidelines, including antihyperglycemic, lipid-lowering, 
and anti-hypertensive therapy (with exception of ACEi or ARB which should remain stable after 
the maximum tolerated dose is achieved). Investigators are encouraged to keep these medications 
dose stable for approximately 4 weeks prior to randomization. In addition, investigators are 
encouraged to keep medications that are known to impact serum creatinine levels (eg, NSAIDs, 
trimethoprim, cimetidine, probenecid, aminoglycosides, amphotericin, ketoconazole, and 
clofibrate) stable during the screening period.
Subjects must be on a stable maximum tolerated labeled daily dose of an ACEi or ARB for a 
period of at least 4 weeks prior to randomization. To reach this requirement, the screening period 
may be extended, up to a total of 8 weeks (inclusive of the 2-week single-blind placebo run-in 
period); however, an additional 2 weeks of screening time may be allowed, if considered 
medically appropriate. Extension beyond this period of time would require concurrence of the
sponsor’s medical monitor. Subjects who have an extended screening period (ie, >2 weeks
between the screening visit and the run-in Week -2 visit) for any reason (eg, undergoing ACEi or 
ARB therapy adjustments during the pre-randomization period) must undergo an additional 
serum chemistry test at the run-in visit (Week -2) to facilitate the calculation of a baseline 
average serum creatinine value, using the values from the Week -2 and randomization visits (see 
Time and Events Schedule, footnote “v”). The baseline average serum creatinine value for 
subjects who do not have an extended screening period will be calculated using the serum 
creatinine values from the screening and randomization visits.
At the Week -2 visit, potential eligible subjects will be counseled to take one capsule of single-
blind placebo once daily, before the first meal of the day, for a duration of 2 weeks. Subjects 
should be instructed to take their last dose of single-blind placebo study drug on the day prior to 
the Baseline (Day 1) visit. The study site staff should not disclose to the subject that during the 
single-blind placebo run-in period subjects will receive placebo capsules. 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 placebo (by counting capsules). 
Potential 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 single-blind placebo run-in period provide investigators with 
the opportunity to evaluate and optimize the subject’s glycemic, lipid and blood pressure 
controls, as well as the management of renal or CV risk factors prior to randomization as 
required (refer to Section 6.2.1, Management of Glycemic Control and Section 6.2.2, 
Management of Renal or CV Risk Factors), and provide subjects with counseling regarding diet 
and exercise consistent with applicable local guidelines.
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9.1.3.
Double-Blind Treatment Phase 
Day 1/Day of Randomization
Eligible subjects (ie, those who have taken 80% of the scheduled single-blind placebo capsules 
during the single-blind placebo run-in period) will return for the Day 1 (baseline) visit, at which 
time they will be stratified according to their pretreatment eGFR value most proximate to the 
baseline visit (eg, screening, unscheduled, or Week -2) and will be randomized within the 
following 3 strata: 1) 30 to <45 mL/min/1.73m2, 2) 45 to <60 mL/min/1.73m2, 3) 60 to 
<90 mL/min/1.73m2. They will be randomly assigned in a 1:1 ratio to once daily treatment with 
canagliflozin 100 mg or matching placebo. Subjects will continue treatment until the study 
completes or the subject is prematurely withdrawn from double-blind study medication (refer to 
Section 10, Subject Completion, Premature Discontinuation of Treatment, or Withdrawal From 
the Study). 
At the randomization visit, in some countries or regions (at the option of local sponsor 
representatives), subjects will be given information for glucose, lipid and BP management. A
glucose meter and materials for SMBG measurements and instructions on the performance of 
SMBG measurement will also be provided to all subjects.  
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.
Subjects who experience doubling of serum creatinine from their baseline average values or 
nonfatal CV events (ie, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, or 
hospitalized unstable angina) during the double-blind treatment phase will remain in the study
and should continue to receive double-blind study drug and complete all assessments at all 
scheduled visits, as appropriate.
Note: Throughout the double-blind treatment phase, ACEi or ARB therapy should remain stable, 
unless changes are medically indicated.
Note: Subjects who are undergoing chronic dialysis or have had renal transplant will discontinue 
the study drug treatment.
9.1.4.
Post-Treatment Follow-up
All subjects should have a follow-up telephone contact (or optional study visit, at the discretion 
of the investigator) approximately 30 days after the last dose of study drug and prior to the 
GTED. 
All subjects who discontinue study medication prematurely should continue to attend all 
subsequent study visits in the same way as the subjects who are still on the study drug treatment, 
and be followed to the GTED, unless the subject has elected to withdraw his/her consent from 
the study and is not agreeable to follow-up. 
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Subjects withdrawn early from the study for any reason (except for “withdrawal of consent, not 
agreeable to follow-up”) will be contacted by telephone with the goal of collecting any events 
that are considered as renal or CV endpoint events (ie, ESKD, doubling of serum creatinine, 
renal or CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, or 
hospitalized unstable angina), and all-cause death (refer to footnote “h” in the Time and Events 
Schedule for details).
9.1.5.
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 (as local regulations allow)
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 study site must attempt to collect vital status 
data, as noted in Section 10.4, 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 study site closes for operational, financial or other reasons and subjects 
are unable to be contacted regarding study site closure, data from that study site will be 
transferred to another study site for a check of public records and/or vital status (at a minimum).
9.2.
Reporting/Adjudication of Events in the Primary and Secondary 
Composite Endpoints and Other Events for Adjudication
Investigators will be counseled to report any event that they assess as potentially being a
component in the primary and secondary composite endpoints (ESKD, doubling of serum 
creatinine, renal death, CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart 
failure, hospitalized unstable angina and all-cause death). All components in the primary and 
secondary composite endpoints will be submitted for adjudication. Medical monitors will also 
have study-wide responsibility to assess adverse events for potential adjudication. For all 
endpoints, investigators will be alerted if the sponsor identifies a potential event based on eCRF 
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entries that had not been specifically identified by the investigator as a potential event on the 
eCRF. 
For serum creatinine values indicative of a sustained 100% increase (ie, doubling) from 
baseline average that are identified by the study site or the sponsor, the result should be 
confirmed by repeat central laboratory measure 30 days and preferably within 60 days after the 
index event. The investigator should make every effort to collect local laboratory data that may 
facilitate identification of events of sustained doubling of serum creatinine. Such situations 
would include recording/reporting in the eCRF the local laboratory values as part of routine 
patient care. Additionally, central or local laboratory values on serum creatinine should be 
collected following a hospitalization in which an acute renal event emerges and is unresolved 
prior to discharge, or when a suspected decline in renal function is anticipated (eg, symptomatic 
uremia). Telephone contacts scheduled between 26-week in-clinic visits will help in determining 
if additional testing has been conducted outside of the study site, or may trigger a serum 
creatinine laboratory measurement if clinically warranted.
The sponsor will review the clinical database, the central laboratory database, and the
Global Medical Safety (GMS) database (which contains hospitalization data) on an ongoing 
basis to identify potential endpoint events. 
Investigators must provide a specific package of information to be submitted for adjudication 
evaluation that will be provided in a procedural manual. An IEAC will assess these events 
according to the committee’s charter and will independently classify the events while blinded to 
treatment assignment.
More detailed information related to study endpoint events reporting and adverse events 
reporting can be found in Section 12, Adverse Event Reporting.
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 overseeing the CREDENCE trial is the George Institute for Global Health.
9.3.2.
Steering Committee
The Steering Committee is made up of external scientific experts who 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, reviewing study results and for their publication. Details of the composition, 
roles, and responsibilities of the committee are documented in the Steering Committee 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 1 statistician. The MSRC will include members from the sponsor and may also involve 
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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 an IDMC.
Details of the composition, roles, and responsibilities will be documented in its charter.
9.3.4.
Independent Data Monitoring Committee
An IDMC will be commissioned for this study to review accumulated, unblinded safety 
information during the study. Details of the composition, roles, and responsibilities will be 
documented in its charter. 
The IDMC will have responsibility for safety review during the study, including serious adverse 
events, events resulting in study drug discontinuation, as well as renal and CV adverse events.
An interim analysis will be conducted when the primary efficacy events have been observed in 
approximately 405 subjects. If the conditional power (based on the assumption that the hazard 
ratio in the remaining study is 0.80) is 10% or lower, the study may be stopped for futility. The 
alpha spending function will be used and the alpha spent in the interim analysis is 0.01 (see 
Section 11.3.5, Interim Analysis). Detailed stopping guidelines will be specified in the IDMC 
charter.
9.3.5.
Independent Endpoint Adjudication Committee
The IEAC will be responsible for adjudicating all renal and CV events that are components in the 
primary and secondary composite endpoints in this study. The IEAC 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.
9.4.
Efficacy Evaluations and Outcomes
9.4.1.
Measures of Efficacy
The key measure of the efficacy is the reduction in the primary composite endpoint of ESKD, 
doubling of serum creatinine, renal or CV death. The secondary measures of efficacy are the 
reduction in the composite endpoint of CV death and hospitalized congestive heart failure; the 
composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE);
hospitalized congestive heart failure; the renal composite endpoint of ESKD, doubling of serum 
creatinine, and renal death; CV death; all-cause death;  and the CV composite endpoint of CV 
death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, and hospitalized 
unstable angina. 
Additional exploratory measures of efficacy include reduction in a composite endpoint of ESKD 
and renal or CV death and reductions in each individual component of the composite endpoints 
including ESKD, doubling of serum creatinine, renal death, CV death, nonfatal MI, nonfatal 
stroke, hospitalized congestive heart failure, hospitalized unstable angina, as well as the changes 
in eGFR and albuminuria over time. 
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9.4.2.
Efficacy Outcomes
Primary Efficacy Outcome
The primary efficacy outcome is a composite endpoint of the first occurrence of ESKD, doubling 
of serum creatinine, renal or CV death. 
The definitions for each individual component in the primary composite endpoint are:

ESKD: Initiation of maintenance dialysis for at least 1 month, or renal transplantation, or a 
sustained eGFR of <15 mL/min/1.73m2 (by CKD-EPI formula and confirmed by repeat 
central laboratory measure 30 days and preferably within 60 days).

Doubling of serum creatinine: from the baseline average determination (sustained and 
confirmed by repeat central laboratory measure 30 days and preferably within 60 days).

Renal death: death in subjects who have reached ESKD, die without initiating renal 
replacement therapy, and no other cause of death is determined via adjudication.

CV death: death due to MI, stroke, heart failure, sudden death, death during a CV procedure 
or as a result of procedure-related complications, presumed sudden CV death, death of 
unknown cause, or death resulting from a documented CV cause other than those listed 
above (eg, aneurysm, peripheral vascular disease [PVD]). Detailed information can be found 
in the IEAC charter.
Confirmatory data for all potential study endpoints will be collected from study investigators and 
will be adjudicated in a blinded fashion by the IEAC.
Secondary Efficacy Outcomes
The secondary efficacy outcomes are reduction in the composite endpoint of CV death and 
hospitalized congestive heart failure, the composite endpoint of CV death, non-fatal MI, and 
non-fatal stroke (ie, 3-point MACE); hospitalized congestive heart failure; the renal composite 
endpoint of ESKD, doubling of serum creatinine, and renal death; CV death; all-cause death; and 
the CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive 
heart failure, and hospitalized unstable angina.
The definitions for each component of the secondary outcomes where not listed above are 
defined in the IEAC charter.
Confirmatory data for the CV composite endpoint will be collected from study investigators and 
will be adjudicated in a blinded fashion by the IEAC.
Exploratory Efficacy Outcomes 
The exploratory efficacy outcomes are reduction in the composite endpoint of ESKD and renal 
or CV death, and reductions in the individual components of the renal and cardiovascular 
composite endpoints (ie, ESKD, doubling of serum creatinine, renal death, CV death, fatal or 
non-fatal MI, fatal or non-fatal stroke, hospitalized congestive heart failure, hospitalized unstable 
angina), as well as changes in eGFR and albuminuria over time.
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9.5.
Safety Evaluations and Outcomes
9.5.1.
Safety Evaluation
Safety and tolerability evaluations, according to the time points provided in the Time and Events 
Schedule, will include the collection of adverse events, safety laboratory tests (including 
chemistry, hematology, and urinalysis), vital signs (pulse, blood pressure), physical examination, 
and body weight.
Adverse Events
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 (GCP), 
and retained at the study sites. All adverse events will be recorded on an eCRF.
Note: For purposes of reporting serious adverse events in this study, non-fatal endpoint events 
that are adjudicated to be components of the primary or secondary endpoint will not be a subject 
to immediate or expedited serious adverse experience reporting requirements (refer to 
Section 12, Adverse Event Reporting).
Adverse Events of Interest and Collection of Additional Information for Adverse Events of 
Interest
For adverse events of interest (see Section 12, Adverse Event Reporting), investigators will be 
asked to provide additional information and documentation to support a detailed assessment. 
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).
Information pertaining to adverse events of interest will be recorded on supplemental case report 
forms.
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 endpoint is reached, or until further follow up is no longer considered by 
the investigator to provide clinically meaningful information. (See Section 9.1.4, Post-Treatment 
Follow-up, for details of follow-up required). 
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.
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General standards for management of hyperkalemia should be applied in case of an elevation in
serum potassium. 
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 
eCRF.
Blood pressure will be measured 3 times in both arms at the screening visit; if there is a 
difference between arms of >10 mmHg in either the mean systolic or diastolic pressure, the arm 
with the higher pressure should be used to measure blood pressure and should be used for all 
subsequent blood pressure measurements during the study. 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.
Guidance for the management of subjects who experience a volume depletion adverse event 
(eg, hypotension, hypovolemia) or a meaningful change in eGFR will be provided in a separate 
document (see Section 15, Study Specific Materials).
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.
Physical Examination
Full physical examination will be performed at the run-in Week -2 visit, and will include a full 
review of body systems (vital signs, as below, head and neck, eyes, chest and lungs, breast, CV, 
extremities and back, abdomen, and neurological examination). A pelvic/genitourinary system 
examination (ie, rectal and prostate or gynecologic examinations) should be performed if 
considered clinically appropriate by the investigator.
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Focused physical examination will be performed at the follow-up visits occurring at Week 52, 
and every 52-weeks thereafter, and will include targeted examinations based on the subject’s 
specific complaints, signs or symptoms of a disease.
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 12.3.3, 
Pregnancy, for instructions in cases of a positive pregnancy test).
9.5.2.
Safety Outcomes
The safety outcomes include the overall safety and tolerability of canagliflozin. 
Modified Rankin Scale
For subjects who experience a stroke, the modified Rankin Scale assessment will be conducted 
through a structured interview during an in-clinic visit approximately 3 months after the event. 
For events occurring at the end of the study (GTED) this evaluation should occur at least 
1 month after the onset of the stroke. In a situation when a subject with a recent stroke would not 
be able to attend an in-clinic visit, the structured interview may be conducted over the phone 
with either the subject or a caregiver. A pre-stroke modified Rankin Score will be retrospectively 
assessed and captured in the eCRF to assist with determining a pre-existing degree of impairment 
associated with a prior stroke or other disability. The modified Rankin Scale assessment form is 
provided in Attachment 6.
9.6.
Pharmacogenomic Evaluations
DNA samples will be analyzed if it is hypothesized that this may help resolve issues with the 
clinical data. 
DNA samples will be used for research related to diabetes or diabetic nephropathy. They may 
also be used to develop tests/assays related to canagliflozin and diabetic nephropathy. 
Pharmacogenomic research may consist of the analysis of one or more candidate genes or of the 
analysis of genetic markers throughout the genome (as appropriate) in relation to canagliflozin or 
diabetic nephropathy clinical endpoints.
This pharmacogenomic evaluation is optional and will only be performed in subjects who give 
informed consent for this specific component of the study and where local regulations permit.
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9.7.
Exploratory Biomarker Evaluations
A set of fasting plasma, serum, and urine samples will be collected (where local regulations 
permit) at the time points specified in the Time and Events Schedule for the following:

Exploratory analysis that may be done to provide insight into the actions of canagliflozin or 
assist in understanding of adverse events possibly associated with the compound. Samples 
may also be used for future exploratory research to improve understanding of the 
pathophysiology of T2DM, diabetic nephropathy, or to assess other pharmacodynamic 
effects of canagliflozin, and

To develop biomarkers that may provide further understanding regarding the risk of 
development of diabetes-related complications. 
This exploratory evaluation is optional and will only be performed in subjects who give informed 
consent for this specific component of the study.
10.
SUBJECT COMPLETION, PREMATURE DISCONTINUATION OF 
TREATMENTINTERVENTION, OR WITHDRAWAL FROM THE STUDY 
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 after the sponsor announces the projected 
GTED and when the GTED actually occurs. Subjects who continue on the study treatment up to 
the projected GTED notification date will continue administering the study drug until the final 
on-site visit (ie, the end of treatment visit/end of study visit). It will be important for sites to 
schedule the last on-treatment visit as soon as possible after being notified of the projected 
GTED. The post-treatment follow up telephone contact should occur approximately 30 days after 
the final on-site visit and must occur prior to the GTED. Subjects who discontinue study drug 
treatment early will also have a final on-site visit as soon as possible after announcement of the 
projected GTED and preferable 30 days before the GTED. Subjects who die prior to the GTED 
are followed until the time of death. The occurrence of a non-fatal renal or CV endpoint, or any 
other safety or efficacy outcome does not comprise study completion and is not a criterion for 
subject withdrawal from the study. 
10.2.
Study Drug Treatment Premature Discontinuation and Reinstitution
10.2.1.
Study Drug Treatment Premature Discontinuation
A subject should 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 interrupted based upon 
a positive urinary hCG, and permanently discontinued if confirmed by a serum -hCG test)

The subject initiates chronic dialysis or renal transplantation
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Note: The requirement for chronic dialysis or renal transplantation are the only endpoints  
for which treatment with double-blind study drug should be discontinued.

The subject is currently using 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 subsequent study 
visits and post treatment follow-up evaluations (see Section 9.1.4, Post-Treatment Follow-up, 
and the Time and Events Schedule). Treatment should be recommenced wherever possible and 
routinely considered at every visit following discontinuation (see Section 10.2.2, Reinstitution of 
Treatment With Study Drug That Has Been Interrupted).
Note: Double-blind study drug should be permanently discontinued for any subject who 
experiences a serious adverse event of biochemically-confirmed DKA, has his/her treatment
allocation formally unblinded by the investigator, or undergoes a renal transplant or initiates
maintenance dialysis.     
Subjects who decide to discontinue double-blind study drug must be interviewed by the 
investigator so as to determine if a specific reason for discontinuing study drug can be identified. 
Subjects should be explicitly asked about the contribution of possible adverse events to their 
decision to discontinue study drug, and investigators should confirm that any adverse event 
information elicited has been documented. If a subject elects to discontinue study drug due to an 
adverse event, the event should be recorded as the reason for study drug discontinuation, even if 
the investigator’s assessment is that the adverse event would not require study drug 
discontinuation. The reason for study drug discontinuation is to be documented in the eCRF and 
in the source documentation. Study drug assigned to the discontinued subject may not be 
assigned to another subject. Subjects who discontinue study drug treatment will not be replaced.
10.2.2.
Reinstitution of Treatment With Study Drug That Has Been 
Interrupted 
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 when it is safe to do so, unless there is a clear 
contraindication at the discretion of the investigator and 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.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
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
Death

Lost to follow-up

Withdrawal of consent
For subjects withdrawing from the study before study completion, an early withdrawal 
evaluation should be performed as soon as possible after stopping the study drug. Refer to the 
Time and Events Schedule for procedures to be conducted at the end-of-treatment/early 
withdrawal evaluation. 
10.3.1.
Lost to Follow-up
If a subject is lost to follow-up, all reasonable efforts must be made by the study site 
personnel to contact the subject and to determine endpoint status and the reason for 
discontinuation/withdrawal. This should include repeated telephone calls, certified letters, 
email requests, etc. To ensure access to follow-up subjects, the study sites should attempt to 
obtain both primary and secondary telephone contact numbers (eg, home, work, and mobile 
phone numbers), as well as other contact information (eg, email addresses) from subjects before 
randomization. In addition, the study site should emphasize the importance of follow-up 
information to the subject before randomization. The measures taken to obtain follow-up 
information must be documented.
10.3.2.
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.
Unless consent is specifically withdrawn, subjects are expected to be followed up through one of 
the alternative follow-up mechanisms discussed in Section 10.4, Circumstances for Reduced 
Follow-up.
Subjects who wish to withdraw from the study should be asked if they are agreeable to be 
contacted to obtain post-study drug follow-up information. Subjects who are not agreeable to 
follow-up contact will be withdrawn from the study as “withdrawal of consent, not agreeable to 
follow-up” on the End of Study eCRF. Subjects who no longer wish to take study drug but agree 
to provide follow-up information will be noted as “Subject discontinued for personal reasons” on 
the End of Treatment eCRF (refer to Section 10.2.1, Study Drug Treatment Premature 
Discontinuation for details). The recording of withdrawal of consent in the eCRF for this trial 
should only occur after a discussion between the investigator and the appropriate sponsor 
representative has taken place.
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 study site should document and sign the reason for the subject’s failure to 
withdraw consent in writing and maintain it with the subjects source records.
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When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
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 Institutional Review Board (IRB) or Independent Ethics Committee (IEC).
A subject who withdraws from the study will have the following options regarding the optional 
research samples:

The collected samples will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research samples, in which case the samples 
will be destroyed and no further testing will take place. To initiate the sample destruction 
process, the investigator must notify the sponsor study site contact of withdrawal of consent 
for the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the sponsor that the 
samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research samples will be destroyed and no further testing will take 
place. The sample destruction process will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study; no further testing will take 
place. Details of the sample retention for research are presented in the main ICF and in the 
separate ICF for optional research samples.
10.4.
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 9.1.5, 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 
study 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 
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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 renal and 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 study 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 study site where a new study doctor will consult with family members, the 
subject’s physicians and medical records, or public records, including the use of locator agencies 
as permitted by local law, to determine the subject’s endpoint status.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor, and also by 
the ARO. A general description of the statistical methods to be used to analyze the efficacy and 
safety data is outlined below. Specific details will be provided in the Statistical Analysis Plan
(SAP).
11.1.
Analysis Sets
The ITT analysis set includes all subjects who are randomly assigned to a treatment group. The 
assessment of the primary and secondary objectives will be based upon this analysis set. 
The safety analysis set includes all randomized subjects who receive at least one dose of double-
blind study medication. The safety analysis will be based on this analysis set.
11.2.
Sample Size Determination
This is an event driven study. A total of approximately 4,200 subjects will be randomized to 
either canagliflozin 100 mg or matching placebo group in a 1:1 ratio. The study aims to observe 
occurrences of the primary efficacy event in 844 unique randomized subjects, on or before the 
GTED, to have 90% power to detect a 20% relative risk reduction (RRR, defined as one minus 
hazard ratio) accounting for the effect of treatment discontinuation on the primary endpoint at
5%, 2-sided significance level. 
The above sample size calculation is estimated based on the following additional assumptions
(ADVANCE 2008; Class 2011; Packham 2012; Amin 2013):

Event rate for the composite endpoint in the placebo arm: 6.5% per year

Premature treatment discontinuation rate: 6% per year

Overall lost-to-follow-up: 1% 

Duration of enrollment period: 27 months 

Duration of study (from first subject randomized to last end of study visit): estimated to be 
60 months
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11.3.
Efficacy Analyses
11.3.1.
Primary Efficacy Analysis
The primary efficacy measure will be the time from randomization to the first occurrence of 
composite endpoint events of ESKD, doubling of serum creatinine, and renal or CV death. The 
date of onset for events of doubling of serum creatinine that are confirmed by the central 
laboratory 30 days (and preferably within 60 days) will be the date that the first doubling from 
baseline average determination is detected from local or central laboratory determinations. The 
baseline value will be determined using the average of 2 pretreatment measures preferably no 
more than 4 weeks apart.
The comparison of the treatment groups will be assessed by means of a stratified Cox 
proportional hazard model with terms of treatment and strata defined by pretreatment eGFR
(30 to <45, 45 to <60, 60 to <90 mL/min/1.73m2). The primary analysis will be based on the 
ITT analysis set up to the GTED. Subjects will be analyzed according to the treatment group that 
they are randomized, regardless of actual treatment received.
Estimates of RRR, hazard ratio and the corresponding 95% CI will be derived from the model. 
Kaplan-Meier estimates for the event curve will be provided for the 2 treatment groups.
In addition, ratios of cause-specific hazards between the treatment groups will be obtained for 
each component of the primary efficacy composite endpoint (ESKD, doubling of serum 
creatinine, renal death, or CV death), with stratification of the baseline hazard by pretreatment 
eGFR group as in the analysis of the primary efficacy composite endpoint. Sensitivity analysis
using a stratified log-rank test will be conducted to assess the robustness of the primary efficacy 
analysis. 
Extensive efforts will be made to collect complete data for all subjects randomized in this study. 
Subjects will be followed up to the end of the study and will complete all required data 
collection, regardless of their compliance with study drug or visits. For subjects who are lost to 
follow up or withdraw consent, efforts will be made to obtain their vital status at the end of study 
from permitted sources.
Efforts will be made to clean up the missing or partially missing event date for primary and 
secondary efficacy endpoints, as well as key safety endpoints, before database lock. Imputation 
rules for the missing or partially missing date will be specified in the SAP.
11.3.2.
Secondary Efficacy Analyses
The time from randomization to the first occurrence of the secondary endpoint events will be 
analyzed separately in a similar fashion as the primary analysis. If superiority of canagliflozin 
100 mg over placebo in reducing the risk of the primary efficacy endpoint is established, the 
treatment effects in secondary endpoints will be tested subsequently in the following hierarchical 
order:

The composite endpoint of CV death and hospitalized congestive heart failure
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
The composite endpoint of CV death, non-fatal myocardial infarction (MI), and non-fatal 
stroke (ie, 3-point MACE)

Hospitalized congestive heart failure

Renal composite endpoint of ESKD, doubling of serum creatinine, and renal death

CV death

All-cause death

CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive 
heart failure, and hospitalized unstable angina
Statistical significance is required before testing the next hypothesis in the hierarchical test 
procedure.
11.3.3.
Exploratory Efficacy Analyses
The time from randomization to the first occurrence of composite endpoint events of ESKD and 
CV death or renal death will be analyzed by a method similar to that used for the primary 
efficacy analysis.
For on-treatment eGFR measurements, a linear mixed effects model will be fitted to eGFR as a 
dependent variable, including treatment, stratification factor, 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. 
Similar modeling analysis will be performed for UACR. Since the distribution of UACR value is 
highly skewed, log transformation of UACR values will be made prior to the modeling. 
When the trial is fully recruited, the baseline characteristics of the subjects will be examined.
Additional covariates can be considered in exploratory analyses. A more detailed description of 
the analyses for all outcomes will be pre-specified in the SAP for this study.
11.3.4.
Multiplicity Adjustment
A closed testing procedure will be implemented to control the overall type I error at 5% for 
primary and secondary endpoints as described in Section 11.3.2, Secondary Efficacy Analyses.
11.3.5.
Interim Analysis
An interim analysis will be conducted when the primary efficacy (adjudicated) events have been 
observed in approximately 405 subjects. The analysis method for primary efficacy endpoint 
described in Section 11.3.1, Primary Efficacy Analysis, will be used for the interim analysis. In 
addition, if the conditional power (based on the assumption that the hazard ratio in the remaining 
study is 0.80) is 10% or lower, the study may be stopped for futility. The alpha spending function
will be used and the alpha spent in the interim analysis is 0.01. Detailed stopping guideline will 
be specified in the Interim Analysis Plan.
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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. 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 all adverse events, as well as laboratory results, and other safety and tolerability 
measurements. 
Adverse Events of Interest
For adverse events of interest (see Section 9.5.1, Safety Evaluation), treatment differences in 
incidence rates and corresponding 95% CI will be provided, and the Kaplan-Meier plots for the
event curve by treatment group will also be generated. 
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. 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.
Further analyses will be described in the SAP for this study, including analyses of prespecified 
adverse events for which additional information is collected from the investigators (see
Section 9.5.1, 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 
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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.
Adverse Events of Interest
For adverse events of interest, investigators will be asked to provide additional information. 
Adverse events of interest include all malignancies,  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, lower extremity events, and pregnancy. 
Adverse Events and Procedures Requiring Reporting Within 24 Hours
Ketone-related events (eg, DKA, ketoacidosis, metabolic acidosis, or acidosis) and pancreatitis 
events have been designated an adverse event of special interest and 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. Events with characteristics suggestive of DKA or 
pancreatitis will be adjudicated by an ad hoc adjudication committee, to verify whether or not the 
event meets a specified definition within the adjudication committee charters. These adverse 
events must be recorded on the supplemental Diabetic Ketoacidosis and Ketone-related Events or 
Pancreatitis eCRF to complement standard information collected on the eCRF AE/SAE page. 
In addition, all lower-extremity amputation procedures are considered adverse events of special 
interest and need to be reported to Janssen within 24 hours of becoming aware of the procedure. 
The underlying condition leading to the lower-extremity amputation must be recorded on the 
supplemental Lower-Extremity Event eCRF to complement standard information collected on 
the AE/SAE eCRF, and the details relating to the amputation procedure must be recorded on the 
Lower-Extremity Amputation eCRF.
Additional information and documentation will be requested from investigators to support a 
detailed assessment of all deaths. Investigators may also be asked to provide additional 
information on other adverse events, based upon review by the MSRC. 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. Some events 
will be subject to adjudication by an ad hoc adjudication committee to standardize the 
diagnosis.
12.1.
Adverse Events as Study Efficacy Endpoints 
All deaths and events that are assessed by the investigator as being one of the components of the 
primary or secondary composite endpoints (ie, ESKD, doubling of serum creatinine, renal death, 
or CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, hospitalized 
unstable angina, all-cause death) should be handled as follows:
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Investigator Responsibilities:
All deaths, renal and CV endpoint events must be reported to the sponsor within 24 hours of 
knowledge of the event. Investigators are also required to submit a specific package of 
information on all such possible events for adjudication; details on assembly and submission of
adjudication packages will be provided in an Adjudication Manual.
Sponsor Responsibilities:
All study endpoint events (ie, ESKD, doubling of serum creatinine, renal death, CV death, 
non-fatal stroke, non-fatal myocardial infarction, hospitalized unstable angina, hospitalized 
congestive heart failure, or all-cause death) will be submitted blinded to the IEAC for 
adjudication. To protect the integrity of the trial, these events that are adjudicated to be 
components of the primary or secondary endpoints will not be unblinded or reported to either 
Health Authorities (HAs) or investigators as safety reports unless otherwise requested by HAs or 
Ethics Committees. After study completion, these events will be included in the final analysis 
which will be unblinded and submitted to HAs with the study report. 
Serious non-fatal events that are adjudicated as not being components of the primary or 
secondary endpoints and are considered possibly, probably, or definitely related to study drug by 
the investigator, will be subject to reporting requirements to HAs, and will be unblinded where
required by local regulations. Such events will be reported blinded to the investigator when and 
where possible. The reporting timeline starts when the IEAC notifies the sponsor of the decision. 
Detailed information for standard reporting of serious adverse events can be found in 
Section 12.3.1, All Adverse Events, and Section 12.3.2, Serious Adverse Events.
Table 1 summarizes the reporting process for serious unexpected and related events.
Table 1:
Reporting of Serious Unexpected and Related Events (Unless Otherwise 
Requested by Health Authorities or Ethics Committees)
Event Type
Expedited Report to 
Health Authorities
and Investigators
Unblinding to 
Health Authorities
Unblinding to 
Investigators
Study endpoint event
N
N
N
Non-endpoint event
Y
Y
N
12.2.
Definitions
12.2.1.
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 
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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 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
See above for handling of components of the composite efficacy endpoint other than renal or CV 
deaths.
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use 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

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
* Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the outcomes listed in the definition above. These 
should usually be considered serious.
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 canagliflozin, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure.
Adverse Event 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 12.2.2, Attribution Definitions.
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12.2.2.
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).
12.2.3.
Severity Criteria
Mild: Awareness of symptoms that are easily tolerated causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the intensity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events, whether serious or non-serious, will be reported from the time a signed and 
dated informed consent form is obtained until completion of the study, ie, GTED (including 
subjects who discontinue study drug treatment). 
Data will be collected in source documents and on the eCRF for all adverse events.
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All deaths will also be recorded.
For adverse events of interest (see Section 9.5.1, Safety Evaluation), a supplemental reporting 
form will be used to collect additional information. Investigators may be asked to provide 
additional information on adverse events, based upon review by the MSRC or the IDMC.
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using a Serious Adverse Event Form, which 
must be completed and signed by a member of the study-site personnel, 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. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
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 the sponsor’s
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 subjects 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 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 subjects, 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. However, consider 
withdrawal of other antihypertensive agents prior to adjusting dose of ACE inhibitors or ARBs.
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The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The reporting process for adverse events as study efficacy endpoints is described in 
Section 12.1, Adverse Events as Study Efficacy Endpoints. The reporting process for other 
serious adverse events that are unlisted (unexpected) and associated with the use of the drug is 
described in Section 12.3.2, Serious Adverse Events. 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 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.
12.3.2.
Serious Adverse Events
Reporting process for all deaths and serious adverse events that are assessed by the investigator 
as being one of the components of the primary or secondary composite endpoints can be found in 
Section 12.1, Adverse Events as Study Efficacy Endpoints.
Reporting process for serious adverse events occurring during the study that are assessed by 
investigator as not a primary or secondary efficacy endpoint, or serious adverse events that are 
adjudicated as not meeting charter-specified event definitions by the IEAC is outlined below.
These serious adverse events must be reported to the appropriate sponsor contact person by 
study-site personnel within 24 hours of their knowledge of the event.
Information regarding these serious adverse events will be transmitted to the sponsor using the 
Serious Adverse Event Form, which must be completed and signed by a member of the 
study-site personnel, and transmitted to the sponsor within 24 hours. The initial and follow-up 
reports of a serious adverse event should be made by facsimile (fax). 
Events that are adjudicated as not meeting with charter-specified event definitions by the IEAC
will be subject to standard reporting requirements, but the reporting time limit will start when the 
sponsor learns that the event is not a renal or CV component event for the composite efficacy 
outcomes as per the IEAC.
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 the 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
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
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)
Any event occurring during the study that is assessed by the investigator as not a primary or
secondary efficacy endpoint, or that is adjudicated as not meeting charter-specified event 
definitions by the IEAC, requiring hospitalization (or prolongation of hospitalization) 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.
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, and congenital anomalies, ectopic pregnancy) are considered 
serious adverse events and must be reported using the Serious Adverse Event Form. Any subject 
who becomes pregnant during the study must immediately discontinue further study treatment.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
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.
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13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, 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 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. A list of 
excipients can be found in the IB.
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 
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 study 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 Clinphone drug 
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accountability module in the IWRS system. 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. Study-site personnel must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label and 
must be stored at the study site in a limited access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug and partially used study drug returned by the 
subject (if applicable), must be available for verification by the sponsor’s or sponsor-delegated 
study 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 study 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 study-site personnel, 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 study 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

The IWRS manual and worksheets

eCRF completion guidelines

Study binder with all other necessary documentation (eg, protocol, IB, clinical trial 
agreement)

Manual of instructions regarding renal or CV events, documentation required, and 
adjudication-related procedures

Guidance for Management of Volume Depletion Adverse Events or eGFR Changes 

ADA Standards of Medical Care in Diabetes

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
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16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The goal of this study is to assess whether canagliflozin has a renal and vascular protective effect 
in reducing the progression of renal impairment in subjects with T2DM, Stage 2 or 3 CKD and 
macroalbuminuria, who are receiving standard of care for glycemic control as well as maximum
tolerated labeled daily dose of ACEi or ARB. 
This double-blind, placebo controlled study does not impose an increased risk of failing to 
achieve optimal glycemic control, as the study design allows adjustment of background AHA 
therapy to take place at any time during the course of the study. Before randomization and 
throughout the study, investigators will be expected to manage all subjects’ diet/exercise and 
background medication regimens so as to achieve goals for controlling Stage 2 or 3 CKD and 
CV risk factors (eg, HbA1c, lipid levels, blood pressure) based upon standard guidelines for the 
care of subjects with T2DM and Stage 2 or 3 CKD. 
Diabetic kidney disease in all subjects enrolled in this study will be managed based on the 
standards of care, according to established local and regional guidelines: All subjects will be 
treated with either ACE inhibitors or ARBs and maintain stable blood pressure, unless there is a 
clinical indication for adjustment. An IDMC is commissioned for this study to review unblinded 
safety information on a periodic basis during the study and an interim analysis is planned when 
the primary efficacy events have been observed in approximately 405 subjects. Significant 
differences in renal protection effect between canagliflozin and placebo (eg, futility or 
overwhelming evidence of efficacy) will result in changes in the trial proceedings. 
Potential subjects will sign an informed consent form before any study-related procedures are 
performed. These subjects will be informed of the risks and requirements of the study and, 
during the study, 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.
The potential risks in the present study include exposure to study drug, with the potential for side 
effects (Section 1.1.2.5, 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, Independent Data Monitoring Committee, an IDMC is commissioned for this 
study to review unblinded safety information on a periodic basis during the study. 
Hypoglycemia is a common adverse event in patients with T2DM. Treatment with canagliflozin 
alone or in combination with other AHAs not associated with hypoglycemia in Phase 2 and 
Phase 3 studies lead to a low incidence of hypoglycemia with no increase in incidence of severe 
hypoglycemia. This is likely based upon the observation that the renal threshold for glucose 
(lowered to approximately 90-100 mg/dL [5.0-5.6 mmol/L] in subjects with T2DM) is not 
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lowered below the usual hypoglycemia threshold (considered as 70 mg/dL [3.9 mmol/L])—
hence even if the steady-state glucose was to decrease to the level of the renal threshold, 
hypoglycemia would not be expected with canagliflozin alone or in combination with other 
AHAs not associated with hypoglycemia, such as metformin in this study. Nonetheless, subjects 
will be routinely monitored with fingerstick glucose levels, and reports of potential episodes of 
hypoglycemia will be carefully collected and evaluated.
Amputations have been designated as adverse events of special interest and will be managed 
based on standard diabetes treatment guidelines.
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. They will 
be measured more frequently at the beginning of the double blind treatment (ie, Day 1, Week 3, 
Week 13, Week 26) and then every 26 weeks thereafter until the end of the study. 
For a subject who completes the study (including all procedures outlined in the pretreatment and 
double-blind treatment phases over approximately 5 to 5.5 years), the total blood volume to be 
collected will be approximately 340 mL, with the maximum amount collected in a single visit 
being approximately 40 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).
This study was designed based on the guidelines for the identification and management of kidney 
disease (NICE 2008; NKF 2012), in general accordance with the US FDA and EMA guidance on 
the development of medications and clinical investigations for the treatment and prevention of 
diabetes mellitus (FDA 2008; EMEA 2012) and in consultation with Health Authorities. This 
study will be conducted under U.S. FDA IND regulations intended for a new indication of 
“Treatment of renal disease in adult patients with type 2 diabetes mellitus, reduced eGFR, and 
albuminuria”. 
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
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16.2.2.
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB)
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved informed consent form (and any other written materials to be provided to 
the subjects)

Investigator’s Brochure (or equivalent information) and amendments

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any), 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.
For participating centers, approval for the collection of optional samples for research and for the 
corresponding ICF must be obtained from the IEC/IRB. Approval for the protocol can be 
obtained independent of this optional research component. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments

Revision(s) to informed consent form and any other written materials to be provided to 
subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

Investigator’s Brochure amendments or new edition(s)

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)
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
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 study 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. A consent form must be signed before performing any 
study-related activities. For subjects who require additional local laboratory assessment solely 
for the purpose of prescreening, either the optional prescreening-specific or full informed 
consent must be obtained. The prescreening-specific informed consent is an abbreviated form of 
the full document that focuses on the risks associated with the prescreening-specific laboratory 
assessments and provides general information about the study without detailing study procedures 
and the potential benefits/risks associated with participating in the study. If an optional 
prescreening-specific informed consent is obtained, and the subject is eligible to enter the 
screening period, the full informed consent must be obtained before screening is initiated. 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 study-site 
personnel 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 
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affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the informed consent form the subject is authorizing such access, and agrees to allow his 
or her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, if needed, or to obtain information about his or her survival status.
The subject will be given sufficient time to read the informed consent form and the opportunity 
to ask questions. After this explanation and before entry into the study, consent should be 
appropriately recorded by means of the subject's personally dated signature. After having 
obtained the consent, a copy of the informed consent form must be given to the subject.
After informed consent for the study is appropriately obtained, subjects will be asked to provide 
consent for optional samples (blood and urine) for research (where local regulations permit). 
Refusal to participate in the optional research will not result in ineligibility for the study. A copy 
of this signed ICF will 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 
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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.
Exploratory DNA or biomarker research is not conducted under standards appropriate for the 
return of data to subjects. In addition, the sponsor cannot make decisions as to the significance of 
any findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (according to local regulations) 
for additional research. Samples may be used to understand effect of canagliflozin on diabetic 
nephropathy, to understand differential drug responders, and/or to develop tests/assays related to 
canagliflozin in diabetic nephropathy. The research may begin at any time during the study or the 
post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3.2, Withdrawal of Consent).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to help ensure access to 
the developed product.
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 
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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 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations) written 
IEC/IRB approval of the protocol, amendments, informed consent form, any recruiting 
materials, and if applicable, subject compensation programs. This approval must clearly 
identify the specific protocol by title and number and must be signed (or sealed, where 
appropriate per local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

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
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
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. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the study 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.
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Designated study-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.
The investigator must verify that all data entries in the eCRFs are accurate and correct.
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 study-site personnel must adjust the eCRF (if 
applicable) and complete the query. A query is generally to be answered within 5 days of 
generation of the query 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:

Study 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)

Study site manager can generate a query for resolution by the study-site personnel

Clinical data manager can generate a query for resolution by the study-site personnel
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, handling, storage 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.
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the clinical study database they will be 
verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
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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 CRO 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 study 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 study-site personnel and are accessible for verification by 
the sponsor site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel. 
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 study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit/contact of the last subject participating in 
the study. The final data from the study site will be sent to the sponsor (or designee) after 
completion of the final subject visit/contact at that study site and in the time frame specified in 
the clinical trial agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
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study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-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 a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study 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 study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding canagliflozin or the sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker 
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 complete 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.
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The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study 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 for the study. Results of 
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report 
has been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report. Study subject identifiers will not be used in publication of results. Any work 
created in connection with performance of the study and contained in the data that can benefit 
from copyright protection (except any publication by the investigator as provided for below) 
shall be the property of the sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the Steering Committee shall have the right to publish such primary 
(multicenter) data and information without approval from the investigator. The investigator has 
the right to publish study site-specific data after the primary data are published. If an investigator 
wishes to publish information from the study, a copy of the manuscript must be provided 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, 
secondary results generally should not be published before the primary endpoints of a study have 
been published. Similarly, investigators will recognize the integrity of a multicenter study by not 
submitting for publication data derived from the individual study site until the combined results 
from the completed study have been submitted for publication, within 12 months of the 
availability of the final data (tables, listings, graphs), 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 ICMJE Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which state 
that the named authors must have made a significant contribution to the conception or design of 
the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 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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blood glucose concentration in subjects with type 2 diabetes - results of a hyperglycaemic glucose clamp study. 
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Ridker PM (2004), Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers 
in the prediction of first atherothrombotic events. Circulation;2004; 109(25 Suppl 1):IV6-19.
Seifter J (2005), Sloane D, Rather A: Concepts in Medical Physiology. Lippincott Williams & Wilkins, 2005.
Shi J (2004) et al. Pharmacokinetics and safety of the ketolide telithromycin in patients with renal impairment. 
J Clin Pharmacol 2004; 44: 234-44.
Thomson SC (2012), Rieg T, Miracle C, et al. Acute and chronic effects of SGLT2 blockade on glomerular and 
tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302:R75-R83.
Turin TC (2012), Coresh J, Tonelli M, et al. Short-term change in kidney function and risk of end-stage renal 
disease. Nephrol Dial Transplant. 2012;27:3835-43.
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Turin TC (2013), Coresh J, Tonelli M, et al. Change in the estimated glomerular filtration rate over time and risk of 
all-cause mortality. Kidney International. 2013;83:684-91.
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.
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.
Viberti G (2002), Wheeldon NM; Microalbuminuria Reduction with Valsartan (MARVAL) Study Investigators. 
Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent 
effect. Circulation. 2002;106:672-678.
Wright EM (2001). Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 2001;280:F10-F18.
Zatz R (1985), Meyer TW, Rennke HG, Brenner BM. Predominance of hemodynamic rather than metabolic factors 
in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A 1985;82:5963–5967.
Zhang Y (2009), et al. Assessment of the impact of renal impairment on systemic exposure of new molecular
entities: evaluation of recent new drug applications. Clin Pharmacol Ther. 2009;85:305-311.
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Attachment 1: Clinical Laboratory Tests
Blood samples for serum chemistry and hematology, and a 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

Follicle-stimulating hormone only for women >45 years of age who have had amenorrhea for at least
6 months and less than 18 months before screening

Fasting serum lipid profile (triglycerides, low-density lipoprotein cholesterol [LDL-C], high-density 
lipoprotein cholesterol [HDL-C], total cholesterol)*. 

HbA1c

Fasting plasma glucose*

Urinalysis
Dipstick done at central laboratory
-specific gravity
-pH
-protein
-blood
-ketones
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, microscopic examination will be performed.

Urine pregnancy testing, unless a serum pregnancy test is preferred at the discretion of the 
investigator or if required by local regulations, for all women unless they are surgically sterile or 
unless there is a documented history of their postmenopausal status
*Subjects must be fasting for at least 8 hours before blood sample collections.
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
Estimated Glomerular Filtration Rate (eGFR)

The estimated glomerular filtration rate (eGFR) will be reported according to the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation** at study visits when serum 
creatinine is measured. The CKD-EPI equation based on serum creatinine, age, sex, and race for 
adults age 18 years expressed as a single equation is: 
CKD-EPI Formula (for Scr expressed in mg/dL) 
eGFR = 141 × min (Scr /, 1)α × max(Scr /, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
= 0.7 for females 
= 0.9 for males 
= -0.329 for females
= -0.411 for males
min =  the minimum of Scr/or 1
max =  the maximum of Scr/or 1
CKD-EPI Formula (for Scr expressed in mol/L) 
eGFR = 141 × min (Scr /, 1)α × max(Scr /, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
= 61.9 for females 
= 79.6 for males 
= -0.329 for females
= -0.411 for males
min = the minimum of Scr/or 1
max = the maximum of Scr/or 1
**Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van 
Lente F, Greene T, Coresh J. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.
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Attachment 2: New York Heart Association Classification of Cardiac Disease
The following table represents the New York Heart Association classification of cardiac disease:
Functional capacity
Objective assessment
Class I. Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain
A. No objective evidence of 
cardiovascular disease
Class II. Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain
B. Objective evidence of minimal 
cardiovascular disease
Class III. Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
C. Objective evidence of moderately 
severe cardiovascular disease.
Class IV. Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
D. Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.
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Attachment 3: Volume of Blood to be Collected From Each Subject During First Year
(including EOT/EW visit)
Volume of Blood to be Collected From Each Subject During First Year (includes EOT/EW visit)
Number of 
additional 
samples every 
year thereafter
Type of Sample
Volume per 
Sample (mL)
No. of 
Samples per 
Subject
Total Volume of 
Blood (mL)a
Hematology
2
3
6
1
Serum chemistry/(FSH x 1)
2.5
6
15
2
Lipid LDL/VLDL
5
3
15
1
HbA1c
2
5
10
2
Biomarkers (serum archive collection)b
8.5
2
17
1
Biomarkers (plasma archive collection)
10
2
20
1
Pharmacogenomic collectionb
10
1
10
0
Approximate Totalc
93
a
Calculated as number of samples multiplied by amount of blood per sample.
b
A blood sample will be collected only from subjects who have consented to provide an optional samples for 
DNA and biomarker research.
c
Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
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Attachment 4: Optional Specimens for Exploratory Research - Sample Collection and Handling
Materials and Labeling

The central laboratory will provide the study site with blood collection tubes, storage tubes, 
preprinted Janssen Research and Development labels (or tubes labeled with preprinted labels), and 
related supplies for the collection and shipment of exploratory samples.

The central laboratory will provide the study site with urine collection containers, storage tubes, and 
preprinted Janssen Research and Development labels (or tubes labeled with preprinted labels), for 
the collection and shipment of urine exploratory samples.

Use of alternative materials will not result in a protocol amendment if preapproved by the 
Bioanalysis Scientist.

Detailed information regarding the collection and storage containers will be provided in the 
laboratory manual from the central laboratory.
Preparation of Exploratory Plasma Samples

Collect one full
blood sample into the appropriate K2EDTA-containing collection tube 
(eg, Vacutainer) provided (10 mL or 5 mL) at the appropriate time point.

Immediately after draw, gently invert the plasma tube 8 times (up-down-up=1 inversion) to 
completely mix tube contents. Place tubes at room temperature, 15C to 25C, until processed.

Record the exact date and time of sampling in the eCRF or laboratory requisition form, as 
appropriate.

Centrifuge blood sample at room temperature within 1 hour of collection in a clinical centrifuge 
according to the specifications in the laboratory manual.

The following steps should be done separately for each blood sample that was collected. Do not 
combine the plasma. Keep aliquots separate.

Immediately after centrifugation, transfer all separated plasma with a clean disposable plastic pipette 
to a prelabeled storage tube. Gently mix the tube by inversion.

Dispense the plasma (0.5 to 1.0 mL aliquots) into 2 pre-labeled microfuge tubes or cryovials 
(1.5- to 2-mL size) and securely cap.

Store the plasma samples in an upright position in a freezer at –70C or colder until transfer to the 
central laboratory. Record the exact time of storage in the eCRF or laboratory requisition form, as 
appropriate. Shipment on dry ice on the day of collection is acceptable if the site does not have a 
freezer at –70C or colder.

The time between blood collection and freezing the plasma must not exceed 2 hours.

Ship specimens on dry ice according to the instructions provided by the central laboratory.

Questions regarding handling the exploratory plasma specimens should be addressed to the contact 
person for the sponsor.

Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis 
Scientist.
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Preparation of Exploratory Serum Samples

Collect one full blood sample into the appropriate plastic collection tube (Serum SST; SST with clot 
accelerator 
and 
gel 
barrier, 
also 
called 
Red 
& 
Black 
Tiger 
top) 
provided 
(8.5 mL or 5 mL) at the appropriate time point.

Immediately after draw, gently invert the serum tube 5 times (up-down-up=1 inversion) to 
completely mix tube contents. Place tube at room temperature, 15°C to 25°C, for a minimum of 
30 minutes or until processed.

Record the exact date and time of sampling in the eCRF or laboratory requisition form, as 
appropriate.

Centrifuge blood sample at room temperature within 45 min of collection in a clinical centrifuge 
according to the specifications in the laboratory manual.
The following steps should be done separately for each blood sample that was collected. Do not combine 
the serum. Keep aliquots separate.

Immediately after centrifugation, transfer all separated serum with a clean disposable plastic pipette 
to a pre-labeled storage tube. Gently mix the tube once by inversion.

Dispense the serum (0.5-1.0 mL aliquots) into 2 pre-labelled microfuge tubes or cryovials (1.5 to 
2 mL size) and securely cap.

Store serum samples in an upright position in a freezer at –70°C or colder until transfer to the 
central laboratory. Record the exact time of storage in the eCRF or laboratory requisition form, as 
appropriate.

Shipment on dry ice on the day of collection is acceptable if the site does not have a freezer at –70°C 
or colder.

The time between blood collection and freezing the serum must not exceed 2 hours.

Ship specimens on dry ice according to the instructions provided by the central laboratory.

Questions regarding handling the exploratory serum specimens should be addressed to the contact 
person for the sponsor.
Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis Scientist.
Preparation of Exploratory Urine Samples

Collect voided urine in the appropriate urine collection container at the time designated in the 
protocol.

Thoroughly mix the urine.

Transfer one 3-mL aliquot into a labeled cryovial.

Store the urine sample in an upright position in a freezer at –70C or colder until transfer to the 
central laboratory. Shipment on dry ice on the day of collection is acceptable if the site does not have 
a freezer at –70°C or colder.

The time between urine collection and freezing should not exceed 1 hour.

Ship specimen on dry ice according to the instructions provided by the central laboratory.

Questions regarding handling the exploratory urine sample should be addressed to the contact person 
for the sponsor.

Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis 
Scientist.
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Attachment 5: Pharmacogenomic Sample Collection and Shipment Procedure
Pharmacogenomic Sample Supplies and Labeling
The central laboratory will provide the investigational site with pre-labeled 10 mL blood collection tubes 
containing potassium or sodium EDTA. Detailed information is provided in the laboratory manual from 
the central laboratory.
Preparation of Pharmacogenomic Samples
Pharmacogenomic samples should be prepared as follows:

Invert the tube 10 to 15 times immediately after collection, to prevent coagulation.

DO NOT centrifuge the sample.

Freeze the samples at or below -20°C in an upright position immediately after collection
Pharmacogenomic Sample Shipment
Once collected, the blood samples must immediately be frozen at or below -20°C in an upright position. 
Samples must remain at this temperature until shipment to the central laboratory. All samples must then 
be shipped with sufficient dry ice to ensure samples remain frozen during shipment. Detailed information 
will be provided in the laboratory manual from the central laboratory.
The following guidelines should be adhered to:

Shipment of the frozen pharmacogenomic blood samples should be arranged with other clinical 
study samples. If this is not possible, a separate shipment for these blood samples should be 
organized, using the courier recommended by the central laboratory.

Notify the courier, at least 24 hours in advance of the planned shipment. Provide the courier with the 
appropriate account number to be used, if applicable.

Package the samples in sufficient dry ice to ensure that the samples remain frozen during shipment.

Label the package with the study number and all other information required by the central 
laboratory.

Include a return address (that includes the investigator’s name) on the outside of each shipping 
container.

Comply with all courier regulations for shipment of biological specimens (include all paperwork).

Retain all documents indicating date, time, and signature(s) of person(s) making the shipment, in the 
study files.

The blood samples should be shipped to the name and address indicated in the central laboratory 
manual.
NOTE: If there are changes regarding the courier or location to which samples are shipped during the 
course of the clinical study, written notification will be provided to the investigator; a protocol 
amendment will not be required.
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Attachment 6: Modified Rankin Scale
MODIFIED
Subject ID:
RANKIN
    Site ID:
SCALE (MRS)
                     Rater:
             Date:         ________________________________
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties and activities
2
Slight disability; unable to carry out all previous activities, but able to look after own
affairs without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to attend to own
bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care and attention
6
Dead
SCORE (0–6):
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INVESTIGATOR AGREEMENT
NCT02065791

SAP_001.pdf: 
1 
Approved, Date: 1 June 2018  
 
Janssen Research & Development  
 
Statistical Analysis Plan 
 
A Randomized, Double-blind, Event-driven, Placebo-controlled, Multicenter Study of 
the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Subjects With 
Type 2 Diabetes Mellitus and Diabetic Nephropathy 
 
Protocol 28431754DNE3001; Phase 3 
 
 JNJ-28431754 (canagliflozin)   
 
Amendment 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Status: 
Approved   
Date: 
1 June 2018 
Prepared by: 
Janssen Research & Development, LLC 
Document No.: EDMS-ERI-85306295, 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. 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
2 
Approved, Date: 1 June 2018  
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
ABBREVIATIONS ........................................................................................................................................ 4 
1. 
INTRODUCTION.................................................................................................................................. 6 
1.1. 
Trial Objectives ................................................................................................................................ 6 
1.2. 
Trial Design ...................................................................................................................................... 7 
1.3. 
Statistical Hypothesis for Trial Objectives ........................................................................................ 8 
1.4. 
Sample Size Justification ................................................................................................................. 9 
1.5. 
Randomization, Blinding, and Stratification ..................................................................................... 9 
2. 
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 10 
2.1. 
Analysis Populations ...................................................................................................................... 10 
2.2. 
Analysis Sets .................................................................................................................................. 10 
2.3. 
Time-to-Event Data ........................................................................................................................ 10 
2.3.1. 
Subject-Level Trial Milestone Dates ........................................................................................... 10 
2.3.2. 
Censoring Rules ......................................................................................................................... 12 
2.4. 
Visit Windows ................................................................................................................................. 12 
3. 
INTERIM ANALYSIS ......................................................................................................................... 13 
4. 
SUBJECT INFORMATION ................................................................................................................ 14 
4.1. 
Baseline Anthropometric and Demographic Characteristics ......................................................... 14 
4.1.1. 
Baseline Disease Characteristics ............................................................................................... 15 
4.2. 
Disposition Information................................................................................................................... 15 
4.3. 
Extent of Exposure and Follow-Up ................................................................................................ 16 
4.4. 
Prior and Concomitant Medications ............................................................................................... 16 
4.5. 
Patient Management of Cardiovascular Risk Factors .................................................................... 17 
5. 
EFFICACY ......................................................................................................................................... 17 
5.1.1. 
Level of Significance ................................................................................................................... 17 
5.1.2. 
Data Handling Rules ................................................................................................................... 17 
5.2. 
Primary Efficacy Endpoint .............................................................................................................. 18 
5.2.1. 
Definition ..................................................................................................................................... 18 
5.2.2. 
Analysis Methods ........................................................................................................................ 18 
5.2.2.1. 
Supportive Efficacy Analyses .................................................................................................. 19 
5.2.2.1. 
Assessment of Model Assumption in the Primary Efficacy Analysis ....................................... 19 
5.3. 
Subgroup Analyses for the Primary Endpoint ................................................................................ 20 
5.4. 
Major Secondary Endpoints ........................................................................................................... 21 
5.4.1. 
Definition ..................................................................................................................................... 21 
5.4.2. 
Analysis Methods ........................................................................................................................ 21 
5.5. 
Multiplicity Adjustment .................................................................................................................... 22 
5.6. 
Other Efficacy Analyses ................................................................................................................. 22 
5.6.1. 
Definition of Exploratory Efficacy Endpoints ............................................................................... 22 
5.6.2. 
Definition of Other Efficacy Endpoints ........................................................................................ 23 
5.6.3. 
Analysis Methods for Other Efficacy Analyses ........................................................................... 23 
6. 
SAFETY ............................................................................................................................................. 24 
6.1. 
Adverse Events .............................................................................................................................. 25 
6.1.1. 
General Adverse Events ............................................................................................................. 25 
6.2. 
Adverse Events of Interest ............................................................................................................. 26 
6.3. 
Modified Rankin Scores for Stroke ................................................................................................ 27 
6.4. 
Hypoglycemia ................................................................................................................................. 27 
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Statistical Analysis Plan 28431754DNE3001; Phase 3  
3 
Approved, Date: 1 June 2018  
6.5. 
Clinical Laboratory Tests................................................................................................................ 28 
6.6. 
Vital Signs ...................................................................................................................................... 29 
REFERENCES ............................................................................................................................................ 30 
ATTACHMENT 1 ........................................................................................................................................ 31 
1. 
DIURETICS ........................................................................................................................................ 32 
1.1. 
Diuretics [loop] ............................................................................................................................... 32 
1.2. 
Diuretics [non-loop] ........................................................................................................................ 33 
ATTACHMENT 2 ........................................................................................................................................ 39 
1. 
MEDICAL HISTORY .......................................................................................................................... 39 
1.1. 
Hypertension .................................................................................................................................. 39 
1.2. 
Dyslipidemia ................................................................................................................................... 39 
1.3. 
Fractures ........................................................................................................................................ 39 
2. 
LIST OF PREFERRED TERMS FOR SELECTED ADVERSE EVENTS OF INTEREST ................ 41 
ATTACHMENT 3 ........................................................................................................................................ 51 
CLINICAL LABORATORY TESTS .............................................................................................................. 51 
ATTACHMENT 4 ........................................................................................................................................ 52 
CRITERIA FOR PRE-DEFINED LIMIT OF CHANGE (PDLC) AND ABNORMAL VALUES ...................... 52 
 
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JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
4 
Approved, Date: 1 June 2018  
ABBREVIATIONS 
ACEi 
angiotensin-converting enzyme inhibitor  
AE 
adverse event 
AHA 
antihyperglycemic agent 
ARB 
angiotensin-receptor blockers 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CI 
confidence interval 
CKD 
CM 
chronic kidney disease  
concomitant medication 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
eGFR 
estimated glomerular filtration rate 
ESKD 
end-stage kidney disease 
GCP 
Good Clinical Practice 
GTED 
global trial end date 
HbA1c 
hemoglobin A1c 
HDL-C 
high-density lipoprotein cholesterol 
IEAC 
Independent Endpoint Adjudication Committee 
IWRS 
Interactive Web Response System 
LDL-C 
low-density lipoprotein cholesterol 
MH 
medical history 
MedDRA 
Medical Dictionary for Regulatory Activities 
ITT 
MACE 
MI 
intent-to-treat 
major adverse cardiovascular event 
myocardial infarction 
PDLC 
pre-defined limit of change 
QD 
once daily 
ROW 
Rest of the World 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
SGLT2 
standard deviation 
sodium-glucose co-transporter 2 
SMBG 
self-monitored blood glucose 
SI 
standard units 
SOC 
system organ class 
T2DM 
TEAE 
UACR 
ULN 
VS 
type 2 diabetes mellitus 
treatment-emergent AE 
urinary albumin/creatinine ratio 
upper limit of normal 
vital sign 
WHODRUG 
World Health Organization Drug Utilization Research Group 
 
 
 
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JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
5 
Approved, Date: 1 June 2018  
Amendment 1 (September 11, 2017) 
The major changes in this amendment include the clarification of alpha spending in the interim and the final 
analysis, the decrease of the number of primary composite events required for the interim analysis from 420 to 405, 
and re-ordering of the secondary endpoints as well as the addition of 2 new endpoints (MACE and hospitalized 
congestive heart failure) in the list of secondary endpoints.   
Amendment 2 (June 1, 2018) 
The reason for this amendment is to update the alpha level used for testing the secondary efficacy endpoints and 
include other minor clarifications of the analyses.  
 
 
 
 
 
 
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JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
6 
Approved, Date: 1 June 2018  
1. 
INTRODUCTION 
This statistical analysis plan (SAP) contains the definitions of analysis sets, derived variables, 
and statistical methods for the final analyses of efficacy and safety data from the canagliflozin 
study 28431754DNE3001. An interim analysis will be conducted when the mean duration of 
follow-up is at least 2 years and the events within the primary composite have been adjudicated 
as endpoints in approximately 405 subjects. Details regarding the interim analysis will be 
provided in a separate SAP. 
1.1. 
Trial Objectives 
Primary Objective 
In subjects with type 2 diabetes mellitus (T2DM), Stage 2 or 3 chronic kidney disease (CKD) 
and macroalbuminuria who are receiving standard of care, to assess the efficacy of canagliflozin 
relative to placebo in reducing: 
• 
the composite endpoint of end-stage kidney disease (ESKD), doubling of serum 
creatinine, and renal or cardiovascular (CV) death. 
Secondary Objectives 
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of 
care, to assess the efficacy of canagliflozin relative to placebo in reducing: 
• 
the composite endpoint of CV death and hospitalized congestive heart failure 
• 
the composite endpoint of CV death, non-fatal myocardial infarction (MI), and non-fatal 
stroke (ie, 3-point major adverse cardiac event [MACE])  
• 
hospitalized congestive heart failure  
• 
the renal composite endpoint of ESKD, doubling of serum creatinine, and renal death 
• 
CV death 
• 
all-cause death  
• 
the CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized 
congestive heart failure, and hospitalized unstable angina 
Exploratory Objectives 
In subjects with T2DM, Stage 2 or 3 CKD and macroalbuminuria who are receiving standard of 
care, to assess efficacy of canagliflozin relative to placebo in reducing: 
• 
the composite endpoint of ESKD, renal or CV death 
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• 
individual components of the renal and cardiovascular composite endpoints (ESKD, 
doubling of serum creatinine, renal death, CV death, fatal or non-fatal MI, fatal or non-
fatal stroke, hospitalized congestive heart failure, hospitalized unstable angina) 
and to assess the impact of canagliflozin relative to placebo on: 
• 
changes in estimated glomerular filtration rate (eGFR) over time 
• 
changes in urinary albumin-to-creatinine ratio (UACR) over time 
Safety Objective 
To assess the overall safety and tolerability of canagliflozin. 
1.2. 
Trial Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, 2-arm, multicenter study 
that will include a total of approximately 4,200 subjects. The study will have a pretreatment 
phase, consisting of a prescreening, screening (up to 8 weeks), and 2-week single-blind placebo 
run-in phase. Subjects will be prescreened on the basis of eGFR and UACR. Only subjects with 
an eGFR of ≥30 to <90 mL/min/1.73m2 and a UACR of level >300 mg/g to ≤5,000 mg/g (as 
confirmed by a local laboratory within the 3 months prior to screening) will be eligible for 
screening by the central laboratory. 
Subjects must be on a maximum tolerated labeled daily dose of an angiotensin-converting 
enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for a period of at least 4 weeks 
prior to randomization. To reach this requirement, the screening phase may be extended (up to 
8 weeks). In addition, other anti-hypertensive, lipid-lowering and antihyperglycemic therapies 
should also be dose stable prior to randomization. 
Subjects who meet all entry criteria will enter the single-blind placebo run-in phase at Week -2. 
During this phase, subjects will be instructed to take one capsule daily in order to assess their 
compliance with study intervention. Subjects who are compliant during the single-blind placebo 
run-in period (subjects must have ≥80% compliance by pill count) will be randomly assigned in 
a 1:1 ratio to canagliflozin or matching placebo group and will enter the double-blind treatment 
phase at the randomization visit (Day 1). Subjects randomized to canagliflozin will receive 
100 mg canagliflozin, to be taken once daily (QD). After randomization, subjects will return to 
the clinic at Week 3, Week 13, Week 26, and every 26 weeks thereafter for laboratory 
assessments, concomitant medication review, adverse event collection and determination of 
clinical endpoints. At Week 39 and at the midpoint between office visits after Week 52, 
telephone contact will be made to check the subject status, including discussing study diary 
entries (ie, collection of self-monitoring of blood glucose (SMBG) and possible hypoglycemic 
event information), concomitant medication use, adverse events, and determining clinical 
endpoints (ie, all local laboratory data related to serum creatinine and eGFR). All subjects treated 
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by the investigator will be managed to reach their glycemic, blood pressure and lipid goals 
according to established local and regional guidelines, with medical therapies used according to 
approved local labels. A post-treatment follow-up contact will take place following the treatment 
phase. Subjects who discontinue study medication prematurely should continue to attend all 
subsequent study visits and be followed to the global trial end date (GTED). This event-driven 
study is estimated to have a total duration of approximately 5 to 5.5 years. 
A Diagram of the study design is provided below: 
Figure 1: 
 
ACEi = angiotensin-converting enzyme inhibitor; UACR = urinary albumin-to-creatinine ratio;  
AHA = antihyperglycemic agent; ARB = angiotensin receptor blocker; BP = blood pressure; eGFR = estimated 
glomerular filtration rate; HbA1c = hemoglobin A1c; R = randomization; T2DM= type 2 diabetes mellitus; 
Wk=week. 
1.3. 
Statistical Hypothesis for Trial Objectives 
Canagliflozin reduces the risk of the composite endpoint of ESKD, doubling of serum creatinine, 
and renal or CV death, relative to placebo, in subjects with T2DM, Stage 2 or 3 CKD and 
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macroalbuminuria, who are receiving standard of care including a maximum tolerated labeled 
daily dose of an ACEi or ARB. 
1.4. 
Sample Size Justification 
This is an event driven study. A total of approximately 4,200 subjects will be randomized to 
either canagliflozin 100 mg or matching placebo in a 1:1 ratio. The study aims to observe the 
occurrence of the primary efficacy events in 844 unique randomized subjects, on or before the 
GTED, to have 90% power to detect a 20% relative risk reduction (RRR, defined as one minus 
hazard ratio) accounting for the effect of treatment discontinuation on the primary endpoint at a 
5%, 2-sided significance level. 
The above sample size is estimated based on the following additional assumptions: 
• 
Event rate for the composite endpoint in the placebo arm: 6.5% per year 
• 
Premature discontinuation rate of study drug: 6% per year 
• 
Overall lost-to-follow-up: 1% 
• 
Duration of enrollment period: 27 months 
• 
Duration of study (from first subject randomized to last end of study visit): estimated to be 
60 months 
This is an event driven trial and in order to ensure the number of events are obtained, the study 
duration and follow-up may be modified, if necessary, based on the observed event rate.   
1.5. 
Randomization, Blinding, and Stratification 
Upon successful completion of screening, eligible subjects will enter a 2-week run-in period, 
during which they will receive single-blind placebo capsules (one capsule to be taken once daily 
before the first meal of the day) to assess compliance with study intervention. 
Subjects who are compliant during the single-blind placebo run-in period will be randomly 
assigned in a 1:1 ratio to canagliflozin 100 mg or matching placebo to be taken once daily, 
before the first meal of the day. All study intervention after randomization will be provided in a 
double-blind manner. 
Eligible subjects will be stratified according to their screening eGFR (≥30 to <45, ≥45 to <60, 
≥60 to <90 mL/min/1.73m2), and will be randomized within the strata. 
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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 receive 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 in this SAP will be referred to as canagliflozin and placebo.  
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 2.3.1) 
up to the GTEDa 
On-Study 
Treated subjects 
Day 1 to the last trial contact date (see Section 2.3.1) 
up to GTEDa 
On-Treatment 
Treated subjects 
Day 1 to the last dose date (see Section 2.3.1) plus Xb 
days or the last trial contact date, whichever is earlier.  
a  
For each subject, data collected up to the final visit will be used for analysis.  If the final visit can’t be arranged, 
the reported data such as public search of mortality will be bounded by the GTED. 
b  X is 2 days for laboratory and vital sign measurements, and 30 days for adverse events (AEs), CV, renal, and 
mortality endpoints.  
2.3. 
Time-to-Event Data 
2.3.1. 
Subject-Level Trial Milestone Dates 
Trial reference start date (Day 1): the first dose date for each subject. 
First dose date: the date on which the first dose of study intervention is taken by the subject. 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 study intervention is 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, 
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impute the date as the date of the scheduled visit after the last visit when the study intervention 
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, imputed last dose date should be no earlier than the first 
dose date. The last dose date is the date of permanent study intervention 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 (CM), vital sign measures (VS) or lab results (LB) as reported on 
their respective electronic case report from (eCRF) page, or  
• 
The date of alternate contact made (eg, family members, relatives, friends, health care 
providers) confirming patient was alive at the time of GTED announcement. 
For subjects who die during the study or are lost to follow-up, or withdraw consent before 
announcement of GTED, the last trial contact date will be defined as the date of death or lost to 
follow-up, or withdrawal of consent. In addition, for subjects who are lost to follow-up, or 
withdraw consent, where permissible, the available subsequent survival information from a 
locator agent or public record search will be used to determine the last contact date.  
Serum Creatinine Event dates: A doubling of serum creatinine event is defined to occur when a 
serum creatinine measurement obtained at a post-baseline protocol visit is greater than or equal 
to twice the baseline average serum creatinine (ie, average value derived from the Day 1 value 
and the value immediately preceding the Day 1 determination, if both values are available; in 
addition, the screening value will be used as baseline if all other pre-treatment values are 
missing). Doubling is confirmed by repeat central laboratory measure after 30 days and 
preferably within 60 days after the index event and adjudicated as an endpoint event by a blinded 
Independent Endpoint Adjudication Committee (IEAC). Similarly, an endpoint of ESKD is 
defined to occur when an eGFR is < 15 ml/min/1.73m2 based on a serum creatinine obtained at a 
post-baseline protocol visit, confirmed by repeat central laboratory measure after 30 days and 
preferably within 60 days after the index event and adjudicated as an endpoint event by the 
IEAC. In both cases, the date of the event will be defined as the date of the blood draw for the 
initial serum creatinine measurement (either by local or central laboratory) triggering the event 
and subsequent adjudication (see Section 5.1.2). If the confirmatory value for doubling of serum 
creatinine or eGFR < 15 ml/min/1.73m2 is not available, the endpoint confirmation will be based 
on the IEAC determination of the event.  
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2.3.2. 
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 their last trial contact day or end of the 
respective data period, if not otherwise specified. 
2.4. 
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.  
The reference start day is study Day 1 which is the first dose day for subjects who took at least 
one dose of study medication or the randomization day for subjects who were randomized but 
did not take any study medication. 
Baseline will be defined as the pre-dosing measurement closest to or including Day 1 (prior to 
dose administration). If the pre-dosing measure 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 two pre-dose measurements 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 ensure that 
all on-treatment 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 presented in the by-visit analyses. 
Note 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, physical 
examination, and other key safety variables. 
Table 2: Time Intervals for Analysis Visit Windows  
Scheduled In-Clinic Visit Time 
Time Interval (Day)a 
Target Time Point (Day)a 
Baseline 
≤1b 
1 
Week 3 
1c-56 
22 
Week 13 
57-137 
92 
Week 26 
138-229 
183 
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Week 39 
230-320 
274 
Week 52 
321-456 
365 
Week 78 
457-638 
547 
Week 104 
639-821 
730 
Week 130 
822-1003 
912 
Week 156 
1004-1186 
1095 
Week 182 
1187-1368 
1277 
Week 208 
1369-1551 
1460 
Week 234 
1552-1733 
1642 
Week 260 
1734-1916 
1825 
Week 286 
1917-2098 
2007 
Week 312 d 
2099-2281 
2190 
Week 338 d 
≥2282 
2373 
a  Relative to the day of the first dose of double-blind medication. 
b  Up to the first dose of double-blind medication. 
c  
Immediately following the first dose of double-blind medication.  For variables without 
time or reference collected at baseline, the first window after baseline starts on Day 2 
according to the protocol. 
d   In case the duration of the study goes longer based on the observed event rate. 
 
3. 
INTERIM ANALYSIS 
An interim analysis will be conducted when the mean duration of follow-up is at least 2 years 
and primary efficacy events have been adjudicated as endpoints in approximately 405 subjects. 
An Independent Data Monitoring Committee (IDMC) will review results of the planned interim 
analysis and make a recommendation whether the study should be continued as planned, 
modified, or terminated prematurely due to efficacy, futility or safety reasons.  
The analysis method for the primary efficacy endpoint described in Section 5.2 will be used for 
the interim analysis. The alpha spent in the interim analysis for the testing of the primary 
composite endpoint is 0.01 (two-sided) which is determined by the alpha spending function 
taking the form of ατϕ with τ as the information fraction and ϕ = 2.19.  
The decision rules that trigger the IDMC to consider the recommendation of early study 
termination will be based on assessment of the primary composite endpoint as well as a “hard” 
composite endpoint of end-stage kidney disease (ESKD), renal death, and CV death, as specified 
below: 
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• 
Stop the study for efficacy, if the p-value (two-sided) of the primary composite endpoint 
comparison is <0.01, and the p-value (two-sided) of the composite endpoint of ESKD, renal 
death, and CV death comparison is <0.025 in favor of canagliflozin. (Note: both composite 
endpoints must meet their respective efficacy standards for the study to be prematurely 
terminated for efficacy) 
• 
Stop the study for futility, if the conditional power (based on the assumption that the hazard 
ratio in the remaining study is 0.80) for achieving the primary composite endpoint at the 
completion of study is <10% and that the overall benefit profile taking into account both 
efficacy and safety would be unlikely to be positive at the final analysis of study completion. 
• 
Otherwise continue the study. 
If the IDMC recommends early study termination due to efficacy, the sponsor will consider 
announcing the global trial end date (GTED) and final clinical visits will be scheduled. The test 
of the primary and the secondary endpoints will be based on the data accrued through the last 
trial contact date up to the GTED (see Table 1).   
4. 
SUBJECT INFORMATION 
4.1. 
Baseline Anthropometric and Demographic Characteristics 
Baseline anthropometric and demographic characteristics will be summarized by treatment group 
and overall (both treatments pooled together) for the ITT analysis sets. Descriptive statistics (N, 
mean, SD, median, and range) will be provided by treatment group and overall for continuous 
variables such as age, body weight, and BMI at baseline.  
The number and percentage of subjects in the categories of the following variables at baseline 
will also be summarized by randomized treatment group: 
• 
Age group: <55, 55 to <65, 65 to <75, ≥75 years old 
• 
Sex: Male, Female 
• 
Race: White, Black or African American, Asian, Others  
• 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Unknown, Not reported 
• 
Baseline BMI category:  <30, and ≥30 kg/m2 
• 
Region: North America, Central/South America, Europe, Rest of the World [ROW]. 
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4.1.1. 
Baseline Disease Characteristics 
Descriptive statistics (N, mean, SD, median, and range) will be provided by treatment group and 
overall for the ITT analysis sets including baseline HbA1c, duration of diabetes (in years), 
baseline eGFR, baseline UACR, baseline SBP/DBP, and baseline status of nicotine use.    
The number and percentage of subjects will be summarized by treatment group and overall for 
the following:  
• 
Baseline HbA1c categories: <7%, ≥7% to <8%, ≥8%  
• 
Baseline eGFR categories:  <45, ≥45 to <60, ≥60 mL/min/1.73m2  
• 
Baseline UACR categories: ≤1000, >1000 mg/g  
The number and percentage of subjects with the complications of diabetes (any and by specific 
complication) at baseline will be summarized by treatment group and overall. The categories of 
the complications of diabetes include diabetic retinopathy, autonomic neuropathy, peripheral 
diabetic neuropathy, other diabetic neuropathy. 
In addition to providing results by specific complication, the number and percentage of subjects 
with at least 2 diabetic complications and all 3 diabetic complications (retinopathy, neuropathy, 
or nephropathy) will be summarized by treatment group and overall.   
The number and percentage of subjects with history of medical conditions by system organ class 
and preferred term (based upon the general MH eCRF) will be summarized by treatment group 
and overall. In addition, the following pre-treatment conditions will also be summarized by 
treatment group and overall. 
• 
Cardiovascular disorders 
• 
Fractures 
• 
Surgeries/Procedures 
4.2. 
Disposition Information 
Subject disposition will be summarized by treatment group and overall using the following: 
• 
Screen failure 
• 
Subjects who are randomized (ITT analysis set) 
• 
Subjects who are treated 
• 
Subjects who prematurely discontinued study medication prior to the announcement of the 
GTED 
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• 
Subjects who completed the study (ie, defined as having been followed until a time point 
between the announcement of the GTED and the GTED, or if the subject had died prior to 
the GTED) 
• 
Subjects without final vital status 
Incidences of premature discontinuation from the double-blinded study intervention and the 
proportion of time on treatment relative to the follow-up period will be provided by treatment 
group. Time to premature discontinuation from the double-blinded study intervention will be 
summarized by treatment group using the Kaplan-Meier method.  
Listings will be provided for subjects whose predominant treatment differs from their 
randomized treatment and for subjects who temporarily took the wrong study medication. 
4.3. 
Extent of Exposure and Follow-Up 
Treatment duration is defined as the amount of elapsed time between the first and the last day 
that study medication was taken (inclusive). It will be calculated (in days) in terms of the 
difference in relative study days between the last and first dose of study medication, plus one 
day.  
Follow-up time is defined as the number of days from Day 1 to the last trial contact day 
(inclusive) for each subject. 
Descriptive statistics (N, mean, standard deviation, median, and range) will be presented by 
treatment group for treatment duration and follow-up.  
4.4. 
Prior and Concomitant Medications 
Prestudy (ie, medications taken before initiation of double-blind study medication) and 
concomitant medications (ie, medications taken after initiation of double-blind study medication 
that were either started prior or after initiation of double-blind study medication) including 
AHAs, ACE inhibitors and ARBs, and all other medications are collected. 
All prestudy and concomitant medications are coded using World Health Organization Drug 
Utilization Research Group (WHODRUG) and Anatomical Therapeutic Chemical (ATC) codes.  
Prestudy and concomitant medications will be summarized by the number of subjects taking 
pre-specified categories of medications by treatment group and overall. 
The proportion of subjects on ARBs and ACEs, anti-thrombotics (including aspirin) and statins 
(ie, HMG-CoA reductase inhibitors) at baseline will be summarized by treatment groups based 
on pre-specified categories (Attachment 1). The proportion of subjects on a maximum labeled 
dose of ARBs and ACEs for diabetic nephropathy or hypertension at baseline, and the reasons 
for subjects not on a maximum labeled dose will be summarized. In addition, non-study drug 
SGLT2 inhibitor use during the follow-up period will be summarized by treatment group.  
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4.5. 
Patient Management of Cardiovascular Risk Factors 
The proportion of subjects with HbA1c <7% and < 8%, SBP < 140 mm Hg, LDL-C < 100 mg/dL, 
and the proportion of subjects on statins and on anti-thrombotics (including aspirin) will be 
summarized by treatment group at Week 52, Week 104, Week 156, Week 208 and Week 260. In 
addition, longitudinal plots of the mean changes from baseline to the end of study in HbA1c and 
SBP will be presented. 
5. 
EFFICACY 
The primary analysis and major secondary analyses will be performed based on the ITT analysis 
set.  
5.1.1. 
Level of Significance 
Unless otherwise specified, all statistical tests except those for the primary efficacy endpoint and 
major secondary efficacy endpoints, will be interpreted at a 2-sided significance level of 5% and 
all confidence intervals at a 2-sided confidence level of 95%.  
At the interim analysis, the primary efficacy endpoint will be tested with alpha of 0.01 as 
determined by the alpha spending function taking form of ατϕ with τ as the information fraction 
and ϕ = 2.19. 
If the IDMC recommends early study termination due to efficacy, the sponsor will consider 
announcing the global trial end date (GTED) and final clinical visits will be scheduled.  The test 
of the primary composite endpoint will be based on the data accrued through the final clinic visit 
where the significance level will be determined by the alpha spending function (Lan et al, 2003 
[1]). 
If the IDMC does not recommend early study termination, the study will be continued until the 
target of 844 events have accrued. The primary composite endpoint will be tested with alpha of 
0.045 in the final analysis.   
Testing of the secondary efficacy endpoints will be based on the data accrued through the final 
clinic visit (regardless if the study stops after the interim analysis or proceeds to the planned 
completion of 844 primary composite events) using a two-sided alpha of 0.038. The overall type 
I error rate will be controlled at the 5% level across the primary and major secondary endpoints 
using a closed testing procedure, which is detailed in Section 5.5.   
5.1.2. 
Data Handling Rules 
Unless otherwise stated, all efficacy analyses will be based on the events and the dates identified 
by the IEAC. The onset of events of doubling of serum creatinine will be confirmed by a central 
laboratory value after 30 days and preferably within 60 days after the initial doubling. The date 
of the first documented doubling of serum creatinine will be considered as the onset date of the 
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event, with the confirmatory value reported by the central laboratory captured as serum 
creatinine value for the event.  
5.2. 
Primary Efficacy Endpoint 
5.2.1. 
Definition 
The primary efficacy endpoint is the composite endpoint of ESKD, doubling of serum creatinine, 
and renal or CV death.  
Definitions for each component of the primary composite endpoint are: 
• 
ESKD: Initiation of maintenance dialysis for at least 30 days, or renal transplantation, or a 
eGFR of <15 mL/min/1.73m2 (by CKD-EPI formula; sustained and confirmed by repeat 
central laboratory measure after at least 30 days and preferable within 60 days) 
• 
Doubling of serum creatinine: from the baseline determination (sustained and confirmed by 
repeat central laboratory measure after at least 30 days and preferable within 60 days) 
• 
Renal death: death in patients who have reached ESKD, die without initiating renal 
replacement therapy, and no other cause of death is determined via adjudication.   
• 
CV death: includes death due to MI, stroke, heart failure, sudden cardiac death, death during 
a CV procedure or as a result of procedure-related complications, or death due to other CV 
causes.  For analytic purposes, undetermined causes of death will be considered CV deaths.   
In determining whether a death event is CV in nature, the endpoint adjudication committee 
will take into consideration both the proximate and underlying causes.   
For subjects who have ESKD and doubling of serum creatinine determined to have occurred on 
the same date by the IEAC, the ESKD will be counted as the component for the primary 
composite endpoint.  
5.2.2. 
Analysis Methods 
Based on the time from study Day 1 to the first occurrence of the primary efficacy endpoint, the 
objective of the primary efficacy analysis is to establish that canagliflozin is superior to placebo, 
in the reduction of the rate of occurrence of the primary efficacy composite endpoint, in subjects 
with T2DM, Stage 2 or 3 CKD and macroalbuminuria, who are receiving standard of care 
including a maximum tolerated labeled daily dose of an ACEi or ARB. 
The hypothesis of the superiority on the primary efficacy endpoint for the comparison of 
canagliflozin versus placebo will be analyzed using a stratified Cox proportional hazard model 
including treatment, with stratification of the baseline hazard by screening eGFR (<45, ≥45 to 
<60, ≥60 mL/min/1.73m2). The primary analysis will be based on the ITT analysis set from study 
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Day 1 up to the GTED. If the study is not stopped prematurely for efficacy based on the interim 
analysis, the superiority will be evaluated at the final analysis using a 2-sided test with α=0.045.  
Estimates of the RRR (defined as one minus the hazard ratio), the hazard ratio and corresponding 
95% CIs will be provided.  
5.2.2.1. 
Supportive Efficacy Analyses 
The cumulative incidence of the primary efficacy composite over time will be presented using 
Kaplan-Meier curves for each of the 2 treatment groups. Cumulative incidence curves will also 
be presented for each of the components of the primary composite (ESKD, doubling of serum 
creatinine, renal death, and CV death) in order to assess competing risks, depending on the event 
counts of the individual components.  
In addition, ratios of cause-specific hazards between the treatment groups will be obtained for 
each component of the primary efficacy composite endpoint (ESKD, doubling of serum 
creatinine, renal death, or CV death), with stratification of the baseline hazard by screening 
eGFR group as in the analysis of the primary efficacy composite. 
To assess the robustness of the primary efficacy analysis, sensitivity analysis of the primary 
efficacy endpoint using a log-rank test stratified by screening eGFR will also be performed. The 
log-rank test does not require the proportional hazards assumption as for Cox proportional 
hazard model.   
Extensive efforts will be made to collect complete event and vital status data for all subjects 
randomized in this study. To illustrate the extent of missingness for the primary efficacy 
endpoint, the numbers of subjects with missing follow-up and the percentages of total missing 
follow-up time vs total number of subjects randomized and expected follow-up time will be 
summarized. Missing follow-up time for subjects who did not die will be calculated from last 
contact date to the announcement of GTED. For each subject, expected follow-up time will be 
calculated from study Day 1 to the earliest date of announcement of GTED or first occurrence of 
the primary efficacy endpoint.  
An On-Treatment analysis (which includes composite endpoints with an onset after the initiation 
of double-blind study medication and before the last study medication date + 30 days) will also 
be performed to assess the consistency of the primary efficacy analysis. This will use a similar 
analysis model to the primary analysis. 
5.2.2.1. 
Assessment of Model Assumption in the Primary Efficacy Analysis 
The proportional hazards assumption for the primary efficacy analysis model will be assessed 
graphically using Log (-log) plots and/or plots of Schoenfeld residuals. In addition, a linear 
non-proportionality test will be performed. If evidence of deviations from the proportional 
hazards assumption is detected, additional Cox regression analyses with time-dependent hazard 
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ratios for the treatment effect may be explored to better understand the degree and nature of the 
treatment effect differences over time. 
5.3. 
Subgroup Analyses for the Primary Endpoint 
The homogeneity of treatment effects on the occurrence of the primary efficacy endpoint across 
subgroups (if a total number of events is greater than 10 for both treatment groups and at least 1 
event in both groups) will be examined (at a 2-sided significance level of 0.10) via a test for the 
treatment by subgroup interaction by adding this term and the subgroup as covariates (viewed as 
class variables) to the primary efficacy analysis model. Factors exhibiting interactions with p < 
0.10 will be identified as exhibiting a possible treatment effect heterogeneity, recognizing that 
one or more p-values under 0.10 may be expected to be observed by chance when multiple 
subgroup factors are examined.  
If a significant interaction is observed, the results will be examined to determine whether the 
interaction is qualitative. If the interaction is qualitative in nature, clinical explanations of the 
significant interaction will be explored. 
Estimates and 2-sided 95% confidence intervals for the hazard ratio (canagliflozin/placebo) will 
be provided for each subgroup. The analyses will be based on the primary efficacy analysis 
model separated for each subgroup. 
The subgroups are listed below: 
• 
Sex: male or female 
• 
Age group: <65, ≥65 years old 
• 
Race group: White, Black or African American, Asian, Other 
• 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported/Unknown 
• 
Region: North America, Central/South America, Europe, and ROW 
• 
Duration of diabetes at baseline <median or ≥ median years 
• 
CV history at baseline: Yes, No 
• 
Baseline BMI: <30 or ≥30 kg/m2 
• 
Baseline HbA1c categories: <8%, ≥8% 
• 
Baseline eGFR:  <45, ≥45 to <60, ≥60 mL/min/1.73m2 
• 
Baseline UACR categories: ≤1000, >1000 mg/g  
• 
Baseline SBP categories: ≤ the median, > the median  
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• 
History of amputation: Yes, No 
5.4. 
Major Secondary Endpoints 
5.4.1. 
Definition 
Major secondary efficacy endpoints include: 
• 
Composite endpoint of CV death and hospitalized congestive heart failure 
• 
Composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE)  
• 
Hospitalized congestive heart failure  
• 
Renal composite endpoint of ESKD, doubling of serum creatinine, and renal death 
• 
CV death 
• 
All-cause death 
• 
CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive 
heart failure, and hospitalized unstable angina 
5.4.2. 
Analysis Methods 
If superiority of canagliflozin over placebo in reducing the risk of the primary efficacy endpoint 
is established, the hypothesis of superiority on major secondary efficacy endpoints of 
canagliflozin versus placebo will be subsequently tested in the following hierarchical order: 
1. Composite endpoint of CV death and hospitalized congestive heart failure 
2. Composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE)  
3. Hospitalized congestive heart failure  
4. Renal composite endpoint of ESKD, doubling of serum creatinine, and renal death 
5. CV death 
6. All-cause death 
7. CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive 
heart failure, and hospitalized unstable angina 
Time from study Day 1 to the first occurrence of a major secondary efficacy endpoint will be 
analyzed using the same approach as the primary analysis based on the data scope from study 
Day 1 to GTED in the ITT analysis set.  
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5.5. 
Multiplicity Adjustment  
A closed testing procedure will be implemented to control the family-wise type I error rate at 5% 
for primary and secondary endpoints. The hypothesis of superiority on primary and major 
secondary efficacy endpoints of canagliflozin versus placebo will be tested in the following 
hierarchical order. If an individual test during any step is not statistically significant, later tests 
will not be declared to be statistically significant. 
Figure 2:  
Hypothesis Testing Sequence 
Superiority on primary efficacy endpoint (α = 0.01 for interim*; 0.045 for the final analysis) 
Composite endpoint of ESKD, doubling of serum creatinine, and renal or CV death. 
↓ 
Superiority on major secondary efficacy endpoint #1 (α = 0.038) 
Composite endpoint of CV death and hospitalized congestive heart failure 
↓ 
Superiority on major secondary efficacy endpoint #2 (α = 0.038) 
Composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE) 
↓ 
Superiority on major secondary efficacy endpoint #3 (α = 0.038) 
Hospitalized congestive heart failure 
↓ 
Superiority on major secondary efficacy endpoint #4 (α = 0.038) 
Renal composite endpoint of ESKD, doubling of serum creatinine, and renal death 
↓ 
Superiority on major secondary efficacy endpoint #5 (α = 0.038) 
CV death 
↓ 
Superiority on major secondary efficacy endpoint #6 (α = 0.038) 
All-cause death 
↓ 
Superiority on major secondary efficacy endpoint #7 (α = 0.038) 
CV composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalized congestive 
heart failure, and hospitalized unstable angina 
* If IDMC recommends early study termination due to efficacy, the primary composite endpoint will be tested after 
final study visit for the last subject completed the study, with the significance level determined by the accrued events 
and the alpha spending function. 
5.6. 
Other Efficacy Analyses  
5.6.1. 
Definition of Exploratory Efficacy Endpoints 
In addition to the primary and major secondary endpoints previously described, the following 
endpoints and measurements will also be analyzed: 
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1. Composite endpoint events of ESKD (defined as a sustained eGFR of <15 mL/min/1.73m2 or 
initiation of dialysis with maintenance for at least 30 days, or renal transplantation) and CV 
death or renal death  
2. Individual components of the renal and cardiovascular composite endpoints (ESKD, 
doubling of serum creatinine, renal death, CV death, fatal or non-fatal MI, fatal or non-fatal 
stroke, hospitalized congestive heart failure, hospitalized unstable angina) 
3. Changes in estimated glomerular filtration rate (eGFR) over time 
4. Changes in urinary albumin-to-creatinine ratio (UACR) over time 
5.6.2. 
Definition of Other Efficacy Endpoints 
1. Composite endpoint events of ESKD (defined as a sustained eGFR of <15 mL/min/1.73m2 
or initiation of dialysis with maintenance for at least 30 days, or renal transplantation) and 
renal death   
2. Composite endpoint events of ESKD (defined as a sustained eGFR <15 mL/min/1.73m2 
with symptoms of uremia or a sustained eGFR of <8 mL/min/1.73m2 or initiation of dialysis 
with maintenance for at least 30 days, or renal transplantation) and CV death or renal death 
3. Composite endpoint events of ESKD (defined as a sustained eGFR <15 mL/min/1.73m2 
with symptoms of uremia or a sustained eGFR of <8 mL/min/1.73m2 or initiation of dialysis 
with maintenance for at least 30 days, or renal transplantation) and renal death 
5.6.3. 
Analysis Methods for Other Efficacy Analyses 
Composite endpoint events (described in Section 5.6.1) 
The time from study Day 1 to the first occurrence of composite endpoint events in each of the 
aforementioned composites will be analyzed by a method similar to that used for the primary 
efficacy analysis based on the data scope from study Day 1 to GTED in the ITT analysis set. 
eGFR change over time 
The on-treatment eGFRs include all central laboratory eGFR measurements from study Day 1 up 
to the last dose plus 2 days. The change from baseline in eGFR will be analyzed using a 
restricted maximum likelihood (REML) repeated measures approach. The analysis will be based 
on observed data and will include the fixed, categorical effects of treatment, stratification factor, 
visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline 
eGFR and baseline-by-visit interaction. An unstructured covariance will be used to model the 
within-patient errors. The adjusted mean changes in eGFR from baseline will be plotted over 
time by treatment group to depict the pattern of change in mean eGFR over time. Linear 
contrasts will be constructed to estimate the treatment effect on the mean change in eGFR to 
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6 months (early effect), the mean change in eGFR from 6 months to 4 years (late effect), and the 
mean change in eGFR from baseline to 4 years (overall effect).  
If the changes in mean eGFR in the above analysis exhibit a linear trajectory after 6 months, a 
multi-slope mixed effects linear spline model will be fitted with separate slopes from baseline to 
month 3, from month 3 to month 6, and from month 6 to the GTED. This model will be 
constructed with fixed effects for the screening eGFR randomization strata and with random 
intercepts and slopes to account for variation in progression rates over time. Likelihood based 
comparisons of goodness of fit will be used to determine if the model should be expanded to 
include additional terms to account for auto-correlation in residual over time, differences in 
variance between the treatment and control groups, or other deviations from the random 
slope-intercept model.  The mean slopes from baseline to month 3 and from baseline to month 6 
will be compared between the treatment groups to estimate the immediate and longer term acute 
effects of canagliflozin vs. placebo. The long-term slopes after month 6 will be used to estimate 
the effect of canagliflozin on the “chronic” slope after 6 months. The estimated mean change in 
eGFR from baseline to 4 years will also be compared under the 3 slope model to estimate the 
overall effect of canagliflozin on the mean change in eGFR.  
A similar analysis based on all central laboratory eGFR measurements from study Day 1 up to 
the end of study will be conducted using the similar model.  
If the distribution of eGFR value is positively skewed, log transformation of eGFR values may 
be considered prior to the modeling.  
UACR change over time 
On-treatment central laboratory UACR will be analyzed using the similar model for eGFR. Log 
transformation of UACR values will be made prior to the modeling, since the distribution of 
UACR value is highly skewed.  
A similar analysis for UACR measurements from study Day 1 up to the end of study will be 
performed using the similar model. 
6. 
SAFETY 
Treatment-emergent safety analyses and summaries will be based on the On-Treatment analysis 
set (Section 2.2). All safety analyses and summaries will utilize this approach unless otherwise 
specified.  
There will be no imputation of missing values for clinical laboratory test results and vital sign 
measurements in the safety analyses, and there will be no hypothesis testing for results from 
safety analyses. 
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The study objective regarding safety and tolerability will be assessed based upon a review of the 
incidence of all adverse events, as well as laboratory results, and other safety and tolerability 
measurements. 
6.1. 
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. Therefore, the preferred terms 
presented in Attachment 2 may be modified to reflect such updates. A treatment-emergent AE 
(TEAE) is defined as an adverse event with an onset after the initiation of double-blind study 
medication and before the last study medication date + 30 days (ie, the On-Treatment analysis 
set). AEs with a start date prior to initiation of double-blind study medication which are 
subsequently reported to have either an increase in intensity or change in attribution in 
relationship to study medication (ie, no attribution to possible, probably, very likely) after the 
initiation of double-blind study medication will also be considered as TEAEs.  
In addition to treatment-emergent AE analyses for selected AEs with an onset after the initiation 
of study medication and regardless of time off the study medication will also be performed.  
6.1.1. 
General Adverse Events 
An overview summary table with the incidence and the exposure-adjusted incidence will be 
provided for: 
• 
Any AEs 
• 
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 and AEs leading to discontinuation of study medication (by system organ class and 
preferred term) will be summarized by treatment group using the On-Treatment analysis set. AEs 
by system organ class (ie, number and percent of subjects with one or more AEs within a system 
organ class) will similarly be summarized by treatment group.  
The overall incidence (ie, number and percent of subjects with one or more AE in each category) 
of AEs, AEs leading to discontinuation, drug-related AEs, drug-related AEs leading to 
discontinuation of study medication, serious AEs, serious AEs leading to discontinuation, serious 
drug-related AEs, serious drug-related AEs leading to discontinuation of study medication and 
deaths, will be summarized by treatment group. 
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For each AE, the percentage of subjects who experienced at least one occurrence of the given 
event will be provided by preferred term, grouped by system organ class (SOC), and presented 
by treatment group. In addition, the incidence of AEs (by preferred term, grouped by SOC, and 
presented by treatment group) will also be summarized by severity (by each designation, and 
pooling mild or moderate), by the relationship to study medication, by the action taken regarding 
the study medication, as well as by the outcome. The relationship to study medication 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), as well as by individual designation. 
Listings will also be generated for deaths, SAEs, and discontinuations due to AEs. 
As a screening tool, the 95% CIs for the percentage difference between canagliflozin and 
placebo will be provided for the AEs which are reported in at least four 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)[2]. No multiplicity adjustment will be 
applied. The exclusion of “0” in the 95% CI around the difference in incidence for a particular 
AE does not necessarily imply that the higher incidence is related to drug. The intent of 
providing the 95% CIs is as a filter to identify AEs that require additional assessment. Adverse 
events for which there is an imbalance in incidence with 0% in placebo and 0.5% or higher in 
canagliflozin will be further evaluated. 
Adverse events that are identified by the above screening procedure will be subject to further 
evaluation. The additional assessment may include some or all of the following:   
1. Investigator assessed relationship of AE to study intervention, investigator assessed intensity 
of AE 
2. Time to AE relative to start of double-blind study medication, duration of AE, action taken 
on study intervention/occurrence of AEs leading to discontinuation 
3. Other relevant safety information such as observations in other canagliflozin trials, 
observations in trials of other members of the SGLT2 inhibitor class, biological plausibility 
of the AE as related to SGLT2 inhibition or to canagliflozin. 
6.2. 
Adverse Events of Interest 
In order to support the additional assessment of particular categories of adverse events, such as 
fractures and volume depletion, medical queries of selected preferred terms have been created. A 
blinded review prior to database lock will be performed to ensure that no reported term 
suggestive of the AE of interest is omitted. The list of preferred terms that are to be combined for 
the assessment of each of the pre-specified adverse events (eg, malignancies, severe 
hypersensitivity reactions [eg, angioedema, anaphylaxis, Stevens-Johnson syndrome], 
photosensitivity reactions, serious adverse events of hepatic injury, nephrotoxicity/acute kidney 
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injury, venous thromboembolic events, diabetic ketoacidosis [DKA], pancreatitis, fractures, and 
amputation) are provided in Attachment 2. The primary analysis of DKA, pancreatitis, and 
fracture will be based on adjudication results. Selected adverse events (eg, DKA, amputation, 
malignancy, and fracture) will be performed in both On-Treatment and On-Study analysis sets. 
The incidences and descriptive statistics of the additional information collected for each AE of 
interest will be summarized by treatment group. Additionally, the percentage of subjects with 
each AE of interest will be summarized by severity and relationship to study intervention. 
Treatment differences in incidence rates and corresponding 95% CI will be provided.  
The Kaplan-Meier plots for the time to first occurrence by treatment group will also be generated 
for certain AEs such as adjudicated fractures and amputation AEs. The time to first occurrence of 
the AE will be defined as the number of days between the study Day 1 and the onset day of the 
first occurrence. Subjects without the AE will be censored at the last dose date plus 30 days or 
the last trial contact date as defined in Section 2.2, whichever is earlier. 
6.3. 
Modified Rankin Scores for Stroke 
The ordinal categories of modified Rankin scores for the events of stroke will be summarized by 
treatment group based on investigator’s assessment. The modified Rankin score will be grouped 
to the ordered categories: 0−2 = nondisabling, 3−5 =disabling, 6 =death. For adjudicated stroke 
cases, the change of the score before and after the event will be calculated and used to assess the 
severity of the event. 
6.4. 
Hypoglycemia 
All hypoglycemic episodes are to be reported on an eCRF page specific for hypoglycemia. If the 
hypoglycemia episode is considered to be an AE/SAE in the opinion of the investigator, the 
episode is also to be recorded on the AE/SAE eCRF page. Hypoglycemia as AEs/SAEs will be 
presented in the tabulation of AEs described above. All additional analyses of hypoglycemia 
episodes will be based on results collected using the hypoglycemia eCRF. Reconciliation will be 
conducted to ensure that all hypoglycemia episodes reported as AEs are also recorded on the 
hypoglycemia eCRF form; however, hypoglycemia episodes reported on the hypoglycemia 
eCRF do not have to be reported as an AE (deferred to the investigator’s determination). 
Analyses discussed below are based upon episodes reported through the hypoglycemia eCRF.  
A subject will be counted as having a documented hypoglycemia episode when there is either a 
biochemically confirmed hypoglycemic episode (ie, concurrent fingerstick glucose or plasma 
glucose ≤70 mg/dL (3.9 mmol/L), and/or a severe hypoglycemic episode, as reported on the 
hypoglycemia eCRF, as follows:  
• 
Biochemically documented hypoglycemia episode: a hypoglycemia episode with a 
concurrent reported glucose value of ≤70 mg/dL (3.9 mmol/L), regardless of whether the 
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episode is associated with symptoms (symptomatic hypoglycemia) or not (asymptomatic 
hypoglycemia) 
• 
Severe hypoglycemia episode: a hypoglycemia episode that has the answer “Yes” 
recorded for any of the following 3 questions on the hypoglycemia eCRF: “Did the 
subject require assistance for this episode?”, “Did the subject lose consciousness during 
the episode?”, or “Did the subject have a seizure during the episode?”  
Only treatment-emergent hypoglycemia episodes (defined the same way as treatment-emergent 
AEs in Section 6.1) reported on the eCRF for hypoglycemia will be summarized.  
The percentage of subjects with documented hypoglycemia episodes (ie, biochemically 
documented and/or severe) and subjects with biochemically documented, and with severe 
hypoglycemia episodes separately, will be summarized by treatment group. For subjects with 
biochemically documented hypoglycemia episodes, the percentage of subjects will be 
summarized for each of the following glucose levels (≤70 mg/dL [3.9 mmol/L], <56 mg/dL 
[3.1 mmol/L], and <36 mg/dL [2.0 mmol/L], “Low” results will be included in all three 
categories) by treatment group. For subjects with severe hypoglycemia episodes, the percentage 
of subjects by each answer of the 3 questions for severe hypoglycemia on the eCRF will be 
summarized by treatment group. Event rate by person-year (total number of episodes/total 
exposure) will be calculated by treatment group separately for documented and for severe 
hypoglycemia.  
Subjects who had 0, 1, 2, or ≥3 documented episodes and subjects who had 0, 1, 2, or ≥3 severe 
hypoglycemic episodes will be summarized by treatment group.   
In addition, the incidence of all episodes of hypoglycemia reported on the eCRF for 
hypoglycemia will be provided (this includes events without concurrent fingerstick glucose 
reported and events with fingerstick glucose >70 mg/dL [3.9 mmol/L]) by treatment group. 
6.5. 
Clinical Laboratory Tests 
Laboratory data will be summarized for each type of laboratory test listed in Attachment 3. 
Normal reference ranges for each test will be provided. Descriptive statistics (N, mean, standard 
deviation, median, and range, as well as the 95% CI for the change from baseline) will be 
reported for each laboratory analyte at baseline and at each scheduled time point for absolute 
value and for change and percent change from baseline. Descriptive statistics will be presented 
for the On-Treatment analysis set (ie, based on measurements on study medication, including up 
to a maximum of 2 days after the last dose of study medication) as well as for the On-Study 
analysis set (ie, all measurements regardless of the time of the last dose of double-blind study 
intervention). Summaries based on both standard units (SI) and conventional units will be 
provided. 
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The percentage of subjects with specific treatment-emergent laboratory values meeting 
pre-defined limit of change (PDLC) criteria will be summarized for these laboratory analytes. 
The 95% CI for the percentage difference between canagliflozin and placebo will be provided for 
each PDLC criterion which have at least 4 or more subjects in any treatment group; a 
corresponding listing will also be provided. The criteria for PDLC values are listed in 
Attachment 4. 
6.6. 
Vital Signs  
Descriptive statistics (N, mean, standard deviation, median, and range, as well as the 95% CI for 
the change from baseline) will be reported for systolic and diastolic blood pressure (SBP and 
DBP), and pulse at each scheduled time point for absolute value and for change from baseline.  
Descriptive statistics will be presented for the On-Treatment analysis set (ie, based on 
measurements on study medication, including up to a maximum of 2 days after the last dose of 
study medication) as well as On-Study analysis set (ie, all measurements regardless of the time 
of the last dose). 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.  
A treatment-emergent vital sign abnormality is defined as a change from baseline and subsequent 
post-baseline value that satisfies the PDLC criteria listed in Attachment 4. For each vital sign 
parameter, the proportion of subjects with a treatment-emergent abnormality will be tabulated by 
treatment group. The 95% CI for the percentage difference between canagliflozin and placebo 
will be provided for each PDLC criterion which have at least 4 or more subjects in any treatment 
group; a corresponding listing will also be provided.  
 
 
 
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REFERENCES 
1. 
Lan K. K. G., Lachin, J M, and Bautista, O. (2003), Over-ruling a group sequential boundary - a stopping rule 
versus a guideline. Statistics in Medicine 22, 3347–3355.  
2. 
Brenda J, Crowe, H etc. 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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ATTACHMENT 1 
Prestudy and Concomitant Medications Classified by ATC Code and/or Other 
Conditions 
Note: The ATC code might be changed based on the latest version at the time of database lock 
Medication 
ATC code and/or Other Conditions 
Anti-Hyperglycemic 
Agents (AHA) 
ATC Code starts with ‘A10’ (Drugs used in diabetes) 
Insulin 
ATC Code starts with ‘A10A’ (Insulins and analogues) 
Biguanides 
ATC Codes start with ‘A10BA’ (Biguanides); and/or appropriate 
‘A10BD’ (combinations of oral blood glucose lowering drugs) 
Sulfonamides 
ATC Codes start with ‘A10BB’ (sulfonamides, urea derivatives), 
’A10BC’ (sulfonamides [heterocyclic]); and/or appropriate 
‘A10BD’ (combinations of oral blood glucose lowering drugs)  
Alpha glucosidase 
Inhibitors 
ATC Code starts with ‘A10BF’ (alpha glucosidase inhibitors) 
Thiazolidinediones 
(PPARγ) 
ATC Codes start with ‘A10BG’ (Thiazolidinediones); and/or 
appropriate ‘A10BD’ (combinations of oral blood glucose lowering 
drugs) and/or ‘A10BX’ (other blood glucose lowering drugs, 
excluding insulins) 
Dipeptidyl peptidase 4 
(DDP-4) Inhibitors 
ATC Codes start with ‘A10BH’ (Dipeptidyl peptidase 4 [DPP-4]); 
and/or appropriate ‘A10BD’ (combinations of oral blood glucose 
lowering drugs) 
GLP 1 
ATC Codes start with ‘A10BJ’ (other blood glucose lowering drugs, 
excluding insulins) 
Glinides 
ATC Codes start with appropriate ‘A10BD’ (combinations of oral 
blood glucose lowering drugs) and/or ‘A10BX’ (other blood glucose 
lowering drugs, excluding insulins) 
SGLT2i 
ATC Code starts with ‘A10BK’ (with ingredient of ‘dapagliflozin’, 
‘canagliflozin’, ‘empagliflozin’, ‘dapagliflozin propanediol 
monohydrate’, or ‘ertugliflozin’) or  
ATC Code start with appropriate ‘A10BD’ (with ingredient of 
‘canagliflozin, metformin hydrochloride’, ‘empagliflozin, 
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Medication 
ATC code and/or Other Conditions 
linagliptin’) 
Other Anti-
Hyperglycemic Agents 
ATC Code starts with ‘A10BX’ (other blood glucose lowering 
drugs, excluding insulins) 
Lipid-Altering 
Medications 
ATC Codes start with ‘C10’ 
• Lipid modifying agents, plain 
ATC Codes start with ‘C10A’ 
• Lipid modifying agents, combinations 
ATC Codes start with ‘C10B’ 
Antihypertensives 
Angiotensin-Converting Enzyme Inhibitors (ACEi): ATC Codes 
start with ‘C09A’ (ACE inhibitors, plain), and/or ‘C09B’ (ACE 
inhibitors, combinations) with one of the following combination 
ingredients containing ACE inhibitors. 
Angiotensin-Receptor Blockers (ARB): ATC Codes start with 
‘C09C’ (Angiotensin II antagonists); and/or ‘C09D’ (Angiotensin II 
antagonists, combinations) with one of the following combination 
ingredients containing an angiotensin II antagonist. 
1. 
DIURETICS 
Diuretics (loop) or diuretics (non-loop): 
1.1. 
Diuretics [loop] 
ATC Codes start with ‘C03C’ (High-ceiling diuretics), and/or ‘C02LA’ (Rauwolfia 
alkaloids and diuretics in combination) with one of the following combination 
ingredients: 
Dihydralazine Sulfate,Furosemide,Reserpine 
Dihydralazine Sulfate,Furosemide,Reserpine,Triamterene 
Furosemide,Reserpine 
 
and/or ‘C03EB’ (High-ceiling diuretics and potassium-sparing agents) with one of the 
following combination ingredients:  
Amiloride Hydrochloride,Bumetanide 
Amiloride Hydrochloride,Furosemide 
Amiloride,Furosemide 
Furosemide Xantinol,Triamterene 
Furosemide,Spironolactone 
Furosemide,Triamterene 
Furosemide Sodium,Potassium Canrenoate 
 
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and/or ‘C09BA’ (ACE inhibitors and diuretics) with one of the following combination 
ingredients:  
Furosemide,Ramipril 
Piretanide,Ramipril 
1.2. 
Diuretics [non-loop] 
ATC Codes start with ‘C03A’ (Low-ceiling diuretics, thiazides), ‘C03B’ (Low-ceiling 
diuretics, excluding thiazides), ‘C03D’ (Potassium-sparing agents), 
  
and/or ‘C02LA’ (Rauwolfia alkaloids and diuretics in combination) with one of the 
following combination ingredients: 
Adonis Vernalis Extract,Benzthiazide,Convallaria Majalis Extract,Drimia Maritima 
Extract,Oleandrin,Potassium Aspartate,Rauwolfia Serpentina 
Ajmaline,Benzylhydrochlorthiazide,Potassium 
Chloride,Raupine,Rescinnamine,Reserpine Hydrochloride,Yohimbine 
Ajmaline,Benzylhydrochlorthiazide,Potassium 
Chloride,Raupine,Rescinnamine,Yohimbine 
Ajmaline,Corynanthine,Hydrochlorothiazide,Raupine,Rescinnamine,Reserpine 
Hydrochloride 
Altizide,Potassium Canrenoate,Rescinnamine 
Bemetizide,Potassium Chloride,Pyridoxine 
Hydrochloride,Reserpine,Retinol,Thiamine Mononitrate,Tocopheryl Acetate 
Bendroflumethiazide,Methiomeprazine,Reserpine 
Bendroflumethiazide,Potassium Chloride,Rauwolfia Serpentina 
Bendroflumethiazide,Potassium Chloride,Reserpine 
Bendroflumethiazide,Rauwolfia Serpentina 
Bendroflumethiazide,Reserpine 
Benziodarone,Hydroflumethiazide,Potassium Chloride,Reserpine 
Benzthiazide,Methoserpidine 
Benzthiazide,Reserpine 
Benzylhydrochlorthiazide,Carbazochrome,Reserpine 
Benzylhydrochlorthiazide,Diisopropylamine Dichloroacetate,Rescinnamine 
Butizide,Carbocromen,Potassium Chloride,Raubasine,Rescinnamine,Reserpine 
Butizide,Potassium Chloride,Raubasine,Rescinnamine,Reserpine 
Butizide,Reserpine,Spironolactone 
Chlorothiazide,Dihydralazine Tartrate,Rauwolfia Serpentina 
Chlorothiazide,Rescinnamine 
Chlorothiazide,Reserpine 
Chlortalidone,Dihydralazine Hydrochloride,Oxazepam,Potassium 
Gluconate,Protoveratrines A And B,Reserpine,Rutoside,Xantinol Nicotinate 
Chlortalidone,Dihydroergocristine,Magnesium Sulfate 
Heptahydrate,Methylergometrini Tartras,Reserpine,Thiourea 
Chlortalidone,Reserpine 
Chlortalidone,Reserpine,Spironolactone 
Clofenamide,Reserpine 
Clofenamide,Reserpine,Rutoside 
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Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Clopamide,Dihydroergocristine Mesilate,Reserpine 
Clopamide,Dihydroergocristine,Reserpine 
Clopamide,Dihydroergotoxine Mesilate 
Clopamide,Reserpine 
Cyclopenthiazide,Potassium Chloride,Reserpine 
Cyclothiazide,Diprophylline,Methoserpidine 
Cyclothiazide,Reserpine 
Deserpidine,Hydrochlorothiazide 
Deserpidine,Methyclothiazide 
Dihydralazine Sulfate,Hydrochlorothiazide,Potassium Chloride,Reserpine 
Dihydralazine Sulfate,Hydrochlorothiazide,Reserpine 
Dihydralazine,Hydrochlorothiazide,Potassium Chloride,Reserpine 
Dihydralazine,Hydrochlorothiazide,Reserpine 
Dihydroergotamine Mesilate,Hydrochlorothiazide,Reserpine 
Ethiazide,Potassium Chloride,Rauwolfia Serpentina 
Flumethiazide,Potassium Chloride,Rauwolfia Serpentina 
Guanethidine Sulfate,Hydrochlorothiazide,Methyldopa,Reserpine 
Hydralazine Hydrochloride,Hydrochlorothiazide,Reserpine 
Hydrochlorothiazide,Mecamylamine Hydrochloride,Neostigmine 
Metilsulfate,Rescinnamine 
Hydrochlorothiazide,Methoserpidine 
Hydrochlorothiazide,Methyldopa,Reserpine,Triamterene 
Hydrochlorothiazide,Nicergoline,Reserpine 
Hydrochlorothiazide,Pentosan Polysulfate,Rauwolfia Serpentina 
Extract,Trichlormethiazide,Xantinol Nicotinate 
Hydrochlorothiazide,Potassium Chloride,Rauwolfia 
Serpentina,Rescinnamine,Reserpine,Retinol Palmitate,Tocopheryl Acetate 
Hydrochlorothiazide,Potassium Chloride,Reserpine 
Hydrochlorothiazide,Reserpine 
Hydrochlorothiazide,Reserpine,Secbutabarbital 
Hydrochlorothiazide,Reserpine,Triamterene 
Hydroflumethiazide,Reserpine 
Inositol Nicotinate,Mefruside,Rescinnamine 
Inositol Nicotinate,Mefruside,Reserpine 
Mefruside,Methyldopa,Reserpine 
Mefruside,Reserpine 
Methyclothiazide,Reserpine 
Polythiazide,Reserpine 
Quinethazone,Reserpine 
Reserpine,Trichlormethiazide 
Reserpine,Xipamide 
 
and/or ‘C02LB’ (Methyldopa and diuretics in combination) with one of the following 
combination ingredients: 
 
Amiloride Hydrochloride,Hydrochlorothiazide,Methyldopa 
Amiloride,Hydrochlorothiazide,Methyldopa 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Benzthiazide,Methyldopa 
Butizide,Methyldopa 
Chlorothiazide,Methyldopa 
Hydrochlorothiazide,Methyldopa 
Mefruside,Methyldopa 
 
and/or ‘C02LC’ (Imidazoline receptor agonists in combination with diuretics) with one 
of the following combination ingredients:  
Bencyclane Fumarate,Clonidine Hydrochloride,Hydrochlorothiazide 
Bendroflumethiazide,Clonidine 
Chlortalidone,Clonidine 
Chlortalidone,Clonidine Hydrochloride 
Chrysanthemum Spp.,Clonidine Hydrochloride,Concha 
Margaritifera,Hydrochlorothiazide,Rutoside 
Clonidine Hydrochloride,Cyclothiazide 
Clonidine Hydrochloride,Hydrochlorothiazide,Triamterene 
 
and/or ‘C02LF’ (Guanidine derivatives and diuretics) with one of the following 
combination ingredients: 
 
Polythiazide,Prazosin Hydrochloride 
Bemetizide,Guabenxan 
Cyclopenthiazide,Guanethidine Sulfate 
Cyclopenthiazide,Guanethidine Sulfate,Potassium Chloride 
Guanethidine Sulfate,Hydrochlorothiazide 
Guanoxan Sulfate,Polythiazide 
 
and/or ‘C02LG’ (Hydrazinophthalazine derivatives and diuretics) with one of the 
following combination ingredients:  
Dihydralazine Tartrate,Hydrochlorothiazide,Mebutamate,Potassium Chloride 
Hydralazine Hydrochloride,Hydrochlorothiazide 
 
and/or ‘C02LK’ (Alkaloids, excluding rauwolfia, in combination with diuretics) with 
one of the following ingredients: 
 
Cryptenamine Tannates,Methyclothiazide 
 
and/or ‘C02LL’ (MAO inhibitors and diuretics) with one of the following combination 
ingredients:  
Methyclothiazide,Pargyline Hydrochloride 
 
and/or ‘C02LX’ (Other antihypertensives and diuretics) with one of the following 
combination ingredients: 
 
Bemetizide,Bupranolol Hydrochloride,Dihydralazine Sulfate,Triamterene 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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and/or ‘C03EA’ (Low-ceiling diuretics and potassium-sparing agents) with one of the 
following combination ingredients:  
Altizide,Spironolactone 
Amiloride Hydrochloride,Bendroflumethiazide 
Amiloride Hydrochloride,Chlortalidone 
Amiloride Hydrochloride,Cyclopenthiazide 
Amiloride Hydrochloride,Hydrochlorothiazide 
Amiloride,Amiloride Hydrochloride,Methyclothiazide 
Amiloride,Hydrochlorothiazide 
Bemetizide,Hesperidin Complex,Thiamine Mononitrate,Triamterene 
Bemetizide,Triamterene 
Bendroflumethiazide,Spironolactone 
Benzthiazide,Triamterene 
Butizide,Potassium Canrenoate 
Butizide,Spironolactone 
Chlortalidone,Spironolactone 
Chlortalidone,Triamterene 
Clofenamide,Triamterene 
Cyclothiazide,Triamterene 
Epitizide,Triamterene 
Hydrochlorothiazide,Spironolactone 
Hydrochlorothiazide,Triamterene 
Hydrochlorothiazide,Triamterene,Verapamil Hydrochloride 
Hydroflumethiazide,Spironolactone 
Mebutizide,Triamterene 
Methyclothiazide,Triamterene 
Metolazone,Triamterene 
Triamterene,Trichlormethiazide 
Triamterene,Xipamide 
 
and/or ‘C03EB’ (High-ceiling diuretics and potassium-sparing agents) with one of the 
following combination ingredients:  
Amiloride Hydrochloride,Bumetanide 
Amiloride Hydrochloride,Furosemide 
Amiloride,Furosemide 
Furosemide Xantinol,Triamterene 
Furosemide,Spironolactone 
Furosemide,Triamterene 
 
and/or ‘C03XA’ (Vasopressin antagonists) with one of the following ingredients or 
combination ingredients: 
 
Conivaptan 
Conivaptan Hydrochloride 
Satavaptan 
Tolvaptan 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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and/or ‘C09BA’ (ACE inhibitors and diuretics) with one of the following combination 
ingredients:  
Benazepril Hydrochloride,Hydrochlorothiazide 
Benazepril,Hydrochlorothiazide 
Captopril,Hydrochlorothiazide 
Cilazapril,Hydrochlorothiazide 
Delapril Hydrochloride,Indapamide 
Delapril,Indapamide 
Enalapril Maleate,Hydrochlorothiazide 
Enalapril,Hydrochlorothiazide 
Fosinopril Sodium,Hydrochlorothiazide 
Fosinopril,Hydrochlorothiazide 
Hydrochlorothiazide,Imidapril Hydrochloride 
Hydrochlorothiazide,Lisinopril 
Hydrochlorothiazide,Lisinopril Dihydrate 
Hydrochlorothiazide,Moexipril Hydrochloride 
Hydrochlorothiazide,Quinapril 
Hydrochlorothiazide,Quinapril Hydrochloride 
Hydrochlorothiazide,Ramipril 
Indapamide,Perindopril 
Indapamide,Perindopril Erbumine 
 
and/or ‘C09BB’ (ACE inhibitors and calcium channel blockers) with one of the 
following combination ingredients:  
Trandolapril,Verapamil Hydrochloride 
 
and/or ‘C09DA’ (Angiotensin II antagonists and diuretics) with one of the following 
combination ingredients: 
 
Trandolapril,Verapamil Hydrochloride 
Candesartan Cilexetil,Hydrochlorothiazide 
Candesartan,Hydrochlorothiazide 
Eprosartan Mesilate,Hydrochlorothiazide 
Hydrochlorothiazide,Irbesartan 
Hydrochlorothiazide,Losartan 
Hydrochlorothiazide,Losartan Potassium 
Hydrochlorothiazide,Olmesartan 
Hydrochlorothiazide,Olmesartan Medoxomil 
Hydrochlorothiazide,Telmisartan 
Hydrochlorothiazide,Valsartan 
 
and/or ‘C09DX’ (Angiotensin II antagonists, other combinations) with one of the 
following combination ingredients:  
Amlodipine Besilate,Hydrochlorothiazide,Valsartan 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Approved, Date: 1 June 2018  
and/or ‘C09XA’ (Renin-inhibitors) with one of the following combination ingredients:  
Aliskiren Fumarate,Hydrochlorothiazide 
Aliskiren,Hydrochlorothiazide 
 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Approved, Date: 1 June 2018  
ATTACHMENT 2 
Medical History and AEs of Interest Defined by MedDRA Preferred Term  
1. 
MEDICAL HISTORY  
1.1. 
Hypertension 
o Essential hypertension 
o Hypertensive crisis 
o Hypertension 
o Hypertensive heart disease 
o Hypertensive angiopathy 
o Retinopathy hypertensive 
o Hypertensive cardiomyopathy 
 
 
1.2. 
Dyslipidemia 
o Blood cholesterol 
o Hypercholesterolaemia 
o Blood cholesterol increased 
o Hyperlipidaemia 
o Blood triglycerides increased 
o Hypertriglyceridaemia 
o Dyslipidaemia 
o Xanthelasma 
 
1.3. 
Fractures 
o Acetabulum fracture 
o Forearm fracture 
o Hip fracture 
o Radius fracture 
o Ankle fracture 
o Fracture 
o Humerus fracture 
o Rib fracture 
o Avulsion fracture 
o Fracture debridement 
o Ilium fracture 
o Scapula fracture 
o Bone fragmentation 
o Fracture delayed union 
o Impacted fracture 
o Skull fracture 
o Cervical vertebral fracture 
o Fracture displacement 
o Chance fracture 
o Skull fractured base 
o Clavicle fracture 
o Fracture malunion 
o Jaw fracture 
o Spinal compression 
fracture 
o Comminuted fracture 
o Fracture nonunion 
o Limb crushing injury 
o Sternal fracture 
o Complicated fracture 
o Fracture reduction 
o Lumbar vertebral fracture 
o Stress fracture 
o Lower limb fracture 
o Fractured coccyx 
o Compression fracture 
o Thoracic vertebral 
fracture 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Approved, Date: 1 June 2018  
o Multiple fractures 
o Fractured ischium 
o Elevation skull fracture 
o Tibia fracture 
o Open fracture 
o Fractured sacrum 
o Epiphyseal fracture 
o Torus fracture 
o Osteoporotic fracture 
o Fractured maxilla 
elevation 
o Facial bones fracture 
o Traumatic fracture 
o Patella fracture 
o Fractured skull 
depressed 
o Femoral neck fracture 
o Ulna fracture 
o Pathological fracture 
o Fractured zygomatic 
arch elevation 
o Femur fracture 
o Upper limb fracture 
o Pelvic fracture 
o Greenstick fracture 
o Fibula fracture 
o Wrist fracture 
o Pubis fracture 
o Hand fracture 
o Foot fracture 
o Spinal fracture 
o Periprosthetic fracture 
o Atypical fracture 
o Atypical femur fracture 
o Closed fracture manipulation 
o Costal cartilage fracture 
o Craniofacial fracture 
o External fixation of fracture 
o Fracture pain 
o Fracture treatment 
o Internal fixation of fracture 
o Limb fracture 
o Loss of anatomical alignment after fracture reduction 
o Open reduction of fracture 
o Open reduction of spinal fracture 
o Osteochondral fracture 
o Sacroiliac fracture 
o Spinal fusion fracture 
 
 
 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Approved, Date: 1 June 2018  
2. 
LIST OF PREFERRED TERMS FOR SELECTED ADVERSE EVENTS 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 
Costal cartilage fracture 
 
Diabetes mellitus with ketoacidosis 
Vulvovaginitis 
Vulvovaginal inflammation  
 
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 
Hyperglycaemic hyperosmolar 
nonketotic syndrome 
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 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Approved, Date: 1 June 2018  
Diabetic ketoacidosis 
Female Mycotic Genital 
Infections 
Fracture 
Greenstick fracture 
Hand fracture 
Hip fracture 
Humerus fracture 
Ilium fracture 
Impacted fracture 
Internal fixation of fracture 
Jaw fracture 
Limb crushing injury 
Limb 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 
Blood glucose decreased 
 
Balanoposthitis infective 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Approved, Date: 1 June 2018  
Hepatic Injury 
Hypoglycaemia 
Male Mycotic Genital Infections 
Ammonia increased 
Erosive balanitis 
Ascites 
Gangrenous balanitis 
Asterixis 
Genital candidiasis  
Autoimmune hepatitis 
Genital infection 
Bacterascites 
Genital infection fungal 
Biliary ascites 
Genital infection male 
Biliary cirrhosis 
Penile infection 
Biliary cirrhosis primary 
Posthitis 
Biliary fibrosis 
Bilirubin excretion disorder 
Biopsy liver abnormal 
Child-Pugh-Turcotte score increased 
Cholaemia 
Cholestasis 
Cholestatic liver injury 
Cholestatic pruritus 
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 encephalopathy 
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 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
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Approved, Date: 1 June 2018  
Hepatic Injury 
Hypoglycaemia 
Male Mycotic Genital Infections 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis toxic 
Hepatobiliary disease 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatotoxicity 
Hyperbilirubinaemia 
Icterus index increased 
Intestinal varices 
Ischaemic hepatitis 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Liver and small intestine transplant 
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 
 
 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
45 
Approved, Date: 1 June 2018  
 
Malignancy Renal Cell Cancer 
Malignancy Testicular 
Osmotic Diuresis  
Bladder adenocarcinoma recurrent 
Apocrine breast carcinoma 
Phaeochromocytoma 
Bladder adenocarcinoma stage 0 
Breast angiosarcoma 
Phaeochromocytoma crisis 
Bladder adenocarcinoma stage I 
Breast angiosarcoma metastatic 
Phaeochromocytoma 
excision 
Bladder adenocarcinoma stage II 
Breast cancer 
Phaeochromocytoma 
malignant 
Bladder adenocarcinoma stage III 
Breast cancer female 
Bladder adenocarcinoma stage IV 
Breast cancer in situ 
Bladder adenocarcinoma stage unspecified 
Breast cancer male 
Bladder cancer 
Breast cancer metastatic 
Bladder cancer recurrent 
Breast cancer recurrent 
Bladder cancer stage 0, with cancer in situ 
Breast cancer stage I 
Bladder cancer stage 0, without cancer in 
situ 
Breast cancer stage II 
Bladder cancer stage I, with cancer in situ 
Breast cancer stage III 
Bladder cancer stage I, without cancer in situ 
Breast cancer stage IV 
Bladder cancer stage II 
Breast neoplasm 
Bladder cancer stage III 
Breast sarcoma 
Bladder cancer stage IV 
Breast sarcoma metastatic 
Bladder squamous cell carcinoma recurrent 
Breast sarcoma recurrent 
Bladder squamous cell carcinoma stage 0 
Contralateral breast cancer 
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 
 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
46 
Approved, Date: 1 June 2018  
 
Malignancy Renal Cell Cancer 
Malignancy Testicular 
Osmotic Diuresis  
Neuroendocrine carcinoma of the bladder 
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 
Bladder adenocarcinoma recurrent 
Apocrine breast carcinoma 
Phaeochromocytoma 
Bladder adenocarcinoma stage 0 
Breast angiosarcoma 
Phaeochromocytoma crisis 
Bladder adenocarcinoma stage I 
Breast angiosarcoma metastatic 
Phaeochromocytoma 
excision 
Bladder adenocarcinoma stage II 
Breast cancer 
Phaeochromocytoma 
malignant 
Bladder adenocarcinoma stage III 
Breast cancer female 
Bladder adenocarcinoma stage IV 
Breast cancer in situ 
Bladder adenocarcinoma stage unspecified 
Breast cancer male 
Bladder cancer 
Breast cancer metastatic 
Bladder cancer recurrent 
Breast cancer recurrent 
Bladder cancer stage 0, with cancer in situ 
Breast cancer stage I 
Bladder cancer stage 0, without cancer in 
situ 
Breast cancer stage II 
Bladder cancer stage I, with cancer in situ 
Breast cancer stage III 
Bladder cancer stage I, without cancer in situ 
Breast cancer stage IV 
Bladder cancer stage II 
Breast neoplasm 
Bladder cancer stage III 
Breast sarcoma 
Bladder cancer stage IV 
Breast sarcoma metastatic 
Bladder squamous cell carcinoma recurrent 
Breast sarcoma recurrent 
Bladder squamous cell carcinoma stage 0 
Contralateral breast cancer 
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 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
47 
Approved, Date: 1 June 2018  
 
Malignancy Renal Cell Cancer 
Malignancy Testicular 
Osmotic Diuresis  
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 
Neuroendocrine carcinoma of the bladder 
 
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 
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 
Papillary renal cell carcinoma 
 
 
    
 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
48 
Approved, Date: 1 June 2018  
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 reaction 
Photodermatosis 
Photokeratitis 
Photoonycholysis 
Photosensitivity reaction 
Polymorphic light eruption 
Solar dermatitis 
Solar urticaria 
Sunburn 
Vaccination site photosensitivity reaction 
 
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 
Pyelitis 
 
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 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
49 
Approved, Date: 1 June 2018  
Renal Related 
Severe Hypersensitivity/Cutaneous AEs 
Upper UTI 
Eyelid oedema 
Face oedema 
First use syndrome 
Fixed drug eruption 
Gingival oedema 
Gingival swelling 
Gleich's syndrome 
Hereditary angioedema 
Hypersensitivity vasculitis 
Idiopathic angioedema 
Idiopathic urticaria 
Kounis syndrome 
Laryngeal dyspnoea 
Laryngeal oedema 
Laryngospasm 
Laryngotracheal oedema 
Limbal swelling 
Lip exfoliation 
Lip oedema 
Lip swelling 
Mucocutaneous ulceration 
Mucosa vesicle 
Mucosal erosion 
Mucosal exfoliation 
Mucosal necrosis 
Mucosal ulceration 
Nikolsky's sign 
Oculomucocutaneous syndrome 
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 
Symmetrical drug-related intertriginous and flexural 
exanthema 
Throat tightness 
Tongue exfoliation 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
50 
Approved, Date: 1 June 2018  
Renal Related 
Severe Hypersensitivity/Cutaneous AEs 
Upper UTI 
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  
Bacterial ureteritis 
Bacterial urethritis 
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 venous occlusion 
Hypovolaemic shock 
Cystitis pseudomonal 
Obstructive shock 
Orthostatic hypotension 
Emphysematous cystitis 
Portosplenomesenteric venous 
thrombosis 
Orthostatic intolerance 
Escherichia urinary tract infection 
Post procedural pulmonary embolism 
Postural orthostatic tachycardia 
syndrome 
Fungal cystitis  
Postpartum venous thrombosis 
Presyncope 
Funguria 
Pulmonary embolism 
Shock 
Genitourinary tract infection  
Pulmonary infarction 
Shock symptom 
Streptococcal urinary tract 
infection 
Pulmonary microemboli 
Syncope 
Ureter abscess 
Pulmonary oil microembolism 
Urine output decreased 
Ureteritis 
Urethritis 
Urethritis noninfective 
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 
 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
51 
Approved, Date: 1 June 2018  
ATTACHMENT 3  
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 
 
• Urinalysis 
• Lipid panel 
o Triglycerides 
o Total cholesterol 
o HDL cholesterol 
o LDL cholesterol 
o LDL/HDL ratio 
• Plasma glucose 
• Hemoglobin A1c 
• Estimated Glomerular Filtration Rate (eGFR) 
The estimated glomerular filtration rate (eGFR) will be reported according to the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at study visits when 
serum creatinine is measured by the central laboratory.  
 
 
NCT02065791


JNJ-28431754 (canagliflozin)   
 
 
 
Statistical Analysis Plan 28431754DNE3001; Phase 3  
52 
Approved, Date: 1 June 2018  
ATTACHMENT 4  
CRITERIA FOR PRE-DEFINED LIMIT OF CHANGE (PDLC) AND ABNORMAL 
VALUES 
Laboratory Test 
Parameter for ANY value and LAST value 
CHEMISTRY 
 
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 
eGFR from creatinine adjusted for 
BSA 
eGFR < 80 mL/min/1.73m2 and decrease > 30% from BL 
eGFR decrease > 50% from BL 
Magnesium 
Composite: <LLN and >25% decrease from BL 
Composite: >ULN and >25% increase from BL 
Phosphate 
Composite: <LLN and >25% decrease from BL 
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 
Albumin 
Composite: <LLN and >25% decrease from BL 
Urate   
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 
 
NCT02065791