Clinical trial NCT03170518
Conditions: Diabetes Mellitus, Type 2
Sponsor: Janssen Research & Development, LLC
Start date: 2017-07-21; Completion date: 2023-09-20
Enrollment: 171 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effect of canagliflozin relative to placebo on glycated hemoglobin (HbA1c) after 26 weeks of treatment, and to assess the overall safety and tolerability of canagliflozin.

Detailed description:

Arms: arm 1: Participants will receive 1 placebo tablet matching canagliflozin 100 milligram (mg) once-daily during the 2-week single-blind placebo run-in period. arm 2: Canagliflozin 100 mg/matching placebo once-daily during first 12 weeks. At Week 13, participants who have glycated hemoglobin (HbA1c) of greater than or equal to (\>=)7.0 percent (%), estimated glomerular filtration rate (eGFR) \>=60 milliliter/minute/1.73 meter square (mL/min/1.73 m\^2) will be re-randomized to either remain on canagliflozin 100 mg/matching placebo or up-titrate to canagliflozin 300 mg/matching placebo till Week 52.
Interventions: intervention 1: Canagliflozin 100 mg intervention 2: Canagliflozin 300 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Canagliflozin 100 mg tablet will be administered orally (by mouth) once-daily. intervention 2: Canagliflozin 300 mg tablet will be administered orally once-daily. intervention 3: Matching placebo tablet will be administered orally once-daily.

Protocol documents:
Prot_002.pdf: 
NCT03170518


JNJ-28431754  (canagliflozin)
Clinical Protocol 28431754DIA3018 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 14 August 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 14
TIME AND EVENTS SCHEDULE .............................................................................................................. 24
ABBREVIATIONS ...................................................................................................................................... 29
DEFINITIONS OF TERMS.......................................................................................................................... 30
1.
INTRODUCTION................................................................................................................................ 31
1.1.
Background .................................................................................................................................... 32
1.1.1.
Pharmacokinetics ....................................................................................................................... 32
1.1.2.
Pharmacodynamics .................................................................................................................... 33
1.1.3.
Efficacy/Safety Studies............................................................................................................... 34
1.2.
Overall Rationale for the Study...................................................................................................... 38
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 39
2.1.
Objectives ...................................................................................................................................... 39
2.2.
Hypotheses .................................................................................................................................... 40
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 40
3.1.
Overview of Study Design.............................................................................................................. 40
3.2.
Study Design Rationale.................................................................................................................. 43
4.
SUBJECT POPULATION.................................................................................................................. 47
4.1.
Inclusion Criteria ............................................................................................................................ 47
4.2.
Exclusion Criteria ........................................................................................................................... 49
4.3.
Prohibitions and Restrictions ......................................................................................................... 51
4.4.
Repeat Testing and Subject Rescreening ..................................................................................... 52
5.
TREATMENT ALLOCATION ............................................................................................................ 52
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 54
6.1.
Blinded Study Drug ........................................................................................................................ 54
6.1.1.
Single-Blind Placebo Study Drug ............................................................................................... 54
6.1.2.
Double-Blind Study Drug ............................................................................................................ 54
6.2.
Concomitant Open-Label Antihyperglycemic Therapies................................................................ 56
6.2.1.
Background Antihyperglycemic Therapies ................................................................................. 56
6.2.2.
Glycemic Rescue Therapy: Criteria and Implementation........................................................... 56
7.
TREATMENT COMPLIANCE............................................................................................................ 58
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 58
9.
STUDY PROCEDURES AND EVALUATIONS................................................................................. 59
9.1.
Study Procedures........................................................................................................................... 59
9.1.1.
Overview..................................................................................................................................... 59
9.1.1.1.
Visit Schedules and Visit Windows.......................................................................................... 59
9.1.1.2.
Visit Reminders- Telephone Contacts..................................................................................... 60
9.1.1.3.
Pregnancy Testing................................................................................................................... 60


JNJ-28431754  (canagliflozin)
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Status: Approved,  Date: 14 August 2020
9.1.1.4.
Subject Diary: Collection of Self-Monitoring of Blood Glucose (SMBG), Ketones, and 
Possible Hypoglycemic Event Information .............................................................................. 60
9.1.1.5.
Archive Samples for Exploratory Research and Specimen for Biomarker Assessment......... 60
9.1.1.6.
Blood Collection....................................................................................................................... 61
9.1.1.7.
Other Routine Examinations.................................................................................................... 61
9.1.2.
Pretreatment Phase.................................................................................................................... 61
9.1.3.
Single-Blind Placebo Run-In Visit (Week -2).............................................................................. 62
9.1.4.
Double-Blind Treatment Phase .................................................................................................. 63
9.1.4.1.
Day 1/Day of Randomization................................................................................................... 63
9.1.4.2.
Visits Following Randomization............................................................................................... 63
9.1.4.3.
Re-Randomization................................................................................................................... 63
9.1.5.
Post-treatment Phase (Follow-Up) ............................................................................................. 64
9.2.
Ketone Monitoring.......................................................................................................................... 65
9.2.1.1.
Pre-specified Ketone Measurements During Run-in Period ................................................... 66
9.2.1.2.
Ketone Measurements During Periods of Increased Risk of Ketonemia ................................ 66
9.2.2.
Management of Blinded Study Drug During Ketonemia............................................................. 67
9.3.
Self-Monitoring of Blood Glucose .................................................................................................. 68
9.4.
Study Management: Committees................................................................................................... 68
9.4.1.
Medical Safety Review Committee............................................................................................. 68
9.4.2.
Independent Data Monitoring Committee................................................................................... 69
9.5.
Efficacy Evaluations....................................................................................................................... 69
9.5.1.
Measures of Efficacy/Efficacy Endpoints.................................................................................... 69
9.6.
Pharmacokinetic Evaluations......................................................................................................... 69
9.6.1.
Sample Collection and Handling ................................................................................................ 69
9.6.2.
Analytical Procedures................................................................................................................. 69
9.6.3.
Pharmacokinetic Parameters ..................................................................................................... 70
9.7.
Biomarker Evaluations ................................................................................................................... 70
9.8.
Safety Evaluations ......................................................................................................................... 70
9.9.
Exploratory Biomarker Evaluations................................................................................................ 74
10.
SUBJECT COMPLETION, PREMATURE DISCONTINUATION OF TREATMENT, OR 
WITHDRAWAL FROM THE STUDY................................................................................................. 74
10.1.
Subject Completion........................................................................................................................ 74
10.2.
Study Drug Treatment Premature Discontinuation, Reinstitution, and Follow-up ......................... 74
10.2.1.
Study Drug Treatment Premature Discontinuation..................................................................... 74
10.2.2.
EOT and 30-Day Follow-up Assessments for Subjects Who Prematurely Discontinue 
Study Drug.................................................................................................................................. 76
10.2.3.
Reinstitution of Treatment with Study Drug that has Been Interrupted ...................................... 76
10.2.4.
Comprehensive Follow-up at Scheduled Study Visits Following Premature 
Discontinuation of Study Drug .................................................................................................... 76
10.3.
Withdrawal from the Study............................................................................................................. 77
10.3.1.
Lost to Follow-up ........................................................................................................................ 77
10.3.2.
Withdrawal of Consent................................................................................................................ 77
10.4.
Withdrawal from the Use of Samples in Future Research............................................................. 78
11.
STATISTICAL METHODS................................................................................................................. 79
11.1.
Analysis Sets.................................................................................................................................. 79
11.2.
Sample Size Determination ........................................................................................................... 80
11.3.
Efficacy Analyses ........................................................................................................................... 80
11.3.1.
Primary Efficacy Endpoint........................................................................................................... 80
11.3.1.1.
Definition.................................................................................................................................. 80
11.3.2.
Multiplicity Adjustment ................................................................................................................ 82
11.3.3.
Secondary Efficacy Endpoints.................................................................................................... 83
11.4.
Pharmacokinetic Analyses............................................................................................................. 83
11.5.
Biomarker Analyses ....................................................................................................................... 84
11.6.
Safety Analyses ............................................................................................................................. 84
12.
ADVERSE EVENT REPORTING ...................................................................................................... 85


JNJ-28431754  (canagliflozin)
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Status: Approved,  Date: 14 August 2020
12.1.
Definitions ...................................................................................................................................... 86
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 86
12.1.2.
Attribution Definitions.................................................................................................................. 87
12.1.3.
Severity Criteria .......................................................................................................................... 88
12.2.
Procedures..................................................................................................................................... 88
12.2.1.
All Adverse Events...................................................................................................................... 88
12.2.2.
Serious Adverse Events ............................................................................................................. 90
12.2.3.
Pregnancy................................................................................................................................... 91
12.3.
Hypoglycemia................................................................................................................................. 91
12.4.
Diabetic Ketoacidosis..................................................................................................................... 91
12.5.
Contacting Sponsor Regarding Safety........................................................................................... 92
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 92
13.1.
Procedures..................................................................................................................................... 92
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 93
14.
STUDY DRUG INFORMATION......................................................................................................... 93
14.1.
Physical Description of Study Drug(s) ........................................................................................... 93
14.2.
Packaging ...................................................................................................................................... 93
14.3.
Labeling.......................................................................................................................................... 93
14.4.
Preparation, Handling, and Storage............................................................................................... 93
14.5.
Drug Accountability ........................................................................................................................ 93
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 94
16.
ETHICAL ASPECTS ......................................................................................................................... 94
16.1.
Study-Specific Design Considerations........................................................................................... 94
16.2.
Regulatory Ethics Compliance....................................................................................................... 96
16.2.1.
Investigator Responsibilities ....................................................................................................... 96
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 96
16.2.3.
Informed Consent/Pediatric Assent............................................................................................ 97
16.2.4.
Privacy of Personal Data ............................................................................................................ 99
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 100
16.2.6.
Country Selection ..................................................................................................................... 100
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 100
17.1.
Protocol Amendments.................................................................................................................. 100
17.2.
Regulatory Documentation .......................................................................................................... 100
17.2.1.
Regulatory Approval/Notification .............................................................................................. 100
17.2.2.
Required Prestudy Documentation........................................................................................... 101
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 101
17.4.
Source Documentation................................................................................................................. 102
17.5.
Case Report Form Completion .................................................................................................... 102
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 103
17.7.
Record Retention ......................................................................................................................... 103
17.8.
Monitoring .................................................................................................................................... 104
17.9.
Study Completion/Termination..................................................................................................... 104
17.9.1.
Study Completion ..................................................................................................................... 104
17.9.2.
Study Termination..................................................................................................................... 104
17.10.
On-Site Audits .............................................................................................................................. 105
17.11.
Use of Information and Publication.............................................................................................. 105
REFERENCES.......................................................................................................................................... 107
INVESTIGATOR AGREEMENT ............................................................................................................... 122


JNJ-28431754  (canagliflozin)
Clinical Protocol 28431754DIA3018 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 14 August 2020
LIST OF ATTACHMENTS
Attachment 1: 
Instructions on Ketone Monitoring and Sick Day Management................................... 108
Attachment 2: 
Suggested Algorithm for Ketone Monitoring and Findings of Elevated Ketones......... 110
Attachment 3:
Method of Blood Pressure Measurement .................................................................... 112
Attachment 4:
Hypoglycemia: Definitions, Symptoms, and Treatment............................................... 113
Attachment 5:
Guideline for Collecting Height Measurements (CDC 2015)....................................... 114
Attachment 6:
Tanner Staging ............................................................................................................ 115
Attachment 7:
Clinical Laboratory Tests ............................................................................................. 119
Attachment 8: 
Maturity-Onset Diabetes of the Young (MODY)........................................................... 121
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Summary of Dose Level and Number of Tablets by Study Period and Treatment................... 55
Table 2:
Glycemic Rescue Criteria ......................................................................................................... 57
Table 3:
Estimated Volume of Blood to be Collected from Each Subject............................................... 61
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 43
Figure 2:
Testing Sequence..................................................................................................................... 82


JNJ-28431754  (canagliflozin)
Clinical Protocol 28431754DIA3018 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 14 August 2020
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
19 December 2016
Amendment 1
27 March 2017
Amendment 2
25 August 2017
Amendment 3
25 June 2018
Amendment 4
14 August 2020
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (14 August 2020)
The overall reason for the amendment:
Due to slower than expected recruitment in the study, a high rate of screen failures, and the goal of maintaining the 
study timeline, the power calculation was modified with the Food and Drug Administration’s (FDA’s) approval and 
without compromising the study’s integrity, thus resulting in a reduced sample size. In addition, minor 
modifications to the inclusion and exclusion criteria have been made.
Applicable Section(s)
Description of Change(s)
Rationale: To reduce the sample size for the overall study and for subjects on background metformin, while 
maintaining adequate power.
Synopsis (Overview 
of Study Design; 
Sample Size 
Determination);  
3.1, Overview of 
Study Design; 
4, Subject Population; 
11.2, Sample Size 
Determination
Reduced the sample size from 172 subjects (86 per group) to 146 subjects (73 per group) 
for the overall study while maintaining adequate power (85%) for detecting differences 
between the treatment groups to address the study’s primary objectives; and reduced the 
sample size for subjects on background metformin (with or without insulin), from 37 
subjects per group to 33 subjects per group while maintaining adequate 85% power.
Rationale: To apply FDA’s recommendation to remove the assessment of canagliflozin as add-on to diet and 
exercise only due to challenges in recruiting pediatric subjects with T2DM who are treatment-naïve (ie, on diet and 
exercise alone) for assessment of canagliflozin as monotherapy and to evaluate a population that is more 
representative of patients who will use canagliflozin.
Synopsis (Sample 
Size Determination; 
Major Secondary 
Objectives; Secondary 
Hypotheses; 
Multiplicity 
Adjustment); 
2.1, Objectives;
2.2, Hypotheses;
11.2, Sample Size 
Determination; 
11.3.1 Primary 
Efficacy Endpoint; 
11.3.2 Multiplicity 
Adjustment 
Deleted the major secondary objective about assessing the effect of canagliflozin relative 
to placebo in the subset of subjects on a background of diet and exercise only on glycated 
hemoglobin (HbA1c) after 26 weeks of treatment.
Deleted the hypothesis for the major secondary objectives.
Deleted that if results are significant, the analysis will then proceed to test the subset of 
subjects on a background of diet and exercise only.
Deleted information related to the target sample of 20 subjects per group and 80% power 
to assess canagliflozin’s efficacy.
Deleted the relevant analysis for the subgroup.
Deleted the test of the subset of subjects on a background of diet and exercise only.


JNJ-28431754  (canagliflozin)
Clinical Protocol 28431754DIA3018 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 14 August 2020
Rationale: To add descriptions of the treatment effect (ie, estimand) per ICH E9(R1) addendum on estimands and 
sensitivity analysis in clinical trials.
11.3.1 Primary 
Efficacy Endpoint
Added the descriptions of the estimand for the primary efficacy endpoint.
Rationale: To modify 3 inclusion/exclusion criteria to improve subject enrollment, by:
1) Increasing the upper limit of HbA1c to be in line with other pediatric T2DM studies. 
2) Changing the time frame for subjects on diet and exercise only, prior to screening. This allows for closer 
alignment with American Diabetes Association guidelines recommending that pharmacologic therapy should begin 
at the time of diagnosis. A reduced amount of time on diet and exercise only for subjects is preferable. 
3) Increasing the upper limit of normal (ULN) for alanine aminotransferase (ALT) is justified because increased 
transaminases and nonalcoholic fatty liver disease are not uncommon in this study population (Nadeau 2005, 
Newton 2016), and there are no contraindications for canagliflozin in relation to ALT up to 5 times ULN. Therefore, 
the study population will be more representative of patients who would use canagliflozin.
Synopsis (Objectives; 
Hypotheses; 
Overview of Study 
Design; Subject 
Population); 
2.1, Objectives; 
2.2, Hypotheses; 
3.1, Overview of 
Study Design; 
3.2, Study Design 
Rationale; 
4.1, Inclusion Criteria
Revised Inclusion Criterion #5 by modifying the upper limit of HbA1c from ≤10.5% to 
≤11.0%.
4.1, Inclusion Criteria
Revised the Inclusion Criterion #5a for diet and exercise from at least 8 weeks prior to 
screening to at least 4 weeks prior to screening.
4.2, Exclusion Criteria
Revised Exclusion Criterion #10 for ALT from >2 times the ULN to>5 times the ULN.
Rationale: To include additional information regarding study visits.
Time and Events 
Schedule (footnote a);
9.1.1.1, Visit 
Schedules and Visit 
Windows
Added that there may be exceptional cases where it is possible, with concurrence of the 
sponsor’s medical monitor, that certain on-site study visits may be replaced by 
telemedicine visits (a remote visit that is done by video or phone call).
Rationale: To correct or clarify minor inconsistencies within the protocol.
Time and Events 
Schedule (footnote y)
Clarified footnote “y” by deletion of fasting lipid panel at Screening and reminder to 
collect fasting lipid panel at Baseline visit/Day 1.
1.1, Background; 
1.1.3, Efficacy/Safety 
Studies; 
3.2, Study Design 
Rationale; 
14.1, Physical 
Description of Study 
Drug(s)
Updated references to the Investigator’s Brochure to Edition 18, May 2020.
1.2, Overall Rationale 
for the Study
Clarified that there are limited approved treatment options for T2DM in subjects ≥10 and 
<18 years of age.


JNJ-28431754  (canagliflozin)
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Status: Approved,  Date: 14 August 2020
3.1, Overview of 
Study Design; 
9.1.5, Post-treatment 
Phase (Follow-up); 
10.2.4, 
Comprehensive 
Follow-up at 
Scheduled Study 
Visits Following 
Premature 
Discontinuation of 
Study Drug
Aligned the list of specific data to be collected after a subject’s early discontinuation of 
study drug.
3.2, Study Design 
Rationale
Deleted the reference to (Lu 2008) and added (Tahara 1993).
6.2.1, Background 
Antihyperglycemic 
Therapies
Clarified that the adjustment to the AHA regimen is permitted during prolonged fasting (ie, 
religious events) and should be carefully implemented so as to avoid events of 
hypoglycemia.
6.2.2, Glycemic 
Rescue Therapy: 
Criteria and 
Implementation
Clarified the rescue initiation process to indicate that any subject that qualifies for 
initiation of rescue therapy should return to the clinic/investigational site.
9.3, Self-Monitoring 
of Blood Glucose 
(Run-in Period 
Management)
Revised the number of times subjects should perform fasting self-monitoring of blood 
glucose (SMBG) measurements from at least 3 times per week to a minimum of 3 days 
during the 2-week run-in period.
9.3, Self-Monitoring 
of Blood Glucose 
(Double-blind 
Treatment Phase 
Glycemic 
Management)
Added information on the SMBG requirement so that, during the double-blind treatment 
phase, investigators will counsel subjects to perform regular fasting SMBG determinations 
a minimum of 3 days per week with additional measurements made as considered 
clinically appropriate by the investigator and per local guidelines.
9.8, Safety 
Evaluations (Clinical 
Laboratory Tests)
Revised the specimen assessment to indicate that
if the subject cannot provide the 
morning void collection on the Week -2 visit, it must be provided prior to the Day 1 visit 
to assess whether the specimen is positive for protein.
10.3.1, Lost to follow-
up
Clarified that a subject’s contact information may be transferred to another study site.
12.2.1, All Adverse 
Events
Clarified that the comprehensive foot evaluation will occur at Day 1 instead of Screening.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, and/or spelling changes were made.
Amendment 3 25 June 2018
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.


JNJ-28431754  (canagliflozin)
Clinical Protocol 28431754DIA3018 Amendment 4
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Status: Approved,  Date: 14 August 2020
The overall reason for the amendment: The primary reason for this amendment is to have an independently 
powered subset of subjects on a background of diet and exercise only where superiority of canagliflozin vs placebo 
can be assessed.
Applicable Section(s)
Description of Change(s)
Rationale: To include analyses of the primary efficacy endpoint in an independently powered subset of subjects on 
a background of diet and exercise only.
Synopsis;
Section 2.1, 
Objectives; Section 
2.2, Hypotheses; 
Section 11.2, Sample 
Size Determination; 
Section 11.3.1, 
Primary Efficacy 
Endpoint;
11.3.2,Multiplicity 
Adjustment
Added major secondary objective and hypothesis.
Rationale: To provide additional clarification on eligibility of subjects for study enrollment. 
Section 4.2, Exclusion 
Criterion (#14)
Changed the sentence “Current participation in a canagliflozin study” to “Previously been, 
or is currently being treated with an SGLT2 inhibitor, or the subject has participated or is 
currently participating in a canagliflozin study”. 
Rationale: Minor errors were noted
Time Event Schedule
Section 9.1.2, 
Pretreatment Phase
Clarification to the Screening Visit: 
A non-fasting blood sample may be collected during the screening visit.
Protocol Amendment 
Table
Typographical error occurred to the version date of Amendment 2. Date changed to reflect 
correct date of 25 August 2017.
Attachment 8
Edits were made to the table to include column headings.
Amendment 2 25 August 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 this amendment is to reflect recommendations 
from the United States (US) Food and Drug Administration (FDA) on the statistical analysis.
Applicable Section(s)
Description of Change(s)
Rationale: In the primary analysis of glycated hemoglobin (HbA1c) change from baseline to Week 26, different 
weights will be assigned depending on the comparison, on the treatment assignment and re-randomization after 
Week 12.   
Synopsis Statistical 
Methods;
Section 11, Statistical 
Methods
The weight will be considered in the analyses when comparing each dose of canagliflozin 
vs. placebo. 


JNJ-28431754  (canagliflozin)
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Status: Approved,  Date: 14 August 2020
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that the requirement for a 24-hour urine sample collection after the first morning void at 
Week -2 is based on presence of “proteinuria” (assessed by dipstick) instead of “albuminuria” as previously stated.
Time and Events 
Schedule (footnote 
cc); Section 9.8 Safety 
Evaluations; 
Attachment 7
If the first morning void on Week -2 visit shows a presence of proteinuria (ie, proteinuria 
+1 and above) based on the central laboratory urine dipstick, a 24-hour urine collection 
will be done during the run-in period. Subjects who require a 24-hour urine collection prior 
to randomization, will also be required to provide a 24-hour urine sample on Week 26 and 
Week 52. Subjects who had a Week -2 first morning void negative for protein and develop 
a positive first morning void after randomization are not required to obtain 24-hour urine 
samples. 
Rationale: To clarify ketone measurement procedure.
4.2 Exclusion Criteria 
(Criterion #8); Section 
9.2 Ketone 
Monitoring; Section 
9.2.1.1 Pre-specified 
Ketone Measurements 
During Run-in Period
Clarified that the routine capillary blood ketone measurements should be obtained in a 
non-fasting state.
Clarified that for elevated capillary blood ketone levels (ie, ≥0.6 mmol/L) subjects will be 
required to record onto the study diary other pertinent information (concomitant blood 
glucose levels, signs/symptoms of illness, precipitating factors, etc). 
Revised the title of this section to “Pre-specified Ketone Measurements During Run-in 
Period” from “Ketone Measurement During the Run-in Period.”
Rationale: To clarify text or reconcile inconsistencies. 
Synopsis Overview of 
Study Design; Section 
3.1 Overview of 
Study Design; Section 
4.1 Inclusion Criteria 
Simplified eligibility criterion to align with the regions.
Time and Events 
Schedule
Modified the reference of Footnote “v”. 
Time and Events 
Schedule (footnote b); 
Section 9.1.1.1 Visit 
Schedules and Visit 
Windows; Section 
9.1.2 Pre-treatment 
Phase
Clarified that the screening period and/or run-in period may be increased by 1 or 2 weeks 
to allow sufficient time for results of pancreatic autoimmunity testing (if needed) to be 
received by the site to assess subject’s eligibility.
Synopsis Overview of 
Study Design; Section 
9.1.4 
Double-blind 
Treatment Phase
Clarified that subjects who are eligible for re-randomization based on Week 12 HbA1c and 
an estimated glomerular filtration rate (eGFR) will be re-randomized in a 1:1 ratio. 
Section 9.6.2 
Analytical Procedures
Removed text to indicate that plasma pharmacokinetic (PK) samples may be stored for 
future analysis of the metabolic profile.  
Section 15 Study-
Specific Materials 
Added ketone strips (blood and urine) and alcohol wipes; removed the manual of 
instructions regarding diabetic ketoacidosis (DKA) events from the study-specifics 
materials. 


JNJ-28431754  (canagliflozin)
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Status: Approved,  Date: 14 August 2020
Applicable Section(s)
Description of Change(s)
Section 16.2.3 
Informed 
Consent/Pediatric 
Assent
Clarified text regarding the informed consent form (ICF) for subjects who have become 
adults during the study.  
Attachment 6
Clarified that the Tanner Staging must be performed by the investigator or site staff and 
not by the subject and parent or legally acceptable representative. 
Attachment 7
Removed glucose, cholesterol, and triglycerides from the serum chemistry panel. 
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 27 March 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: To modify the study design to allow the assessment of canagliflozin when 
used with and without titration which is more reflective of how canagliflozin may be used in this pediatric 
population, and to add ketone monitoring procedures.
Applicable Section(s)
Description of Change(s)
Rationale: This revised treatment strategy is more likely to represent real-world prescribing practices and is 
consistent with treatment guidelines for non-insulin titratable anti-hyperglycemic agents which consist of starting at 
a lower dose and re-assessing the need to increase the dose after at least 3 months of treatment when typically, near-
maximal to maximal HbA1c-lowering effect is observed. In the proposed revised study design, subjects will initially 
be treated with canagliflozin 100 mg (or placebo) and their HbA1c will be evaluated after 12 weeks. Those who fail 
to achieve the HbA1c goal of <7.0% will be re-randomized to either remain on canagliflozin 100 mg (or placebo) or 
to up-titrate to canagliflozin 300 mg (or placebo). This titration strategy, which is aligned with the canagliflozin 
prescribing information, will allow the evaluation of whether increasing the dose of canagliflozin is beneficial to 
pediatric patients.
Synopsis Objectives 
and Hypotheses;
2.1 Objectives; 
Synopsis Hypotheses;
2.2 Hypotheses; 
Synopsis Overview of 
Study Design; 3.1 
Study Design; 6. 
Dosage and 
Administration
To change the study design from a 3-arm study (placebo, canagliflozin 100 mg, and 
canagliflozin 300 mg) to a 2-arm study that compares placebo to canagliflozin 
administered at a starting dose of 100 mg and a re-randomization of subjects who fail to 
achieve a HbA1c goal of <7.0% after 12 weeks of treatment and who have adequate renal 
function to either up-titrate to 300 mg (or matching placebo) or remain on 100 mg (or 
matching placebo).


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Applicable Section(s)
Description of Change(s)
Rationale: Given the mechanism of action of canagliflozin it is possible that mild ketonemia might be detected 
especially with fasting in otherwise non-acutely ill subjects. According to the recent American Association of 
Clinical Endocrinologists (AACE) position statement (Handelsman 2016), daily or routine measurement of urine 
ketones is not recommended as this measurement can be misleading. Instead, measurement of blood ketones is 
preferred for diagnosis of diabetic ketoacidosis (DKA). Therefore, proposed ketone monitoring strategy employs the 
use of capillary ketone measurements to be obtained whenever subjects are ill, or may be at increased risk for 
ketosis (eg, non-compliance with insulin treatment, low-carb diet, etc). This “trigger-based monitoring” approach is 
expected to increase compliance in this population that is unlikely to adhere to daily monitoring with either urine or 
blood ketones.
Synopsis Overview of 
Study Design; 
Synopsis Safety 
Evaluations; Time and 
Events Schedule; 3.1 
Study Design; 3.2 
Study Design 
Rationale;
4.2 Exclusion Criteria; 
9.1.3 Single-Blind 
Placebo Run-In Visit 
(Week -2);
9.2 Ketone 
Monitoring; 9.8 Safety 
Evaluations;
Attachment 1; 
Attachment 2
To add ketone monitoring procedures (capillary blood measurement on 3 days during the 
2-week run-in period and in the case of intercurrent illness/stress or other precipitating 
factor) and related eligibility criteria, and to provide instructions on sick day management.
Rationale: To change requirement for fasting procedures/visits when no fasting samples are required to be 
collected, and to allow more flexibility with visits schedule windows.
4.1 Inclusion Criteria;
4.2 Exclusion Criteria; 
9.1.1. Overview; 
Attachment 7
Changed requirement for fasting procedures/visits.
Rationale: The glycemic rescue criteria have been revised based on feedback from the Pediatric Diabetes 
Consortium (PDC) that indicated that fasting plasma glucose (FPG) in this population is of limited value given the 
variability of this measurement that may lead to unnecessary rescue or to unnecessary unscheduled visits to obtain 
repeat measurements to confirm whether rescue criterion is met. Instead, the sponsor proposes to trigger rescue 
based on changes in HbA1c from baseline. This will not only eliminate the “noise” of daily glucose fluctuation but 
will also likely significantly reduce the study burden to subjects, decrease the likelihood that subjects will drop-out, 
and increase compliance with study procedures as subjects will not be required to fast when attending study visits to 
obtain FPG measurements.
Synopsis Glycemic 
Rescue; 3.1 Study 
Design; 6.2.2.
Glycemic Rescue 
Therapy: Criteria and 
Implementation
Replaced the former glycemic rescue criteria of FPG and HbA1c, with changes from 
baseline in HbA1c to align with HbA1c re-randomization criterion and with reduction of 
fasting visits.


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Applicable Section(s)
Description of Change(s)
Rationale: Based on data from the PDC, many pediatric patients with T2DM have a baseline HbA1c of <7.0% 
(Tamborlane 2016), especially those who are on diet and exercise alone and on metformin monotherapy, the latter of 
which will likely represent the largest proportion of subjects recruited into the canagliflozin pediatric study. In light 
of the anticipated low baseline HbA1c values and the acknowledged recruitment difficulties and challenges for the 
study, the sponsor has re-examined the original statistical assumptions and believes that the current standard 
deviation (SD) of 1.0% for HbA1c change from baseline should be lowered to 0.9%. Furthermore, due to the change 
in study design above, the sponsor proposes to evaluate the HbA1c efficacy of canagliflozin by comparing all 
subjects who are randomized to canagliflozin to all subjects who are randomized to placebo. These 2 proposed 
changes will allow a reduction in sample size from 285 subjects to 172 subjects (86/group) and increases the 
likelihood of completing the study and evaluating the primary hypothesis.
Synopsis Overview of 
Study Design, 
Statistical Methods; 
3.1 Study Design; 
4. Subject Population; 
11.2. Sample Size 
Determination
Reduced the overall sample size and statistical testing order due to the change in study 
design.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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SYNOPSIS
A Randomized, Multicenter, Double-Blind, Parallel-Group, Placebo-Controlled Study to 
Investigate the Efficacy and Safety of Canagliflozin in Children and Adolescents (≥10 to <18 years) 
with Type 2 Diabetes Mellitus
OBJECTIVES AND HYPOTHESIS
Objectives
In children and adolescents (10 to <18 years) with type 2 diabetes mellitus (T2DM) who have 
inadequate glycemic control (ie, hemoglobin A1c [HbA1c] of 6.5% to 11.0%), either on diet and 
exercise only, or on diet and exercise and metformin monotherapy, or on diet and exercise and insulin 
monotherapy, or on diet and exercise and combination therapy with metformin and insulin:
Primary Objectives

To assess the effect of canagliflozin relative to placebo on HbA1c after 26 weeks of treatment.

To assess the overall safety and tolerability of canagliflozin.
Major Secondary Objectives

After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo in the subset of 
subjects on a background of metformin (with or without insulin) on HbA1c

After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:

Fasting plasma glucose (FPG) 

Proportion of subjects with HbA1c <7.5%, <7.0%, and <6.5%

Time to rescue therapy and proportion of subjects receiving rescue therapy

Body weight 

After 52 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:

HbA1c and FPG

Proportion of subjects with HbA1c <7.5%, <7.0%, and <6.5% 

Time to rescue therapy and proportion of subjects receiving rescue therapy

Body weight
Additional Secondary Objectives

After 12 weeks of treatment to assess the effects of canagliflozin relative to placebo on HbA1c

After 26 weeks of treatment, to assess the effect of canagliflozin 100 mg relative to placebo on 
HbA1c

After 26 weeks of treatment, to assess the effect of canagliflozin 100 mg followed by a dose increase 
to 300 mg relative to placebo on HbA1c

After 26 weeks and 52 weeks of treatment, to assess the effect of canagliflozin relative to placebo 
on:

Body mass index (BMI)


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
Fasting plasma lipids (ie, low-density lipoprotein-cholesterol [LDL-C], high-density 
lipoprotein-cholesterol [HDL-C], total cholesterol, non-HDL-C, LDL-C to HDL-C ratio, 
non-HDL-C to LDL-C ratio, and triglycerides)

Systolic and diastolic blood pressure 

Growth velocity and Tanner Staging

Markers of calcium and phosphate homeostasis, (calcium, magnesium, phosphate, parathyroid 
hormone [PTH], 25-hydroxy Vitamin D, calcitonin; urinary excretion of calcium and 
phosphate)

Bone turnover markers (serum osteocalcin and serum collagen type 1 carboxy-telopeptide 
[CTx])

Urinary albumin/creatinine ratio
Hypotheses
In children and adolescents (10 to <18 years) with T2DM who have inadequate glycemic control 
(ie, HbA1c of 6.5% to 11.0%), either on diet and exercise only, or on diet and exercise and metformin 
monotherapy, on diet and exercise and insulin monotherapy or on diet and exercise and combination of 
metformin and insulin:
Primary Hypothesis

After 26 weeks of treatment, canagliflozin reduces HbA1c relative to placebo.
Secondary Hypotheses

After 26 weeks of treatment, canagliflozin reduces HbA1c relative to placebo in the subset of subjects 
on background of metformin (with or without insulin).
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, 2-arm, parallel-group, multicenter study. At least
146 subjects with T2DM 10 and <18 years of age who have inadequate glycemic control (ie, HbA1c of 
6.5% to 11.0%) and who meet 1 of the criteria below will be eligible to be screened:

Are on diet and exercise only for at least 4 weeks prior to screening,
or

Are on diet and exercise and a stable dose of metformin monotherapy 1,000 mg per day or 
maximum tolerated dose (MTD) per day (defined by the investigator) for at least 8 weeks prior to 
screening,
or

Are on diet and exercise and a stable insulin monotherapy regimen for at least 8 weeks prior to 
screening (stable dose is defined as no change in the insulin regimen [ie, type{s} of insulin] and
15% change in the total daily dose of insulin [averaged over 1 week to account for day to day
variability]),
or

Are on diet and exercise and a stable combination therapy with metformin and insulin for at least 
8 weeks prior to screening.


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Note: Subjects who are on diet and exercise and a stable dose of metformin extended release (XR) for at 
least 8 weeks prior to screening may be included in the study; however, they will be switched from 
metformin XR to metformin immediate release (IR) (at the same daily dose or nearest appropriate dose) at 
the single-blind placebo run-in visit and will be enrolled in the study if the metformin IR is well tolerated 
during the 2-week single-blind placebo run-in period prior to Visit 3/Day 1.
Eligible subjects will go directly into a 2-week single-blind placebo run-in period and may then be 
randomized if they meet all other enrollment criteria. The goal is to have at least 30% of participants that 
will be 10 to <15 years of age, 30% to <65% of participants that will be female in each age group (10 to 
<15 years and 15 to <18 years), and 30% of participants that will have ethnicity and lifestyle comparable 
to Europe. 
Subjects who meet all enrollment criteria will be randomly assigned in a 1:1 ratio to once-daily 
administration of canagliflozin 100 mg or matching placebo and enter a 52-week double-blind 
placebo-controlled treatment phase consisting of a 26-week core double-blind treatment period, followed 
by a 26-week double-blind extension treatment period. Randomization will be stratified by 
antihyperglycemic agent (AHA) background (ie, diet and exercise only; metformin monotherapy; insulin 
monotherapy, or combination therapy of insulin and metformin) and age group [10 to <15 years old; 
15 to <18 years old]. Subjects who at Week 12 have an HbA1c of 7.0% and an estimated glomerular 
filtration rate (eGFR) 60 mL/min/1.73m2 will be re-randomized in a 1:1 ratio to either remain on 
double-blind canagliflozin 100 mg (or matching placebo) or to up-titrate to double-blind canagliflozin 
300 mg (or matching placebo).
The total duration of the study, including the 1-week screening phase, the 2-week single-blind placebo
run-in period, the 52-week double-blind placebo-controlled treatment phase, and the 30-day follow-up
post-treatment phase is approximately 59 weeks for each subject.
The key efficacy evaluations include HbA1c, FPG, body weight, proportion of subjects reaching HbA1c
goals, and use of rescue medication. 
Safety and tolerability evaluations will include the monitoring of adverse events, collection of 
hypoglycemia events, capillary blood ketone monitoring, physical examinations, measurement of body 
weight, vital sign measurements, clinical laboratory tests, self-monitoring of blood glucose (SMBG), 
bone turnover markers, markers of calcium and phosphate homeostasis, urinary albumin/creatinine ratio, 
growth velocity and Tanner Staging. 
Early withdrawal evaluations will be performed in subjects who prematurely discontinue study drug and 
in subjects who withdraw from the study (either on their own and/or by parent[s]/legal guardian[s]). The 
early withdrawal visit evaluation should be performed as soon as possible after the last dose of study drug 
is taken. Subjects who discontinue study drug prematurely should continue to attend all subsequent study 
visits and be followed to the end of the study (Week 52).
All subjects, regardless of their study completion status, will have a follow-up telephone contact (or 
optional study visit, at the discretion of the investigator) approximately 30 days after their last dose of 
study drug is taken to collect information on any serious adverse events and adverse events of interest. 
Subjects who discontinue the study during the double-blind treatment phase will not be replaced.
Re-randomization 
At Week 12, subjects’ glycemic status will be assessed by the central laboratory. Following the review of 
the Week 12 unmasked HbA1c and eGFR values, the following will occur:


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
Subjects with an HbA1c value <7.0% or eGFR <60
mL/min/1.73m2 will not undergo 
re-randomization and instead will continue their current treatment assignment (ie, canagliflozin 
100 mg or matching placebo) for the remainder of the study. 

Subjects with an HbA1c value 7.0% and eGFR 60 mL/min/1.73m2 will be re-randomized (in a 
blinded fashion via the interactive web response system [IWRS]) to either

remain on their original treatment assignment (ie, canagliflozin 100 mg or matching placebo) or 

up-titrate canagliflozin 100 mg to 300 mg (or matching placebo). To maintain the study blind, 
subjects randomized to placebo will undergo a mock up-titration.
For subjects with a Week 12 HbA1c 7.0% and who are on insulin and have experienced recurrent (ie, at 
least 2 episodes within a 7-day period) episodes of hypoglycemia after randomization, consideration 
should be given to down-titrate insulin prior to the blinded up-titration (or mock up-titration) to 
canagliflozin 300 mg. 
Since the unmasked central laboratory HbA1c values will not be immediately available at the Week 12 
visit, subjects (or their parent/legal guardian) will be informed whether the subject is eligible for 
re-randomization via a telephone contact. If the subject is eligible for re-randomization, then the subject 
and/or their parent/legal guardian will return to the site, preferably within 1 week from Week 12 to return 
any unused study drug and obtain new blinded study drug according to IWRS assignment. Although no 
additional study or laboratory procedures will occur at this visit, and the subject is not required to be 
physically present, the subject’s attendance is highly encouraged to allow the site to provide new dosing 
instructions related to the double-blind treatment.
Management of double-blind study drug based on renal function: 

Subjects who have undergone re-randomization and subsequently have a confirmed eGFR 
<60 mL/min/1.73m2 will undergo down-titration (or mock down-titration) of blinded study drug at an 
unscheduled down-titration visit; only those subjects who were re-randomized to the canagliflozin 
300 mg dose will actually titrate down (in a blinded fashion via the IWRS). Subjects randomized to 
canagliflozin 100 mg or placebo will undergo a mock down-titration and will continue on their 
randomized treatment.

If at any time during the study, a subject has an eGFR of <45 mL/min/1.73m2 that is confirmed within 
1 week, the subject must be discontinued from study drug. Subjects discontinued from study drug and 
who do not withdraw consent will remain in the study and will be followed for post-treatment 
evaluations for the duration of the study. 

Prior to down-titrating or discontinuing canagliflozin due to eGFR <60 mL/min/1.73m2 or 
<45 mL/min/1.73m2, respectively, a repeat determination should be performed within 1 week and 
study drug down-titrated or discontinued if the repeat determination confirms that the value still 
meets the criteria (unless a reversible acute cause is identified [eg, short-term illness or transient 
volume depletion] in which case an additional repeat determination can be performed after resolution 
of the illness).

All subjects will receive a new medication kit assignment through the IWRS at the unscheduled 
down-titration visit. The investigator, or qualified assigned designee, will provide the subject with 
double-blind treatment medication, updated instructions on dosing and a new subject diary. The 
subject will be instructed to continue with the diet and exercise regimen and the completion of the 
study diary.
Note: Once a subject has up-titrated to canagliflozin 300 mg, down-titration is not allowed unless for 
confirmed eGFR <60 mL/min/1.73m2. Therefore, if after up-titration to canagliflozin 300 mg a subject 


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experiences recurrent hypoglycemia (ie, at least 2 episodes within a 7-day period), consideration should 
be given to down-titrate background AHA(s) such as insulin (or metformin).
Glycemic Rescue
Subjects who meet the protocol-specified glycemic rescue criteria, despite reinforcement of compliance 
with background AHA therapy, study drug and lifestyle counseling, may return to the clinic for a rescue 
visit, per the investigator’s judgment, where he/she may either alter background AHA therapy 
(ie, metformin and/or insulin) or initiate an approved AHA for the pediatric population as per the local 
label. Rescued subjects will continue in the study on double-blind study drug.
SUBJECT POPULATION
Eligible subjects must be between the ages of 10 and <18 years at the time of screening, have a 
diagnosis of T2DM before screening, with C-peptide at screening >0.6 ng/mL (>0.2 nmol/L) and an 
HbA1c of 6.5% to 11.0%. At the time of screening, subject may be on diet and exercise only, or on 
stable dose of metformin monotherapy 1,000 mg per day or MTD per day, or on a stable insulin 
monotherapy regimen, or on a stable combination therapy with metformin and insulin.
Note: Subjects who are on diet and exercise and a stable dose of metformin XR for at least 8 weeks prior 
to screening may be included in the study, however they will be switched from metformin XR to 
metformin IR (at the same daily dose or nearest appropriate dose) at the single-blind placebo run-in visit 
and will be enrolled in the study if the metformin IR is well tolerated during the 2-week placebo run-in 
period prior to Visit 3/Day 1. 
DOSAGE AND ADMINISTRATION
Single-Blind Study Drug
During the 2-week single-blind placebo run-in period, subjects will take 1 placebo tablet matching 
canagliflozin 100 mg once-daily before the first meal of the day. 
Double-Blind Study Drug
During the first 12 weeks of the double-blind treatment phase, subjects will take 1 tablet of canagliflozin 
100 mg or matching placebo once-daily before the first meal of the day. 
At Week 13, subjects who have a Week 12 HbA1c of 7.0% and eGFR 60 mL/min/1.73m2 will be 
re-randomized in a 1:1 ratio to either remain on double-blind canagliflozin 100 mg (or matching placebo) 
or to up-titrate to double-blind canagliflozin 300 mg (or matching placebo). A double-dummy approach 
will be used to maintain the blind to dose-assignments as indicated below: 

Subjects initially randomized to placebo and undergoing re-randomization at Week 13 will continue 
receiving 1 tablet of placebo matching canagliflozin 100 mg and will ADD 1 tablet of placebo 
matching canagliflozin 300 mg for the remainder of the double-blind treatment period.

Subjects initially randomized to canagliflozin 100 mg and re-randomized to remain on canagliflozin 
100 mg at Week 13 will continue receiving 1 tablet of canagliflozin 100 mg and will ADD 1 tablet 
of placebo matching canagliflozin 300 mg for the remainder of the double-blind treatment period.

Subjects initially randomized to canagliflozin 100 mg and re-randomized to up-titrate to 
canagliflozin 300 mg at Week 13 will switch to 1 tablet of placebo matching canagliflozin 100 mg 
and will ADD 1 tablet of canagliflozin 300 mg for the remainder of the double-blind treatment 
period. 


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Subjects not undergoing re-randomization (ie, HbA1c of <7.0% or eGFR <60 mL/min/1.73m2) at Week 13 
will continue to receive 1 tablet of canagliflozin 100 mg or matching placebo for the remainder of the 
double-blind treatment period.
A summary of study drug administration is provided in the table that follows.
Summary of dose level and number of tablets by study period and treatment.
Study Period
Criteria for re-
randomization
Treatment Group: 
canagliflozin
Treatment Group: 
placebo
Day 1 to re-
randomization
Not applicable
1 tablet of canagliflozin 100 
mg
1 tablet of placebo matching 
canagliflozin 100 mg 
Re-randomization
to Week 52
NOT eligible for re-
randomization if: 
HbA1c< 7.0% or
eGFR <60 
mL/min/1.73m2
1 tablet of canagliflozin 100 
mg 
1 tablet of placebo matching 
canagliflozin 100 mg
Re-randomization
to Week 52
Eligible for re-
randomization if: 
HbA1c ≥7.0% and
eGFR ≥60 
mL/min/1.73m2
1 tablet of canagliflozin 100 
mg 
                         AND
1 tablet of placebo matching 
canagliflozin 300 mg
or
1 tablet of canagliflozin 300 
mg 
                       AND
1 tablet of placebo matching 
canagliflozin 100 mg
1 tablet of placebo matching 
canagliflozin 100 mg 
                AND
1 tablet of placebo matching 
canagliflozin 300 mg
EFFICACY EVALUATIONS/ENDPOINTS
Primary Efficacy Endpoint
The primary efficacy endpoint will be the change in HbA1c from baseline to Week 26. 
Major Secondary Efficacy Endpoints
Key secondary endpoints will include the change from baseline to Week 26 and change from baseline to 
Week 52 in FPG, body weight, and proportion of subjects with an HbA1c <7.5%, <7.0% and <6.5%, and 
time to rescue and proportion of subjects receiving rescue therapy. 
Additional Secondary Efficacy Endpoints
Additional secondary endpoints include change from baseline to Week 12 in HbA1c, and change from 
baseline to Week 52 of BMI, fasting lipid profile, systolic and diastolic blood pressure, and HbA1c.
PHARMACOKINETIC EVALUATIONS
Venous blood samples of 4 mL will be collected at Week 12, Week 26, end-of-treatment (EOT Week 52), 
and at early withdrawal visit for determination of plasma trough concentrations of canagliflozin in all 
subjects. On the days when pharmacokinetic (PK) blood samples are collected, subjects will be instructed 
to refrain from taking the study drug before the clinic visit and to bring the study drug to the clinic visit. 
The subjects will be instructed to take the dose of study drug immediately before the subject’s next meal. 
The subjects will record the time that the study drug was taken on the day preceding the clinic visit. The 


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exact dates and times of blood sampling must be recorded in the electronic case report form (eCRF) or 
laboratory requisition form. 
ARCHIVE SAMPLES FOR EXPLORATORY RESEARCH AND SPECIMEN FOR 
BIOMARKER ASSESSMENT 
Fasting plasma, serum, and urine archive samples will be collected (where local regulations permit) to 
allow for biomarker analyses and exploratory research related to canagliflozin or T2DM and obesity.
SAFETY EVALUATIONS
Safety and tolerability evaluations, according to the time points provided in the Time and Events 
Schedule will include: 

Collection/monitoring of adverse events 

Collection of potential hypoglycemic episodes (eg, from the subject diary provided to subjects)

Ketone monitoring

Physical examinations 

Body weight 

Vital signs (blood pressures and pulse rates) 

Safety laboratory tests (including chemistry, hematology, urinalysis)

SMBG

Bone turnover markers (serum osteocalcin and serum collagen type 1 CTx) 

Markers of calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH, 25-hydroxy 
Vitamin D, calcitonin, urinary excretion of calcium and phosphate)

Urinary albumin/creatinine ratio

Assessment of growth velocity and Tanner Staging 
STATISTICAL METHODS
Analysis Sets
The full analysis set (FAS) population includes all subjects who are randomly assigned to a treatment 
group, have received at least one dose of study drug and have a baseline HbA1c measurement. The per 
protocol (PP) analysis set consists of all FAS subjects who complete the 26-week double-blind treatment 
phase and have no major protocol deviations that may affect the interpretation of the primary efficacy 
endpoint. Major protocol deviations will be defined in the Statistical Analysis Plan (SAP).
The safety analysis set will include randomized subjects who take at least 1 dose of study drug.
The primary efficacy analyses, to demonstrate the superiority of canagliflozin compared with placebo, 
will be based on the FAS population. Supportive analyses include the PP analysis set, which will also be 
performed for the primary endpoint of HbA1c. 
Efficacy data will be analyzed according to the initial randomization assignment, regardless of the actual 
treatment received. Safety data will be analyzed according to the predominant treatment received, in the 
event that subjects received a treatment other than that to which they were randomly assigned to receive. 
The approach used to handle study deviations will be detailed in the SAP.


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Sample Size Determination
The primary hypothesis of the study is that canagliflozin is superior to placebo in glycemic control, as 
measured by the change from baseline to Week 26 in HbA1c. The sample size calculation is based on the 
2-stage randomization design using a 2-sample, 2-sided t-test with Type 1 error rate of 0.05. Based on the 
following assumptions on treatment effect (0.4 to 0.5%) and an associated common standard deviation of 
0.9% and assuming 50% of the subjects will meet the re-randomization criteria at Week 12, it is estimated 
that at least 66 subjects per group will be required to achieve approximately 85% power to meet the 
study’s primary objectives. To account for attrition due to study discontinuation in a longitudinal analysis, 
a 10% sample size inflation factor is employed, and a total of at least 146 subjects (73 per arm) will be 
randomized in this study.
Treatment group
Meeting re-
randomization 
criteria at Week 12
Placebo-subtracted group difference 
in change in HbA1c from baseline to 
Week 26
canagliflozin 100 mg to canagliflozin 100 mg
No
0.5%
canagliflozin 100 mg to canagliflozin 100 mg
Yes
0.4%
canagliflozin 100 mg to canagliflozin 300 mg
Yes
0.5%
For the subjects who are on background metformin (with or without insulin), it is estimated with the 
following assumptions that at least 33 subjects per group (after accounting for attrition due to study 
discontinuation) will be required to achieve approximately 85% power to assess the efficacy of 
canagliflozin on a background of metformin.
Treatment group (add-on to metformin)
Meeting re-
randomization 
criteria at Week 12
Placebo-subtracted group difference 
in change in HbA1c from baseline to 
Week 26
canagliflozin 100 mg to canagliflozin 100 mg
No
0.75%
canagliflozin 100 mg to canagliflozin 100 mg
Yes
0.65%
canagliflozin 100 mg to canagliflozin 300 mg
Yes
0.75%
Safety Analyses
Subjects in the safety analysis set (defined as subjects who are randomized and dosed) will be included in 
the denominators for the summaries of adverse events, exposure, and concomitant medication data. There 
will be no imputation of missing values for clinical safety laboratory test results, vital sign measurements, 
and evaluations in the safety analyses. 
All safety analyses (except hypoglycemia) will be summarized regardless of the use of rescue medication; 
given the potential confounding due to rescue medication, analyses related to hypoglycemia will only be 
presented prior to rescue medication.
Efficacy Analyses
The primary efficacy endpoint will be the change in HbA1c from baseline at Week 26.
Estimand
The primary efficacy estimand is described according to the following attributes:

Population: children and adolescents (≥10 to <18 years) with T2DM who have an HbA1c ≥6.5% to 
≤11.0%

Variable: change in HbA1c from baseline to Week 26

Treatments: canagliflozin vs placebo


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
Intercurrent event (events that preclude observation of the variable or affects its interpretation): 
treatment discontinuation or initiation of rescue medication, variable is used regardless of early 
treatment discontinues or initiation of rescue medication

Treatment policy strategy: the measurements of the variable of interest are used regardless of the 
occurrence of the intercurrent event

Population-level summary for the variable: the placebo-subtracted difference (ie, canagliflozin
versus placebo) in least-squares mean change of HbA1c from baseline  at Week 26 along with the 
2-sided 95% CI
This estimand targets the effect of canagliflozin on the variable measured and follows an “ITT principle” 
strategy.
The main analysis of the primary efficacy outcome will be based on all HbA1c measurements (regardless 
of the occurrence of treatment discontinuation or initiation of rescue medication) and will employ pattern 
mixture modelling using multiple imputation methods. The imputed datasets will be analyzed using 
analysis of covariance (ANCOVA) with terms for treatment, stratification factors, and baseline HbA1c. 
Additional details will be specified in the SAP.
The following sensitivity analyses will be performed: 

The primary efficacy endpoint will be analyzed using a mixed model for repeated measures 
(MMRM) based on restricted maximum likelihood. The analysis will use the observed data and will 
include the fixed, categorical effects of treatment, stratification factors (ie, background AHA and age 
group), visit, and treatment-by-visit interaction, as well as the fixed, continuous covariates of 
baseline and baseline-by-visit interaction. An unstructured covariance will be used to model the 
within-patient errors. This sensitivity analysis will constitute the primary analysis based on a specific 
health authority request.

The change from baseline in HbA1c will be analyzed using an ANCOVA model with treatment and 
the stratification factors as fixed effects and baseline HbA1c value as a covariate. The treatment 
differences in the least-squares means and the 2-sided 95% CI will be estimated based on this model. 
The last-observation-carried-forward (LOCF) method will be applied when the Week 26 values are 
missing.
The following supplementary analysis will be performed using the primary estimand:

A re-randomization test (Proschan 2011) (utilizing the MMRM as described above) will be used to 
determine the p-value for the primary efficacy comparison (ie, comparing all subjects who are 
randomized to canagliflozin to all subjects who are randomized to placebo). The re-randomization 
test will fix the observed HbA1c data, regenerate treatment assignments for the entire study using the 
same minimization algorithm employed in the study and compute the test statistics corresponding to 
the primary efficacy comparison. This process will be repeated at least 1,000 times. The p-value for 
the primary efficacy comparison will be defined as the proportion of re-randomized studies whose 
test statistic for that comparison is at least as extreme as that of the original treatment assignment.
The primary efficacy endpoint will also be performed in the FAS in the subset of subjects on a 
background of metformin (with or without insulin) using the main analysis methods described above. 
Analyses for the other AHA subgroups in the FAS may also be performed.
Additional details on the data handling rules (including the data window used for analysis) will be 
described in the SAP.


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Multiplicity Adjustment
To strongly control the family-wise error rate at the 5% significance level, a sequential testing procedure 
will be applied first in testing the primary endpoint for all subjects (ie, FAS). If the results are significant
(2-sided alpha level of 0.05), it will then proceed to test the subset of subjects on a background of 
metformin (with or without insulin) to placebo. 
The comparisons by canagliflozin dose to placebo will be presented and analyzed using the weights in the
analyses described below.

When comparing the subjects who initially receive canagliflozin 100 mg with no dose increase to 
300 mg to placebo: All subjects start with a weight of 1. After Week 12, subjects with an HbA1c
7.0% and eGFR 60 mL/min/1.73m2 who are re-randomized to continue canagliflozin 100 mg will 
have a weight of 2. The subjects who are re-randomized to up-titrate to canagliflozin 300 mg will 
have a weight of 0. 

When comparing the subjects who initially receive canagliflozin 100 mg followed by a dose increase 
to 300 mg to placebo: All subjects start with a weight of 1. After Week 12, subjects with an HbA1c
7.0% and eGFR 60mL/min/1.73m2 who are re-randomized to continue canagliflozin 100 mg will 
have a weight of 0 and those who are re-randomized to up-titrate to canagliflozin 300 mg will have a 
weight of 2.
Secondary Efficacy Endpoints
The categorical secondary efficacy endpoint of maintaining HbA1c <7.0% (and HbA1c <6.5% and HbA1c
<7.5%) will be analyzed longitudinally using a generalized linear mixed model in the FAS population. 
The model will include the fixed, categorical effects of treatment, stratification factors (ie, background
AHA and age group), visit, and treatment-by-visit interaction, as well as the fixed, continuous covariates 
of baseline and baseline-by-visit interaction. An unstructured covariance will be used to model the within 
subject errors. The odds ratio and 2-sided 95% CI for the treatment comparisons at Week 26 
(canagliflozin compared to placebo) will be estimated based on this model. 
Continuous endpoints (except for triglycerides) will be analyzed with an MMRM model described before 
in the FAS population. For the endpoints with post-baseline assessments taken only at Week 26 and Week 
52, an ANCOVA model similar to the primary efficacy endpoint will be used at Week 26. The least-
squares means for the treatment comparisons and their 2-sided 95% confidence intervals will be estimated 
based on this model. The analysis of percent change in triglycerides may be based on nonparametric 
methods (given the anticipated skewed nature of this parameter) or alternative methods, to be further 
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Key: EOT= end-of-treatment; Wk= week; SB PBO= single-blind placebo; TC= telephone contact
a.
All visits will be scheduled based on the date of randomization (Day 1). The study visits should generally occur within a 7-day recommended window (ie, ±7 days) around the 
protocol-specified visit schedule during the double-blind treatment phase. There may be exceptional cases where it is possible, with the concurrence of the sponsor’s medical 
monitor, that certain on-site study visits may be replaced by telemedicine visits (a remote visit that is done by video or phone call).
b.
The run-in start visit should generally be 1 week after the screening visit (with a recommended window of +/- 4 days). Subjects who at screening may require testing of pancreatic 
autoimmunity (ie, GAD-65 and/or IA antibodies) or who require a repeat of other screening procedures may have the duration of the screening period and/or run-in period 
increased by 1 to 2 weeks to allow sufficient time for the assessments to be obtained.
c.
Subjects who have a Week 12 HbA1c of 7.0% and eGFR 60 mL/min/1.73m2 will be re-randomized to either remain on double-blind canagliflozin 100 mg (or matching placebo) 
or to up-titrate to double-blind canagliflozin 300 mg (or matching placebo). See Section 9.1.4.3, Re-randomization.
d.
Early withdrawal visit evaluations will be performed in subjects who prematurely discontinue study drug (see Section 10.2, Study Drug Treatment Premature Discontinuation, 
Reinstitution, and Follow-up) and in subjects who withdraw consent from the study (either on their own and/or by their parents[s]/legal guardian[s]). See Section 10.3, Withdrawal 
from the Study). The early withdrawal visit evaluation should be performed as soon as possible after the last dose of study drug is taken.
e.
A telephone follow-up contact (or optional study visit, at the discretion of the investigator) will be conducted for all subjects approximately 30 days after the last dose of study 
drug to collect serious adverse events and adverse events of interest since the last visit unless the subject has died, has been lost to follow-up, or has withdrawn consent. If a 
telephone contact or study visit is not possible, follow-up information may be collected via email or other electronic means. This follow-up is not required in subjects who 
discontinue study drug prematurely and continue to attend all subsequent study visits. 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.
f.
The informed consent form for the parent(s)/legal guardian(s) (and the assent form for minor subjects, as described in Section 16.2.3, Informed Consent/Pediatric Assent) must be 
signed before any study procedure is performed.
g.
Inclusion/Exclusion criteria must be reviewed at all visits up to and including the baseline visit/Day 1. Eligibility cannot be confirmed until the results of screening procedures and 
all screening laboratory test results are returned and reviewed.
h.
Record any medications taken from up to 30 days before screening (and up to 6 months before screening for AHAs) until the first dose of double-blind study drug on Day 1 
(baseline) as prestudy therapy in the corresponding eCRF.
i.
Concomitant therapy includes all medications since the first dose of study drug on Day 1; after study drug discontinuation, use of AHA therapies will be recorded at the final visit 
or contact.
j.
Eligibility for re-randomization will be based on HbA1c and eGFR values obtained at Week 12. At this visit sites should schedule appointment for Week 13 for ALL subjects and 
confirm or cancel by phone upon review of laboratory results.
k.
Only those subjects who qualify for re-randomization will return to the site at Week 13 where the site personnel will dispense new bottles of study drug and provide new dosing 
instructions. Subjects not undergoing re-randomization will not return to the site at Week 13.
l.
See Section 6.2.2, Glycemic Rescue Therapy: Criteria and Implementation, for additional details for subjects meeting the protocol-specified glycemic rescue criteria.
m.
Three consecutive blood pressure readings will be taken. (see Attachment 3, Method of Blood Pressure Measurement). Pulse rate will be measured once after subject has been 
sitting for at least 5 minutes at each clinic visit.
n.
Whenever possible, body weight will be measured using the same calibrated scale at each visit. Subjects will be weighed at approximately the same time of day on the same scale 
wearing underwear and a gown and without shoes. Note: if disrobing for weighing is logistically impossible, the subject must be dressed as lightly as possible, with consistency 
from visit to visit. Subjects will be instructed to empty their bladders before being weighed.
o.
Height will be measured using a stadiometer. (see Attachment 5, Guideline for Collecting Height Measurements).
p.
See Attachment 6: Tanner Staging for guidance on Tanner Staging. Note: once subjects have reached Stage 5, no later assessments are required.
q.
Physical examinations will include a review of body systems (head and neck, eyes, chest and lungs, cardiovascular, extremities and back, and abdomen examination). Significant 
findings that are present must be documented in the source and eCRF.
r.
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). Subjects will receive information regarding the signs and symptoms of and treatment for hypoglycemia (see Attachment 4, Hypoglycemia: Definitions, Symptoms, and 
Treatment) and the signs and symptoms of DKA (see Attachment 1, Instructions on Ketone Monitoring and Sick Day Management).
s.
Subjects will be instructed to return with their completed diaries to the study site for review by study-site personnel at each clinic visit (eg, for review of hypoglycemic events, 
insulin dosage changes [only for subjects who are on insulin], self-monitoring of blood glucose values, ketone levels, concomitant medications, timing of study drug taken and any 
missed doses of study drug).


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t.
Hypoglycemic episodes should be recorded on the hypoglycemia eCRF and also on the adverse event eCRF if considered as an adverse event by the investigator 
(see Attachment 4 Hypoglycemia: Definitions, Symptoms, and Treatment).
u.
Subjects will be provided with and instructed on the use of a home blood glucose/ ketone monitoring system. Subjects will also be instructed on how to measure urine ketones (to 
be only used as a back-up procedure in case capillary ketones cannot be assessed). Blood glucose and blood and urine ketone testing supplies will also be provided as necessary.
v.
Consistent with standard diabetes treatment guidelines, all study participants should be provided with routine preventative foot care and early intervention for foot problems (see 
Section 12.2.1, All Adverse Events for further detail).
w.
Adverse events will be monitored throughout the study from the time of signing the informed consent form until the end of the study (see Section 12.2.1, All Adverse Events).
x.
Specific details about specimen collection, storage, packaging, and shipping will be provided in the laboratory manual. For FPG, fasting C-peptide, and lipids, subjects must be 
fasting for at least 8 hours before blood sample collection, except for the screening visit when non-fasting blood samples may be collected. A set of plasma, serum, and urine 
samples 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.
y.
Hematology and serum chemistry are performed at the screening visit and should not be repeated at baseline, unless the screening visit was performed more than 4 weeks before 
the baseline visit. No fasting lipid panel will be collected at the Screening Visit; please ensure to collect fasting lipid panel at the Baseline visit/Day 1.
z.
Serum (β-human chorionic gonadotropin [β-hCG] pregnancy testing will be performed for all female subjects of childbearing potential at the screening visit. Additional urine (or 
serum) 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. Serum pregnancy test must be performed and the result reviewed before randomization.
aa.
The urine sample for albumin/creatinine ratio should not be collected if the subject is menstruating, has exercised vigorously in the past 24 hours, or had a fever or an active 
infection within the past 2 days of the clinic visit.
bb. Subjects will be given urine collection containers at each of the clinic visits preceding the first morning urine collection time points. 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 who have atypical sleep patterns, the collection should be made at the end of the
subject’s usual sleep period. Study research staff is encouraged to contact the subject before this clinic visit as a reminder to the subject that he/she will need to provide a urine
specimen at a particular visit (only 1 urine specimen is necessary at the indicated visit for the determination of albumin/creatinine ratio).
cc.
If the first morning void on Week -2 visit shows a presence of proteinuria (ie, proteinuria +1 and above) based on the central laboratory urine dipstick, 24-hour urine collection 
will be done during the run-in period. Subjects who require a 24-hour urine collection prior to randomization, will also be required to provide a 24-hour urine sample on Week 26 
and Week 52. Subjects who had a Week -2 first morning void negative for protein and develop a positive first morning void after randomization are not required to obtain 24-hour 
urine samples. Instead, in these subjects first morning urine sample will be collected for the remainder of the study. 
dd. Only required in subjects with no documented history of absence of pancreatic autoimmunity. 
ee.
Subjects will be instructed to refrain from taking the study drug the morning of the clinic visit. The subject will be instructed to take the dose of study drug before the subject's next 
meal, after the study visit. The subject will record the time that the study drug was taken on the day preceding the clinic visit. Refer to laboratory manual for further information
regarding the collection, handling, shipment and labeling of pharmacokinetic samples.


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ABBREVIATIONS
ACR
ADA
albumin/creatinine ratio
American Diabetes Association
ADR
adverse drug reaction
AHA
antihyperglycemic agent
AUC
area under the curve
BMD
BMI
bone mineral density
body mass index
CANVAS
Canagliflozin Cardiovascular Assessment Study
CI
confidence interval
CRF
case report form (paper or electronic as appropriate for this study)
CSR
CV
CTx
clinical study report
cardiovascular
carboxy-telopeptide 
DKA
diabetic ketoacidosis
DXA
eCRF
dual energy X-ray absorptiometry
electronic case report form
eDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency 
EOT
end-of-treatment
EU
FAS
European Union
full analysis set
FDA
Food and Drug Administration
FPG
fasting plasma glucose
GAD
glutamic acid decarboxylase
GCP
Good Clinical Practice
HbA1c
glycated hemoglobin
hCG
human chorionic gonadotropin
HDL-C
high-density lipoprotein-cholesterol
IA2
IB
islet cell antigen 2
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ID
identification
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IR
immediate release
IRB
Institutional Review Board
IWRS
LADA
interactive web response system
latent autoimmune diabetes of adulthood
LC-MS/MS
LCT
LDL
LH
liquid chromatography/mass spectrometry/mass spectrometry
Leydig cell tumors
low-density lipoprotein-cholesterol
Luteinizing hormone
LOCF
last-observation-carried-forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
MODY
mixed model for repeated measures
Maturity-Onset Diabetes of the Young
MSRC
Medical Safety Review Committee
MTD
PD
PDC
PG
maximum tolerated dose
pharmacodynamics
Pediatric Diabetes Consortium
plasma glucose
PI
package insert
PK
pharmacokinetic


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PP
per protocol
PPG
PQC
post-prandial plasma glucose
product quality complaint
PTH
parathyroid hormone
RTG
SAE
renal threshold for glucose
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SGLT2
sodium-glucose co-transporter 2
SU
SMBG
sulphonylurea
self-monitoring of blood glucose
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
UGE
urinary glucose excretion
UGT
ULN
UDP-glucuronosyltransferases
upper limit of normal
US
United States
UTI
urinary tract infection
XR
extended release
DEFINITIONS OF TERMS
Cmax
tmax
maximum plasma drug concentration
time to reach the maximum observed plasma concentration
t1/2
elimination half-life (to be used in one or noncompartmental model)


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1.
INTRODUCTION
Canagliflozin (JNJ-28431754) is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2) 
that has been developed as an oral antihyperglycemic agent (AHA) for the treatment of adults 
with type 2 diabetes mellitus (T2DM). It has been approved by several Health Authorities, 
including the United States (US) Food and Drug Administration (FDA) and the European 
Medicines Agency (EMA). Canagliflozin is used as an adjunct to diet and exercise to improve 
glycemic control in adults with T2DM; to reduce the risk of major adverse cardiovascular (CV) 
events in adults with T2DM and established CV disease; and to reduce the risk of end-stage 
kidney disease, doubling of serum creatinine, CV death, and hospitalization for heart failure in 
adults with T2DM and diabetic nephropathy with albuminuria. (Not all indications are approved 
in all markets.)
Type 2 diabetes mellitus is a chronic, progressive disorder that occurs across a broad age range, 
is rarely seen in children <10 years of age and occurs with rising incidence as age increases. 
Once diet and exercise are no longer sufficient, children, adolescents, and adults with T2DM 
may initially have adequate glycemic control with a single oral agent, usually metformin. Over 
time, however, maintaining good glycemic control requires the use of combinations of oral 
agents, then insulin in combination with oral agents, and finally the implementation of a 
multi-injection per day insulin regimen. Recent clinical treatment guidelines published by the 
American Academy of Pediatrics state that all youth with newly diagnosed T2DM should be 
treated immediately with insulin, if pre-specified criteria are met. In all other cases, treatment 
with metformin should be initiated (Copeland 2013). Thus, treatment-naïve patients, managed 
only with diet and exercise, are very uncommon. Currently, in addition to insulin, the only FDA 
and EU approved oral agent in children and adolescents 10 years of age with T2DM is 
metformin. Therefore, there is an unmet need for additional options to treat children and 
adolescents 10 years of age with T2DM. 
The present study will examine the efficacy and safety of canagliflozin in children and 
adolescents 10 and <18 years of age. This is a 52-week randomized, double-blind, 
placebo-controlled, parallel-group study, consisting of a 26-week core double-blind treatment 
period followed by a 26-week extension double-blind treatment period. Eligible subjects will be 
either on diet and exercise alone, on diet and exercise and a stable dose of metformin 
monotherapy, on diet and exercise and a stable insulin monotherapy regimen, or on diet and 
exercise and a stable combination therapy with metformin and insulin. The results of this study 
plus the available extensive data in the adult population with T2DM as well as model-based 
analyses on exposure-response pharmacokinetics/pharmacodynamics (PK/PD) in adults and 
children/ adolescents, is expected to provide sufficient information to assess the benefit/risk ratio 
of canagliflozin in pediatric subjects with T2DM.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.


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1.1.
Background
For more detailed and current information regarding the preclinical characterization of 
canagliflozin PK (ie, absorption, distribution, metabolism, and excretion) and toxicology, and 
clinical study results in adults, refer to the current version (Edition 18) of the Investigator's 
Brochure (IB) for canagliflozin (IB JNJ-28431754 2020). One Phase 1 PK/PD study of 
canagliflozin (DIA1055) in subjects 10 to <18 years of age has been completed. Data from 
17 subjects enrolled in Study DIA1055 indicate that the safety, PK, and PD of canagliflozin in 
the adolescent T2DM population is comparable to that observed in diabetic adults for both the 
canagliflozin 100 mg and 300 mg doses and consequently no dose-adjustment is necessary for 
this population ([Clinical Study Report CSR] JNJ-28431754 DIA1055 2016).
In a juvenile rat oral toxicity study (beginning dosing interval corresponds to a developmental 
age of approximately 2 years old in human infants) with canagliflozin (4, 20, 65, 100 mg/kg/day) 
administered orally for 10 weeks (day 21 to 90 postnatal) followed by a 4-week recovery period, 
renal and bone findings in immature rats were consistent with those in adult rats in the 
repeat-dose toxicity studies. There was a dose-related increase in the incidence and severity of 
renal tubular and pelvic dilatation, with a similar incidence and severity as for adult rats at the 
same doses. At the end of 4-week recovery, renal tubular dilatation was fully reversible, whereas 
renal pelvic dilatation was partially reversible in males at 20 mg/kg and fully reversible in the 
other dose groups. Dose-related hyperostosis observed was consistent with effects at the same 
dose levels in adult rats and was fully reversible at the end of the 4-week recovery. In general, 
findings were consistent with those in the 3- and 6-month repeat-dose studies in adult rats, and 
there were no new or unexpected effects. At the no-observed adverse effect level (NOAEL) of 
4 mg/kg/day, area under the curve (AUC) values were up to 2.4x and 0.6x the AUC for the 
100 and 300 mg doses in humans, respectively.
1.1.1.
Pharmacokinetics
In adults, 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 and subjects with T2DM (50 mg to 300 mg once-daily and 300 mg twice-daily), after 
oral administration of single and multiple doses, mean canagliflozin area under the curve 
(AUC)0-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 


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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 UDP-glucuronosyltransferases [UGT2B4]) and M7 (formed by UGT1A9), were 
present. Co-administration with rifampin, a nonselective inducer of several uridine 
5'-diphospho-glucuronosyltransferase (UGT) enzymes, decreased canagliflozin AUC by 51%, 
which may decrease efficacy. There was an increase in the AUC and Cmax of digoxin when 
co-administered with canagliflozin 300 mg. Subjects taking concomitant digoxin should be 
monitored appropriately. The Cmax of canagliflozin was not meaningfully altered by renal 
impairment. 
Based on in vitro data and the clinical drug-drug interaction studies conducted to date, the 
potential for clinically significant CYP450 based PK interactions appears to be low.
The Phase 1, multiple-dose, PK study (Study DIA1055), conducted in subjects with T2DM who 
were 10 to <18 years of age and on a stable dose of metformin, demonstrated that plasma 
canagliflozin concentrations increased rapidly following administration of both treatments. Mean 
tmax for canagliflozin after 14 days of once-daily 100- or 300-mg dose administration ranged 
from 1.64 to 2.44 hours (range of 1 to 4 hours) across both treatments. Mean Cmax and AUCτ
values in the 9 pediatric T2DM subjects receiving canagliflozin 300 mg once-daily were higher 
than the 8 pediatric T2DM subjects receiving canagliflozin 100 mg once-daily. Mean t1/2 for 
canagliflozin after 14 days of once-daily 100- or 300-mg dose administration ranged from 
11.3 to 15.2 hours (range of 8.0 to 29.3 hours) across both treatments. In general, the 
pharmacokinetics observed in the 8 pediatric T2DM subjects receiving 100 mg once-daily and 
the 9 pediatric T2DM subjects receiving 300 mg once-daily doses of canagliflozin were 
consistent with those of adult subjects.
1.1.2.
Pharmacodynamics
In adult subjects with T2DM following single and multiple oral doses (30 to 600 mg once-daily 
and 300 mg twice-daily), canagliflozin treatment dose dependently increased urinary glucose 
excretion (UGE)0-24h, with mean UGE0-24h of approximately 100 g/day typically observed with 
doses of 100 mg once-daily or higher. 
In subjects with T2DM, canagliflozin treatment with 100 mg and 300 mg once-daily lowered 
renal threshold for glucose (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. 
In Study DIA1055, conducted in subjects with T2DM who were ≥10 to <18 years of age and on 
a stable dose of metformin, both doses of canagliflozin lowered the RTG, increased UGE, and 


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lowered PG concentrations in a manner that is consistent with the relationship defined by adult 
subjects with T2DM.
1.1.3.
Efficacy/Safety Studies
The canagliflozin clinical program was designed to assess the efficacy and safety of 
canagliflozin in individuals with T2DM.
In the Phase 3 studies in adults, 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 included studies in special 
populations of subjects with T2DM: subjects with renal impairment (estimated glomerular 
filtration rate [eGFR] 30 to <50 mL/min/1.73m2), subjects with or at high risk for CV 
complications, and older subjects. The latter 2 studies also included subjects on incretin-based 
therapies, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 
(GLP-1) agonists. 
Efficacy
Results of the Phase 3 studies demonstrated the efficacy of canagliflozin in reducing HbA1c in a 
broad range of adult subjects with T2DM, both with recent onset as well as long-standing 
diabetes and on a range of different background AHAs. A clinically meaningful improvement in 
glycemic control was seen when canagliflozin was given as monotherapy and when given in dual 
combinations (add-on to metformin or to SU agents), in triple oral AHA combinations (add-on to 
metformin plus an SU agent or metformin plus pioglitazone), in combination with insulin (alone 
or in combination with other agents), or as an add-on to existing diabetes therapy (any approved 
oral or parenteral therapy). In the monotherapy study, HbA1c reductions of -0.91% and -1.16% 
relative to placebo for canagliflozin 100 mg and 300 mg, respectively, were observed. In the 
studies examining specific add-on combination uses, the efficacy of canagliflozin in lowering 
HbA1c, relative to placebo, was generally consistent ranging from -0.62% to -0.74% with the 
100-mg dose and from -0.73% to -0.92% with the 300-mg dose. Across all studies, the 300-mg
dose consistently provided greater HbA1c lowering relative to the 100-mg dose. Because 
reduction in diabetic microvascular complications is continuous with improvements in glycemic 
control, the additional glucose-lowering efficacy with the 300-mg dose is considered likely to be 
clinically relevant. 
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, and 
ethnicity), body mass index (BMI), or geographic region. Greater reductions in HbA1c relative to 
placebo were observed with canagliflozin among subjects with higher baseline HbA1c and higher 
eGFR values compared with subjects with lower baseline values. In subjects with moderate renal 
impairment (ie, baseline eGFRs between 30 to 60 mL/min/1.73m2), the mean placebo-subtracted 
reduction in HbA1c was 0.38% and 0.47% on canagliflozin 100 mg and 300 mg, respectively. A 


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total of 24% and 32% of subjects achieved a target HbA1c <7.0% at the end-of-treatment (EOT) 
on canagliflozin 100 mg and 300 mg, respectively compared to 17% of subjects on placebo. 
With regard to other glycemic endpoints, canagliflozin provided improvements in FPG as well as 
in the post-prandial glucose (PPG) excursion. Canagliflozin also provided improvements in 
beta-cell function and a reduction in beta-cell stress as reflected by a decrease in the proinsulin/ 
C-peptide ratio. The improvement in beta-cell function and reduction in beta-cell stress is 
consistent with the sustained effect of canagliflozin on both HbA1c and FPG observed in the 
52-week studies.
Weight and Blood Pressure Effects 
In addition to the observed glycemic improvements, treatment with canagliflozin resulted in 
consistent, statistically significant reductions in total body weight relative to placebo. Weight 
loss with canagliflozin appeared dose-related (with -1.4% to -2.7% reductions with 100 mg 
and -1.8% to -3.7% reductions with 300 mg, relative to placebo). Results of specialized body 
composition investigations using dual energy X-ray absorptiometry (DXA) in 2 of the Phase 3 
studies showed that the body weight reduction with canagliflozin was attributable to a greater 
decrease in body fat mass relative to lean body mass. 
Reductions in systolic blood pressure were observed with canagliflozin in Phase 3 studies 
(ranging from -2.2 to -5.7 mm Hg of systolic blood pressure with canagliflozin 100 mg dose, 
and -1.6 to -7.9 mm Hg with the 300-mg dose, relative to placebo, in placebo-controlled 26-week 
studies), and were generally statistically significantly greater for both doses relative to placebo, 
and also greater relative to comparator agents (glimepiride and sitagliptin). 
Safety 
For a complete review of the adverse drug reactions (ADRs) and laboratory findings associated 
with canagliflozin, please refer to the current version (Edition 18) of the canagliflozin IB 
(IB JNJ-28431754 2020). 
The safety and tolerability profile that emerges from the development program for canagliflozin 
shows a medication that is overall well tolerated. The incidence of discontinuations due to 
adverse events was slightly higher than seen in the control group, though generally low. The 
small increase in discontinuations due to adverse events were generally related to specific ADRs, 
described below, with each particular ADR infrequently leading to discontinuations; there was 
no increase in serious adverse events or deaths in the canagliflozin treatment groups relative to 
control groups. 
Adverse drug reactions were observed that relate to the osmotic diuretic effect of canagliflozin, 
with increases in UGE leading to a diuretic action; this included ADRs of pollakiuria (increased 
urinary frequency), polyuria (increased urinary volume), and thirst. Adverse drug reactions 
related to reduced intravascular volume were observed including postural dizziness, orthostatic 
hypotension, and hypotension. Risk factors for volume-related adverse events on canagliflozin 
treatment were 75 years of age, eGFR of 30 to 60 mL/min/1.73m2 and use of loop diuretics. 


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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 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 17/3,569 (0.5%) and 3/1,924 (0.2%) of men treated with canagliflozin and control, 
respectively. In women, genital mycotic infections (including candidal vulvovaginitis) occurred 
more commonly with a prior history of genital mycotic infections and did not generally lead to 
discontinuation. A modest increase in the incidence of adverse events of urinary tract infection 
(UTI) (mostly lower UTIs) was observed with canagliflozin relative to control, without an 
increase in serious adverse events of UTI.
Based on the observations from the 2-year rat carcinogenicity study (findings of renal tubular 
cell cancers, Leydig cell tumors [LCTs], and pheochromocytomas), an extensive preclinical 
toxicology program was conducted that demonstrated that these tumors related to effects of 
canagliflozin in rats, not seen in humans (including rises in luteinizing hormone [LH] associated 
with LCT, and carbohydrate malabsorption leading to associated metabolic effects, including 
marked hypercalciuria, inducing renal tubular tumors and pheochromocytomas). In the clinical 
program, there were no reports of LCT or pheochromocytoma and no imbalance in the low 
incidence across groups of renal cell cancers. 
In preclinical studies in rats, hyperostosis (increased trabecular bone) was observed. Mechanistic 
toxicology studies demonstrated that hyperostosis, like the tumors discussed above, related to 
carbohydrate malabsorption in rats treated with canagliflozin, with consequent marked 
hypercalciuria (which is not seen in human). Overall, no meaningful changes in serum and 
urinary calcium and serum parathyroid hormone [PTH] and 1,25-dihydroxyvitamin D were seen 
in subjects treated with canagliflozin. Unlike the findings in rats, modest increases in markers of 
bone turnover, including serum collagen type 1 carboxy-telopeptide (CTx) and osteocalcin, were 
seen in subjects with T2DM treated with canagliflozin. Based on the lack of carbohydrate 
malabsorption or alterations in calcium metabolism in humans treated with canagliflozin, 
hyperostosis seen in rats treated with canagliflozin is considered to be of no relevance to human 
safety. 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 


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groups, respectively, placebo-adjusted). Using a data-cutoff of May 2013, in a cardiovascular 
study of 4,327 adult subjects with known or at high risk for cardiovascular disease 
(Study DIA3008), the incidence rates of bone fracture were 1.6, 1.6, and 1.1 per 100 
subject-years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, 
respectively, with the fracture imbalance initially occurring within the first 26 weeks of therapy. 
In other T2DM studies with canagliflozin, which enrolled a general diabetes population of 
approximately 5,800 adult subjects, no difference in fracture risk was observed relative to 
control.
Increases in low-density lipoprotein-cholesterol (LDL-C) were observed in a pooled analysis of 
placebo-controlled 26-week studies with canagliflozin, 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-high-density lipoprotein-cholesterol 
(HDL-C), and LDL particle number were approximately half as large as the rise in LDL-C. The 
changes in the CV risk profile with canagliflozin include reductions in systolic blood pressure 
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 (TG) 
were also observed with canagliflozin. The cross-program CV meta-analysis (including results 
from the dedicated CV safety study) observed a hazard ratio of 0.91 for a pre-specified 
composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke, and 
hospitalized unstable angina (95% confidence interval [CI]: 0.68, 1.22), showing no signal for an 
increase in the CV risk.
In the adult 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. Analyses of eGFR post-discontinuation showed 
reversibility of the initial reductions in eGFR observed with canagliflozin. To assess the effects 
of canagliflozin on the progression of diabetic nephropathy, the proportion of subjects with 
categorical progression of albuminuria based upon the urinary albumin/creatinine ratio (ACR) 
was assessed in 4 Phase 3 studies (DIA3004, DIA3005, DIA3008, and DIA3009). Numerically 
greater mean and median reductions in urinary ACR with both doses of canagliflozin (100 mg 
and 300 mg) relative to placebo or comparator were observed in all 4 studies. 
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%, 4/5,337), 0.0763 (0.11%, 6/5,350), and 0.0238 (0.03%, 2/6,909) 
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 
[T1DM]) or tested positive for glutamic acid decarboxylase (GAD) 65 antibodies after being 
diagnosed with a serious DKA-related event. Eight of the 10 subjects on canagliflozin were 


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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 <250 mg/dL (<13.9 mmol/L). As a result, DKA is considered 
a rare ADR.
An increased risk of lower limb amputations associated with canagliflozin use compared with 
placebo was observed in the Canagliflozin Cardiovascular Assessment Study (CANVAS) (5.9 vs 
2.8 events per 1000 patient-years) and CANVAS-Renal (7.5 vs 4.2 events per 1000 
patient-years), 2 randomized, placebo-controlled trials evaluating adults with type 2 diabetes 
who had either established CV disease or were at risk for CV disease. The risk of lower limb 
amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens. 
Infections were the events most commonly associated with amputations, and most amputations 
were of the toe. The factors associated with the greatest risk for amputation included prior 
amputation, peripheral vascular disease, and neuropathy.
A recently completed, dedicated renal study (Canagliflozin and Renal Events in Diabetes with 
Established Nephropathy Clinical Evaluation Trial [CREDENCE]; DNE3001) evaluated 
canagliflozin as a treatment to reduce the progression of diabetic nephropathy in adult subjects 
with T2DM, Stage 2 or 3 chronic kidney disease and macroalbuminuria, receiving background 
standard of care, including a maximum tolerated labeled daily dose of an angiotensin converting 
enzyme inhibitor or angiotensin II receptor blockers. In the CREDENCE Dataset, there were a 
total of 133 subjects who experienced an atraumatic lower limb amputation, 70 subjects 
(87 events) and 63 subjects (96 events) in the canagliflozin and placebo groups, respectively. The 
exposure-adjusted incidence rate of lower limb amputations was comparable between the 2 
groups: 1.23 and 1.12 per 100 subject-years in the canagliflozin and placebo groups, 
respectively.
In Study DIA1055, conducted in subjects with T2DM who were 10 to <18 years of age and on 
a stable dose of metformin, 17 subjects received study drug (canagliflozin 100 mg [N=8] or 
canagliflozin 300 mg [N=9]) for 14 days. Overall, 52.9% of subjects reported at least 1 adverse 
event. The most frequently reported adverse event (2 subjects) was nausea. There were no 
deaths or serious adverse events reported during the study. None of the subjects discontinued the 
study drug due to an adverse event. Overall, no new, unexpected, or unusual safety signals were 
reported in the study.
1.2.
Overall Rationale for the Study
The present study will examine the efficacy and safety of canagliflozin in children and 
adolescents 10 and <18 years of age. This is a 52-week randomized, double-blind, placebo-
controlled, parallel-group study, consisting of a 26-week core double-blind treatment period, 
followed by a 26-week extension double-blind treatment period. There are limited treatment 
options for T2DM in subjects 10 and <18 years of age, and as the prevalence of T2DM in the 
pediatric population is increasing over time (Copeland 2013), there is a substantial unmet need 


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for treatment options in this population. The current study will evaluate efficacy and safety of 
canagliflozin in pediatric subjects with T2DM.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
In children and adolescents (10 to <18 years) with T2DM who have inadequate glycemic 
control (ie, HbA1c of 6.5% to 11.0%), either on diet and exercise only, or on diet and exercise 
and metformin monotherapy, on diet and exercise and insulin monotherapy, or on diet and 
exercise and a combination therapy with metformin and insulin:
Primary Objectives

To assess the effect of canagliflozin relative to placebo on HbA1c after 26 weeks of 
treatment.

To assess the overall safety and tolerability of canagliflozin.
Major Secondary Objectives

After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo for the 
subset of subjects on a background of metformin (with or without insulin) on HbA1c 

After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:

FPG 

Proportion of subjects with HbA1c <7.5%, <7.0% and <6.5%

Time to rescue therapy and proportion of subjects receiving rescue therapy

Body weight 

After 52 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:

HbA1c and FPG

Proportion of subjects with HbA1c <7.5%, <7.0% and <6.5% 

Time to rescue therapy and proportion of subjects receiving rescue therapy

Body weight
Additional Secondary Objectives

After 12 weeks of treatment to assess the effects of canagliflozin relative to placebo on 
HbA1c

After 26 weeks of treatment, to assess the effect of canagliflozin 100 mg relative to placebo 
on HbA1c

After 26 weeks of treatment, to assess the effect of canagliflozin 100 mg followed by a dose 
increase to 300 mg relative to placebo on HbA1c

After 26 weeks and 52 weeks of treatment, to assess the effect of canagliflozin relative to 
placebo on:


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
BMI

Fasting plasma lipids (ie, LDL-C, HDL-C, total cholesterol, non-HDL-C, LDL-C to 
HDL-C ratio, non-HDL-C to LDL-C ratio, and triglycerides)

Systolic and diastolic blood pressure 

Growth velocity and Tanner Staging

Markers of calcium and phosphate homeostasis, (calcium, magnesium, phosphate, PTH, 
25-hydroxy Vitamin D, calcitonin; urinary excretion of calcium and phosphate)

Bone turnover markers (serum osteocalcin and serum collagen type 1 CTx)

Urinary ACR
2.2.
Hypotheses
In children and adolescents (10 to <18 years) with T2DM who have inadequate glycemic 
control (ie, HbA1c of 6.5% to 11.0%), either on diet and exercise only, or on diet and exercise
and metformin monotherapy, on diet and exercise and insulin monotherapy, or on diet and 
exercise and a combination of metformin and insulin:
Primary Hypothesis

After 26 weeks of treatment, canagliflozin reduces HbA1c relative to placebo.
Secondary Hypotheses

After 26 weeks of treatment, canagliflozin reduces HbA1c relative to placebo in the subset of 
subjects on background of metformin (with or without insulin).
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, 2-arm, parallel-group, multicenter study. 
Subjects with T2DM 10 and <18 years of age who have inadequate glycemic control (ie, HbA1c
of 6.5% to 11.0%) and who meet 1 of the criteria below will be eligible to be screened: 

Are on diet and exercise only for at least 4 weeks prior to screening,
or

Are on diet and exercise and a stable dose of metformin monotherapy 1,000 mg per day or 
maximum tolerated dose (MTD) per day (defined by the investigator) for at least 8 weeks 
prior to screening, 
or

Are on diet and exercise and a stable insulin monotherapy regimen for at least 8 weeks prior 
to screening (stable dose is defined as no change in the insulin regimen (ie, type[s]) of 
insulin) and 15% change in the total daily dose of insulin [averaged over 1 week to account
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or

Are on diet and exercise and a stable combination therapy with metformin and insulin for at 
least 8 weeks prior to screening as described above.
Note: Subjects who are on diet and exercise and a stable dose of metformin extended release 
(XR) for at least 8 weeks prior to screening may be included in the study; however, they will be 
switched from metformin XR to metformin IR (at the same daily dose or nearest appropriate 
dose) at the single-blind placebo run-in visit and will be enrolled in the study if the metformin IR 
is well tolerated during the 2-week single-blind placebo run-in period prior to Visit 3/Day 1.
Eligible subjects will go directly into a 2-week single-blind placebo run-in period and may then 
be randomized if they meet all other enrollment criteria. The goal is to have at least 30% of 
participants that will be 10 to <15 years of age, 30% to <65% of participants that will be female 
in each age group (10 to <15 years and 15 to <18 years), and 30% of participants that will 
have ethnicity and lifestyle comparable to Europe.
At least 146 subjects who meet all enrollment criteria will be randomly assigned in a 1:1 ratio to 
once-daily administration of canagliflozin 100 mg, or placebo and enter a 52-week double-blind 
placebo-controlled treatment phase consisting of a 26-week core double-blind treatment period, 
followed by a 26-week double-blind extension treatment period. Randomization will be stratified 
by AHA background (ie, diet and exercise only; metformin monotherapy; insulin monotherapy; 
or combination of insulin and metformin) and age group (10 to <15 years old; 15 to <18 years 
old). Subjects who at Week 12 have an HbA1c of 7.0% and an eGFR 60 mL/min/1.73m2 will 
be re-randomized in a 1:1 ratio to either remain on double-blind canagliflozin 100 mg (or 
matching placebo) or to up-titrate to double-blind canagliflozin 300 mg (or matching placebo).
Study Phases

Pretreatment phase 

Screening visit (Week -3) 

Single-blind placebo run-in period: 2 weeks (Week -2 visit to baseline [Day 1])

Double-blind treatment phase: 52 weeks including a 26-week core double-blind treatment 
period and a 26-week double-blind extension treatment period

Starting at the baseline (Day 1) visit and completing at the Week-52 visit (or the EOT 
visit for subjects discontinuing study drug early).

Post-treatment phase: 30-day follow-up contact

Telephone follow-up contact (or optional study visit, at the discretion of the 
investigator) 30 days after the last dose of study drug. 
The total duration of the study, including the 1-week screening phase, the 2-week single-blind 
placebo run-in period, the 52-week double-blind placebo-controlled treatment phase and the 
30-day follow-up post-treatment phase, is approximately 59 weeks for each subject.


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The key efficacy evaluations include HbA1c, FPG, body weight, proportion of subjects with 
HbA1c <7.5%, <7.0%, and <6.5%, and use of rescue medication. For a complete list of efficacy 
measures and endpoints, see Section 9.5, Efficacy Evaluations.
Safety and tolerability evaluations will include the monitoring of adverse events, collection of 
potential hypoglycemic events (eg, from the subject diary provided to subjects), capillary blood 
ketone monitoring, physical examinations, body weight, vital signs (blood pressures and pulse 
rates), safety laboratory tests (including chemistry, hematology, urinalysis), self-monitoring of 
blood glucose (SMBG), bone turnover markers (serum osteocalcin and serum collagen type 1 
CTx), markers of calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH, 
25-hydroxy Vitamin D, calcitonin, urinary excretion of calcium and phosphate), urinary ACR, 
growth velocity, and Tanner Staging.
An internal Medical Safety Review Committee (MSRC), and an IDMC, will review data from 
this study. Refer to Section 9.4, Study Management: Committees, for details.
Subjects who prematurely discontinue study drug will require an immediate EOT assessment 
(either on the day of study drug discontinuation or as soon as possible following study drug 
discontinuation). It is the intent that subjects who discontinue study drug will continue in the 
study according to the visit schedule described in the Time & Events Schedule. After early 
discontinuation of study drug, subjects will continue to be followed up for specific data 
collection, including vital signs, body weight, laboratory assessments, serious adverse events, 
adverse events of interest, and adverse events of special interest for the duration of the study. See 
Section 10.2.4, Comprehensive Follow-up at Scheduled Study Visits Following Premature 
Discontinuation of Study Drug, for more detail. (Refer to Section 12, Adverse Event Reporting 
for a list of adverse events of special interest that will be collected). All subjects, regardless of 
their completion status, will have a follow-up telephone contact (or optional study visit, at the 
discretion of the investigator) approximately 30 days after their last dose of study drug is taken to 
collect information on any serious adverse events and adverse events of interest. 
Subjects who discontinue the study during the double-blind treatment phase will not be replaced.
Re-randomization 
At Week 12, subjects’ glycemic status will be assessed through an HbA1c level determined by the
central laboratory. Following the review of the Week 12 unmasked HbA1c and eGFR results, 
subjects may be eligible to be re-randomized at Week 13 to either remain on their original 
treatment assignment (ie, canagliflozin 100 mg or matching placebo) or up-titrate canagliflozin 
100 mg to 300 mg (or matching placebo). Refer to Section 9.1.4.3, Re-randomization, for details.
Glycemic Rescue
Subjects who meet the protocol-specified glycemic rescue criteria, despite reinforcement of 
compliance with background AHA therapy, study drug and lifestyle counseling, will initiate an 
approved AHA for the pediatric population as per the local label and will continue in the study 


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on double-blind study drug (see Section 6.2.2, Glycemic Rescue Therapy: Criteria and 
Implementation).
A diagram of the study design is provided.
Figure 1:
Schematic Overview of the Study
3.2.
Study Design Rationale
The goal of this study is to investigate the efficacy and safety of canagliflozin for the treatment 
of children and adolescents (10 to <18 years) with T2DM with inadequate glycemic control 
(ie, HbA1c of 6.5% to 11.0%), as monotherapy, or as add-on to metformin and/or insulin. 
Blinding, Control, Study Phase/Periods, Treatment Groups
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. Randomization 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, and to enhance the validity of statistical comparisons across 
treatment groups. Blinded treatment will be used to reduce potential bias during data collection 
and evaluation of clinical endpoints.


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The 2-week single-blind placebo run-in period before randomization will allow sufficient time 
for investigators to assess whether subjects demonstrate compliance with study procedures, 
including compliance with administration of study drug. The single-blind placebo run-in period 
also helps to assure that subjects entering the study will have no difficulty with administration of 
the study drug.
The 52-week double-blind treatment phase (with the primary endpoint analysis conducted at 
Week 26) should allow sufficient time to fully evaluate the effect of canagliflozin on the primary 
glycemic endpoint, provide sufficient time to assess secondary efficacy endpoints, and to assess 
safety and tolerability of this agent, relative to placebo, in pediatric subjects. Hemoglobin A1c, 
the primary efficacy endpoint of the study, reaches full steady-state after approximately 12 to 
16 weeks following a change in glycemic control (Tahara 1993).
Dosage Selection, Route of Administration, Dose Interval
Canagliflozin has been approved by several Health Authorities including the FDA and EMA as 
an adjunct to diet and exercise to improve glycemic control in adults with T2DM. As per the US 
Package Insert (USPI) and EU Summary of Product Characteristics (SmPC), the recommended 
starting dose of canagliflozin in adults with T2DM is 100 mg. The dose can be increased to 
300 mg in patients requiring additional glycemic control. The formulation and route of 
administration proposed for use in the pediatric population is the same as that used for the adult 
population, ie, tablet for oral use. The sponsor believes the current canagliflozin tablet 
formulation is age appropriate for the 10 to <18 years old pediatric population. 
The effects of canagliflozin when administered using an up-titration algorithm was evaluated in a 
randomized, placebo-controlled, parallel-group, 2-arm, 26-week multicenter study (DIA4004). In 
this study, adult subjects with T2DM who had inadequate glycemic control (HbA1c 7.5% to 
10.5%) on maximally or near-maximally effective dose metformin and sitagliptin 100 mg were 
randomized to the addition of either placebo or canagliflozin 100 mg. After 6 weeks or 
treatment, only subjects meeting pre-specified up-titration criteria were required to up-titrate to 
canagliflozin 300 mg (or matching placebo). At the end of the 26-week treatment period, 
canagliflozin had been up-titrated to 300 mg in 85% of subjects, and compared to placebo 
provided clinically important glycemic improvements (ie, HbA1c change from baseline, 
proportion to <7.0% HbA1c goal, and FPG change from baseline), and clinically important 
reduction in body weight and systolic blood pressure (SBP). In addition, canagliflozin treatment 
was associated with a safety and tolerability profile consistent with expectations, including an 
increased incidence of adverse events of genital mycotic infections. Adverse events related to 
osmotic-diuresis (eg, polyuria, pollakiuria, thirst) were similar but numerically increased in the 
canagliflozin group and perhaps lower than expected based on the rates observed in other studies 
with this agent at the 300-mg dose (CSR JNJ-28431754 DIA4004 2016)
Based on the above information, in this study canagliflozin will be administered using a titration 
strategy which is likely to be followed in common clinical practice. Subjects will initially be
randomized to a starting dose of canagliflozin 100 mg (or placebo). Subjects who after 12 weeks 
of treatment fail to achieve the HbA1c goal of <7.0% and have normal renal function (eGFR 


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≥60 mL/min/1.73m2) are eligible to be re-randomized to either up-titrate to canagliflozin 300 mg 
(or placebo) or to remain on canagliflozin 100 mg (or placebo). 
Choice of Efficacy Measures
The efficacy measures in this pediatric study are the same as those evaluated in the canagliflozin 
T2DM program in adults. The HbA1c levels will be measured throughout the study to evaluate 
glycemic control, as it is an accepted endpoint for AHAs and is predictive of the risk for 
microvascular diabetic complications. Fasting plasma glucose, another important measure of 
glycemic control, is closely correlated with HbA1c and will also be measured throughout the 
study. Hemoglobin A1c provides information on glycemic control throughout the day, both 
fasting and post-meal, while FPG reflects only overnight glucose control before the first morning 
meal. Additional secondary measures of efficacy (ie, serum lipids, blood pressure) will be 
evaluated to identify additional treatment effects of canagliflozin on comorbidities often seen in 
patients with T2DM.
Rescue Medication
To assure that subjects are not exposed to prolonged poor glycemic control, the investigator may 
apply progressively stricter glycemic rescue criteria based upon HbA1c (or SMBG/FPG at their 
discretion). Rescue criteria can be found in Table 2 in Section 6.2.2, Glycemic Rescue Therapy: 
Criteria and Implementation.
Glycemic rescue procedures and therapies will be implemented as outlined in Section 6.2.2, 
Glycemic Rescue Therapy: Criteria and Implementation.
Rationale for Monitoring of Ketosis, Diabetic Ketoacidosis and Sick Day Management 
Algorithms
As described in Section 1.1.3, Efficacy/Safety Studies, treatment with canagliflozin may lead to 
an increased risk of DKA in subjects with T2DM. However, the risk of DKA and ketone-related 
adverse events in subjects with T2DM treated with canagliflozin is notably lower compared to 
the risk of DKA commonly observed in subjects with T1DM. Canagliflozin lowers blood glucose
by increasing UGE, which is associated with potential increases in glycogenolysis, 
gluconeogenesis, and fatty acid oxidation. Based on its mechanism of action, it is possible that 
mild ketonemia might be detected especially with fasting in otherwise non-acutely ill subjects. In 
a Phase 3 study in Japanese subjects with T2DM involving canagliflozin as an add-on to existing 
therapy, the median total ketone body level increased to approximately 0.2 mmol/L within 4 to 
8 weeks (reference range 0.13 mmol/L), but then declined to approximately 0.15 mmol/L in 
each of the groups by Week 24, and then remained stable thereafter. Total ketone bodies were 
transiently increased in 22/1,297 subjects to 3.0 mmol/L and to 5.0 mmol/L in 6 subjects; no 
subjects developed DKA (Inagaki 2015). 
Since canagliflozin lowers blood glucose in an insulin-independent fashion it is expected that 
subjects treated with insulin and receiving canagliflozin may require less insulin to avoid 
hypoglycemia in maintaining acceptable blood glucose control. As the insulin-to-glucagon ratio 
is a key determinant in controlling hepatic ketogenesis, a reduction in this ratio subsequent to a 


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decrease in the insulin dose could in turn increase a subject’s susceptibility to developing DKA. 
In patients with T2DM who have an acute illness or other stressor, insulin resistance is increased, 
leading to a reduced insulin action and further reduction in the “functional” insulin-to-glucagon 
ratio. 
It should be noted that given the glucosuric effect of canagliflozin, an atypical DKA presentation 
characterized by concomitant blood glucose levels that are lower (ie, <250 mg/dl or 
<13.9 mmol/L) than what would be expected in subjects with DKA treated with insulin alone 
could potentially delay the recognition of DKA. As subjects generally monitor blood glucose 
levels during an illness and are then prompted to check concomitant serum or urine ketones 
when blood glucose levels are elevated, the impetus (elevated blood glucose) to check for 
ketones may be missing, and patients and health care providers could fail to recognize the need 
to increase their insulin dose. Thus, the opportunity to treat DKA early in its course may be 
missed and the subject could be at risk to progress to a more advanced state of DKA.
To reduce the risk of subjects delaying the recognition of ketosis and/or progression to overt 
DKA, subjects will be counseled on when and how to measure ketone levels, recognize and 
monitor signs and symptoms of DKA, and receive instructions on when to contact the site or 
seek medical attention (see Attachment 1, Instructions to Patients on Ketone Monitoring and 
Sick Day Management, and Attachment 2, Suggested Algorithm for Ketone Monitoring and 
Findings of Elevated Ketones). In this study, the ketone level that will trigger procedures 
described in the attachments is 0.6 mmol/L. This cut-off was chosen as there is general 
consensus among investigators that normal serum levels of ketone bodies can be defined as 
<0.5 mmol/L. Hyperketonemia can be defined as levels in excess of 1.0 mmol/L and DKA can 
be defined as levels of in excess of 3.0 mmol/L (Laffel 1999).
Collection of Additional Information for Selected Adverse Events
The safety profile of canagliflozin has been well-established in the Phase 3 program, which 
included approximately 10,000 subjects from randomized, controlled clinical studies. 
(IB JNJ-28431754 2020) For adverse events of interest, investigators will be asked to provide 
additional information on separate electronic case report forms (eCRFs) (Refer to Section 12, 
Adverse Event Reporting for a list of adverse events of special interest that will be collected). 
The detailed information on collection and reporting of all adverse events is also described in 
Section 9.8, Safety Evaluations. Investigators may also be asked to provide additional 
information on other adverse events, based upon review by the MSRC, and the IDMC, 
(Section 9.4.1, Medical Safety Review Committee, Section 9.4.2, Independent Data Monitoring 
Committee). 
Additional Safety Measures
The urinary albumin to creatinine ratio (from the first morning void) will be measured over 
the duration of the study.
Bone turnover markers (serum osteocalcin and serum collagen type 1 CTx), and markers of 
calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH, 25-hydroxy 


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Vitamin D, calcitonin; urinary excretion of calcium and phosphate) will also be measured over 
the duration of the study.
Pharmacokinetics
Blood samples (only at trough) for PK analysis will be collected to document the steady-state PK 
exposure of canagliflozin. The potential effects of demographic characteristics and other subject 
covariates on the PK of canagliflozin may be evaluated. In addition, the PK data from this study 
may be integrated with plasma concentration-time data collected across other clinical 
development studies and subjected to population PK analysis. Refer to Section 9.6, 
Pharmacokinetic Evaluations, for more detail.
Archive Samples for Exploratory Research and Specimens for Biomarker Assessment
Fasting plasma, serum, and urine archive samples will be collected (where local regulations 
permit) to allow for biomarker analyses and exploratory research related to canagliflozin or 
T2DM and obesity. Refer to the laboratory manual for further information regarding the 
collection and handling of exploratory blood and urine samples.
4.
SUBJECT POPULATION
At least 146 subjects with T2DM will be randomly assigned to treatment in this study in a
1:1 ratio such that at least 73 subjects will be randomized to each treatment group. For a
discussion
of
the
statistical
considerations,
refer
to
Section
11.2,
Sample
Size 
Determination.
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 must consult with the appropriate sponsor representative and resolve any issues
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 4.4, Repeat Testing and 
Subject Rescreening.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study: 
1.
Male or female between the ages 10 to <18 years at the time of screening. 
2.
Diagnosis of T2DM. 
3.
Random C-peptide at screening >0.6 ng/mL (>0.2 nmol/L) as determined by the central 
laboratory. 
Note: If the C-peptide is ≤0.6 ng/mL (≤0.2 nmol/L) in the presence of low concomitant 
blood glucose (ie, <70 mg/dL [<3.9 mmol/L]), a repeat C-peptide measurement should be 
obtained to assess eligibility.


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4.
Absence of pancreatic autoimmunity (GAD, and islet cell antigen 2 [IA2] antibody negative) 
as confirmed by subject history (documented in medical records) or if not available, by 
central clinical laboratory evaluation at the time of screening.
5.
HbA1c of 6.5% to 11.0% and meets 1 of the inclusion criteria below:
a.
On diet and exercise only for at least 4 weeks prior to screening,
b.
On diet and exercise and a stable dose of metformin monotherapy 1,000 mg per day or 
MTD per day (defined by the investigator) for at least 8 weeks prior to screening,
c.
On diet and exercise and a stable insulin monotherapy regimen for at least 8 weeks prior 
to screening (stable dose is defined as no change in the insulin regimen [ie, type{s} of
insulin] and 15% change in the total daily dose of insulin [averaged over 1 week to 
account for day to day variability]),
d.
On diet and exercise and a stable combination therapy with metformin and insulin for at 
least 8 weeks prior to screening, as described above. 
Note: Subjects who are on diet and exercise and a stable dose of metformin XR for at 
least 8 weeks prior to screening may be included in the study, however they will be 
switched from metformin XR to metformin IR (at the same daily dose or nearest 
appropriate dose) at the single-blind placebo run-in visit and will be enrolled in the 
study if the metformin IR is well tolerated during the 2-week single-blind placebo 
run-in period prior to Visit 3/Day 1.
6.
Each subject (or their legally acceptable representative) must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of and procedures required for the 
study and are willing to participate in the study. Assent is also required of children capable 
of understanding the nature of the study (approximately 7 years of age and older) as 
described in Section 16.2.3, Informed Consent/Pediatric Assent. 
7.
Before randomization, a female subject must be either:
a.
Not of childbearing potential defined as:

premenarchal 

permanently sterile (eg, bilateral tubal occlusion [which includes tubal ligation 
procedures as consistent with local regulations]), hysterectomy or bilateral 
salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy, 
or
b.
Of childbearing potential and

heterosexually active and practicing a highly effective method of contraception 
(failure rate of <1% per year when used consistently and correctly) including 
combined (estrogen-
and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, and transdermal; 
progestogen-only hormone contraception associated with inhibition of ovulation: 
oral, injectable, or implantable;
intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); vasectomized partner (provided that the partner 
is the sole sexual partner of the female subject of childbearing potential and the 
absence of sperm has been confirmed; if not, additional highly effective method of 
contraception should be used), and agrees to remain on a highly effective method 


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of contraception throughout the study and for at least 30 days after the last dose of 
study drug. 
Note: Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the use of 
contraceptive methods for subjects participating in clinical studies. 

not heterosexually active (ie, female subject agrees to refrain from heterosexual 
intercourse during the entire period of risk associated with the study drug).
Note: Female subjects who are not heterosexually active at screening must agree to 
utilize a highly effective method of contraception if they become heterosexually 
active during their participation in the study.
8.
Female subjects of childbearing potential must have a negative highly sensitive serum 
-human chorionic gonadotropin (-hCG) pregnancy test at the screening visit.
9.
Adequate compliance with placebo single-blind run-in procedures, including 80% 
compliance (by tablet count) with single-blind placebo medication.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study: 
Diabetes-Related/Metabolic
1.
History of DKA, T1DM, pancreas or -cell transplantation, or diabetes secondary to
pancreatitis or pancreatectomy or maturity-onset diabetes of the young (MODY). See 
Attachment 8, Maturity-Onset Diabetes of the Young (MODY). 
2.
On any AHAs other than metformin, or injectable insulin within 8 weeks of the first dose of 
study drug (ie, Day 1).
3.
Repeated (ie, 2 or more over a 1-week period) fasting SMBG glucose measurements 
>270 mg/dL (>15 mmol/L) during the pretreatment phase, despite reinforcement of diet and 
exercise counseling.
Note: Subjects with fingerstick glucose >270 mg/dL (>15 mmol/L) may have their AHA 
regimen adjusted and be rescreened once on a stable regimen for at least 8 weeks.
4.
Severe hypoglycemia (defined as an event for which the subject required assistance from 
another person, or which resulted in seizure or loss of consciousness) within 6 months prior 
to Day 1. (See Attachment 4, Hypoglycemia: Definition, Symptoms and Treatment).
5.
History of hereditary glucose-galactose malabsorption or primary renal glucosuria.
Renal/Cardiovascular
6.
Renal disease that required treatment with immunosuppressive therapy or a history of 
dialysis or renal transplant.
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Gastrointestinal
7.
Known significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis).
Laboratory
8.
Persistent elevation in capillary blood ketones 0.6 mmol/L in the absence of concomitant 
illness or other identified precipitating factor during the screening period. Persistent 
elevation is defined as capillary blood ketone values 0.6 mmol/L obtained on 
2 consecutive days.
Note: Subjects with capillary ketone levels 0.6 mmol/L in the presence of precipitating 
factors (eg, acute illness, non-compliance with insulin treatment) may have the screening or 
run-in period extended by up to 2 weeks if it is the investigator’s opinion that precipitating 
factor/concomitant illness will be resolved and the subject will no longer meet the exclusion 
criterion. If, following resolution of the precipitating factor(s), the repeat assessment of 
capillary blood ketones shows values 0.6 mmol/L, the subject must be excluded.
Note: To avoid the confounding effect of overnight fasting on ketogenesis, for the 
pre-specified ketone assessment procedures, the blood ketone measurements should be 
obtained in a non-fasting state. If non-symptomatic ketone elevations are found in the 
fasting state, subjects should be instructed to repeat the ketone measurement after breakfast.
9.
eGFR is <60 mL/min/1.73m2 as assessed by Schwartz formula (see Attachment 7, Clinical 
Laboratory Tests).
Note: A one-time repeat measurement is allowed, at the discretion of the investigator, if the 
value for eGFR is not consistent with prior values. 
10. Alanine aminotransferase level >5.0 times the upper limit of normal (ULN) or total bilirubin 
>1.5 times the ULN at screening (for elevations in bilirubin: if, in the opinion of the 
investigator and agreed upon by the sponsor’s medical officer, the elevation in bilirubin is 
consistent with Gilbert’s disease, the subject may participate).
Other Conditions
11. History of malignancy within 5 years before screening (eg, any evidence of active disease 
within 5 years, or diagnosis of malignancy within this period).
Note: Subjects with squamous or basal cell carcinomas of the skin, carcinomas in situ of the 
cervix, 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, may 
participate.
12. Major surgery (ie, requiring general anesthesia) within 12 weeks before screening, or has not 
fully recovered from surgery, or planned surgery during the participation of the current 
study.
Note: Subjects with planned surgical procedures to be conducted under local anesthesia may 
participate. 


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13. History of non-traumatic 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
14. Previously been or is currently being treated with an SGLT2 inhibitor, or the subject has 
participated, or is currently participating in a canagliflozin study. 
15. Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients (refer to 
the Investigator’s Brochure).
16. Current use of corticosteroid medication or immunosuppressive agent, or likely to require 
treatment with a corticosteroid medication (for longer than 2 weeks in duration) or an 
immunosuppressive agent.
Note: Subjects using inhaled, intranasal, intra-articular, or topical corticosteroids, or 
corticosteroids in therapeutic replacement doses may participate.
17. Current use of anticonvulsant medication or is likely to require treatment with 
anticonvulsant medication.
18. Received an active investigational drug (including vaccines) or used an investigational 
medical device within 12 weeks before the planned start of treatment.
General 
19. History of drug or alcohol abuse within 3 years before screening. 
20. Pregnant or breast-feeding or planning to become pregnant during the study.
21. Child or adolescent of an employee at the investigational study center, whose parent/legally 
accepted representative has direct involvement in the proposed study or other studies under 
the direction of that investigator or study center.
22. 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.
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 screening. Before 
randomization, subjects whose status changes after screening, such that they now meet an 
exclusion criterion, should be excluded from participation. Section 17.4, Source Documentation, 
describes the required documentation to support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:

Female subjects of childbearing potential who are heterosexually active, must remain on a 
highly effective method of birth control throughout their participation in the study and for at 
least 30 days after the last dose of study drug (refer to Section 4.1, Inclusion Criteria and 
refer to Section 12.2.3, Pregnancy, for instructions in cases of a positive pregnancy test). 


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
Prohibited medications include other SGLT2 inhibitors, or other AHAs that are not approved 
for use in pediatric population (including commercially available canagliflozin). Subjects 
must not take any other investigational agents during the study (if a subject prematurely 
discontinues the study drug but continues to participate in the post-treatment follow-up 
phase, entering another investigational study is discouraged but is not prohibited; however, 
entering another canagliflozin study is prohibited).

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.

Exceptionally strenuous exercise may affect urine protein excretion and other safety 
laboratory results; for this reason, strenuous exercise should be avoided within 72 hours 
before planned study visits.
4.4.
Repeat Testing and Subject Rescreening
During the screening period and prior to initiation of the single-blind placebo run-in period at 
Week -2, a non-qualifying laboratory test value 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 be rescreened once, at the discretion of the 
investigator and with concurrence of the sponsor’s medical monitor. Additional rescreening may 
be discussed with the sponsor’s medical monitor to evaluate eligibility into the study on a case 
by case basis. Rescreening will typically require that all screening parameters be repeated, 
including the signing of a new ICF 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.
5.
TREATMENT ALLOCATION
Stratification
Dynamic randomization (ie, covariate-adjusted randomization) will be used in an effort to 
maintain balance between treatment groups with respect to the following stratification factors: 
AHA background (ie, diet and exercise only; metformin monotherapy; insulin monotherapy or 
combination of metformin and insulin) and age group (10 to <15 years old; 15 to <18 years 
old). The stratification process will be handled after logging on to the IWRS being used for the 
study.
Randomization and Blinding Procedures
In dynamic randomization, a new subject is sequentially assigned to a particular treatment group 
by taking into account the specific covariates and previous assignments of subjects. This 
approach uses the method of minimization by assessing the imbalance of sample size among the 


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covariates listed above. Subjects will be randomized to 1 of 2 treatment groups based on a 
computer-generated dynamic randomization algorithm prepared by or under the supervision of 
the sponsor before the study. This approach seeks to maintain balance between treatment groups 
with respect to the AHA background and age group. The goal is to have at least 30% of 
participants that will be 10 to <15 years of age, 30% to <65% of participants that will be female 
in each age group (10 to <15 years and 15 to <18 years), and 30% of participants that will 
have ethnicity and lifestyle comparable to Europe. 
Based on this approach, 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 the treatment code, which is linked to the dynamically-generated randomization 
schedule, will be assigned after logging on to the IWRS designated by the sponsor. The requestor 
must use his/her own user identification (ID) and personal identification number (PIN) when 
accessing the IWRS and will then enter 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 matching study drug kit for the subject. As subjects are 
randomized to treatment, the IWRS will assign a study drug kit to be dispensed at that visit. New 
study drug kits will be assigned each time the IWRS is assessed for dispensing additional study 
drug. 
At the baseline (Day 1) visit, all eligible subjects, regardless of the treatment assignment to 
canagliflozin 100 mg will be assigned canagliflozin 100 mg kits and matching placebo kits. 
The dynamically-generated 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 by assessing 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 document. The documentation received from the IWRS indicating 
the code break must be retained with the subject’s source documents in a secure manner 
(eg, sealed envelope) so as not to unblind the treatment assignment to the study site or sponsor 
personnel. The investigator is also advised not to reveal the study treatment assignment to the 
study site (except as necessary for the clinical management of the subject) or sponsor personnel.


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In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. The translation of randomization codes into treatment and control 
groups will be disclosed only to those authorized.
To avoid the potential unblinding after randomization (Day 1), FPG values will be masked to the 
study sites and to sponsor. Similarly, HbA1c values will be masked, except for (1) Day 1 value, 
(2) Week 12 value, and (3) after glycemic rescue therapy has been initiated.
In addition, unless required by urgent subject management, investigators should obtain all 
post-baseline urinalyses through the central laboratory and not by a local laboratory so as to 
avoid potential for unblinding related to urine glucose results (which will not be reported by the 
central laboratory). Investigators will be counseled to avoid performing local urinalysis with 
dipstick. 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.
Blinded Study Drug
6.1.1.
Single-Blind Placebo Study Drug 
Upon completion of initial screening, all eligible subjects will receive 1 placebo tablet (1 placebo 
tablet matching canagliflozin 100 mg) 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 2-week 
single-blind placebo run-in period drug is placebo.
6.1.2.
Double-Blind Study Drug
On Day 1, subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups: 
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 their dose of canagliflozin 100 mg or matching 
placebo, once daily, before the first meal of the day. 
At Week 13, subjects who have a Week 12 HbA1c of 7.0% and eGFR 60 mL/min/1.73m2 will 
be re-randomized to either remain on double-blind canagliflozin 100 mg (or matching placebo) 
or to up-titrate to double-blind canagliflozin 300 mg (or matching placebo). A double-dummy 
approach will be used to maintain the blind to dose-assignments as indicated below:


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
Subjects initially randomized to placebo and undergoing re-randomization at Week 13, will 
continue receiving 1 tablet of placebo matching canagliflozin 100 mg and will ADD 1 tablet 
of placebo matching canagliflozin 300 mg for the remainder of the double-blind treatment 
period.

Subjects initially randomized to canagliflozin 100 mg and re-randomized to remain on 
canagliflozin 100 mg at Week 13, will continue receiving 1 tablet of canagliflozin 100 mg 
and will ADD 1 tablet of placebo matching canagliflozin 300 mg for the remainder of the 
double-blind treatment period.

Subjects initially randomized to canagliflozin 100 mg and re-randomized to up-titrate to 
canagliflozin 300 mg at Week 13, will switch to 1 tablet of placebo matching canagliflozin 
100 mg and will ADD 1 tablet of canagliflozin 300 mg for the remainder of the double-blind 
treatment period. 
Subjects not undergoing re-randomization (ie, HbA1c of <7.0% or eGFR <60 mL/min/1.73m2) at 
Week 13 will continue to receive 1 tablet of canagliflozin 100 mg or 1 tablet of placebo 
matching canagliflozin 100 mg for the remainder of the double-blind treatment period.
A summary of study drug administration is provided in Table 1.
Table 1:
Summary of Dose Level and Number of Tablets by Study Period and Treatment
Study Period
Criteria for re-randomization
Treatment Group: 
canagliflozin
Treatment Group: placebo
Day 1 to re-
randomization
Not applicable
1 tablet of canagliflozin 
100 mg
1 tablet of placebo matching 
canagliflozin 100 mg 
Re-
randomization 
to Week 52
NOT eligible for re-
randomization if: 

HbA1c <7.0% or

eGFR <60 mL/min/1.73m2
1 tablet of canagliflozin 
100 mg 
1 tablet of placebo matching 
canagliflozin 100 mg
Re-
randomization 
to Week 52
Eligible for re-randomization 
if: 

HbA1c 7.0% and
eGFR 60 mL/min/1.73m2
1 tablet of canagliflozin 
100 mg 
                         AND
1 tablet of placebo matching 
canagliflozin 300 mg
or
1 tablet of canagliflozin 
300 mg 
                       AND
1 tablet of placebo matching 
canagliflozin 100 mg
1 tablet of placebo matching 
canagliflozin 100 mg 
                AND
1 tablet of placebo matching 
canagliflozin 300 mg
The study drug must be swallowed whole with liquid and not chewed, divided, dissolved, or 
crushed. If the subject does not take the study drug within 12 hours after the first meal of the day, 
the dose of study drug should be skipped for that day and the subject should be instructed to take 
the study drug on the following day before the first meal of the day.
Study drug treatment may be interrupted (eg, for safety and/or tolerability reasons such as 
hospitalizations for major surgical procedure or serious medical illness). In addition, study drug 
treatment should be interrupted in clinical situations known to predispose to ketoacidosis 


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(eg, prolonged fasting due to acute illness or surgery [see Section 9.2.2, Management of Blinded 
Study Drug During Ketonemia]).
For subjects who develop conditions that are associated with amputations, such as a 
lower-extremity infection, skin ulcer, osteomyelitis, gangrene, or critical limb ischemia, study 
drug should be interrupted until the condition has resolved in the opinion of the investigator. In 
the event of an amputation, restarting of dosing with canagliflozin should only be done after 
careful consideration of the individual risk:benefit and following discussion with the sponsor.
Study drug treatment interruption, occurring for any reason, will be documented on the eCRF. 
Study drug should be reinstituted once the subject has recovered and the safety and/or tolerability 
concern is no longer present. 
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol. 
On the days of study visits when fasting blood samples are collected (refer to the Time and 
Events Schedule that follows the synopsis), subjects will be instructed to refrain from taking the 
study drug before the clinic visit. The subject will be instructed to take the dose of study drug 
before the subject’s next meal.
6.2.
Concomitant Open-Label Antihyperglycemic Therapies
6.2.1.
Background Antihyperglycemic Therapies
Subjects should remain on a stable AHA regimen (doses and medications) from screening to 
Week 52, unless glycemic rescue criteria are met (refer to Section 6.2.2, Glycemic Rescue 
Therapy: Criteria and Implementation). Adjustment to the AHA regimen, including adjustments 
in insulin doses and insulin type and metformin, is permitted during prolonged fasting (eg, 
religious events), and should be carefully implemented so as to avoid events of hypoglycemia. 
After initiation of rescue therapy, adjustment of AHA therapy will be performed by the 
investigator, consistent with standard diabetes guidance. Treatment may include reinforcement of 
lifestyle counseling, up-titration to maximum labeled doses of current AHAs, or the initiation 
and up-titration of any approved AHAs. Investigators should make all reasonable efforts to 
achieve and maintain the subject’s individualized target glycemic control, and may add 
unscheduled visits, if clinically appropriate, to monitor glycemic control, and adjust the subject’s 
regimen. All adjustments to the AHA regimen should be documented in the appropriate eCRF.
Use of AHAs and adjustments to the AHA regimen (dose or agents) should be consistent with 
the labeled use of the AHA within the country of the investigational site.
6.2.2.
Glycemic Rescue Therapy: Criteria and Implementation
To assure that subjects are not exposed to prolonged poor glycemic control, the investigator may 
apply glycemic rescue criteria based upon HbA1c. These criteria are designed such that they take 
into account changes in HbA1c from baseline, with cut-offs that are progressively stricter with 


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increasing baseline HbA1c values. In particular, subjects should be started on glycemic rescue if 
they meet the increases in HbA1c relative to their individual Day 1/Baseline HbA1c value as 
described in Table 2. Subjects should be counseled to increase the frequency of SMBG 
monitoring if they experience an increase in their usual fasting and/or post-meal glucose levels 
and to contact the site if they experience sustained hyperglycemia. Sustained hyperglycemia is 
defined as 80% of non-fasting SMBG values >300 mg/dL (>16.7 mmol/L) or fasting SMBG 
values >200 mg/dL (>11.1 mmol/L) over a 1-week period. If, after reinforcement of compliance 
with study drug, non-study drug AHA therapy and lifestyle counseling, the subject continues to 
experience sustained hyperglycemia, the subject may come into the clinic (at an unscheduled 
visit, if needed) to obtain an HbA1c measurement and to determine eligibility for glycemic rescue 
therapy. If the HbA1c value meets a rescue threshold, the investigational site will be alerted and 
receive the unmasked HbA1c result. Once the protocol-specified glycemic rescue criterion has 
been met, the subject should return to the clinic for a rescue visit at which time, per the 
investigator’s discretion, he/she may either alter background AHA therapy (ie, metformin and/or 
insulin) or initiate an approved AHA for the pediatric population as per the local label. 
Double-blind study drug is to be continued after initiation of rescue therapy.
It should be noted that if the subject does not meet HbA1c rescue criterion (either at scheduled or 
unscheduled visit), the subject may be still rescued if it is the investigator’s opinion, based on 
recent SBMGs/FPG values, that the subject’s glycemic control is progressively deteriorating and 
unlikely to improve with reinforcement of compliance with background AHA therapy and diet 
and exercise counseling. If a subject has scheduling conflicts and cannot attend an unscheduled 
visit at the site to assess the HbA1c criterion, the site may instruct the subject to obtain an HbA1c 
assessment at a local laboratory. 
Table 2:
Glycemic Rescue Criteria
Baseline HbA1c
HbA1c change from baseline
<9.0%
>0.8%
≥9.0%
>0.5%
Key: HbA1c=glycated hemoglobin
Any subject that qualifies for initiation of rescue therapy should return to the investigational site, 
per the investigator’s judgment, after an overnight fast, for measurement of HbA1c, FPG, and 
serum chemistry.
If new rescue therapy is initiated, it will be supplied locally by the sponsor or reimbursed by the 
sponsor as appropriate. Investigators must complete the appropriate eCRF (documenting 
initiation of therapy) for subjects starting on rescue medication.
For subjects rescued based on SMBG and/or FPG instead of HbA1c, the most recent values 
supporting such decision will be documented into the appropriate eCRF.
Notes: 

Subjects who meet the protocol-specified glycemic rescue criteria prior to Week 12, despite 
reinforcement of compliance with background AHA therapy, study drug, and lifestyle
counseling, will NOT undergo early re-randomization (via a re-randomization visit). Instead 


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subjects will initiate glycemic rescue therapy and be evaluated at Week 12 to determine if 
they meet eligibility for re-randomization.

If rescue criterion is met based on the Week 12 HbA1c value, then the subject will return to 
the site for the Week 13 visit to undergo re-randomization AND initiate concomitant rescue 
therapy. 
7.
TREATMENT COMPLIANCE
The investigator or designated study research staff will maintain a log of all drug dispensed and 
returned. Drug supplies for each subject will be inventoried and accounted for throughout the 
study. Subjects who are poorly compliant with taking the study should receive counseling on the
importance of dosing compliance and may continue in the study, at the investigator’s discretion.
Subjects will receive clear instructions on compliance with study procedures at the screening 
visit. During the study, the investigator or designated study research staff will be responsible for 
providing additional instructions to reeducate any subject who is not compliant with taking the 
study drug or with completing the diary, as required.
Study drug interruption occurring for any reason will be documented on the appropriate eCRF.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapy includes any therapy used before the first dose of double-blind study drug. 
Concomitant therapy is any therapy used after the first dose of double-blind study drug is 
administered on Day 1.
Prestudy therapies administered up to 30 days before screening (and up to 6 months before 
screening for AHAs) and up to the time of the first dose of double-blind study drug must be 
recorded.
All therapies (prescriptions or over-the-counter medications, including vitamins and herbal 
supplements; non-pharmacologic therapies such as, 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.
Disallowed Therapies
No other SGLT2 inhibitors (including commercially available canagliflozin), or other AHAs that 
are not approved for use in pediatric population, may be used as concomitant medications, and 
subjects should not take any other investigational agents during the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.


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9.
STUDY PROCEDURES AND 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.
9.1.1.1.
Visit Schedules and Visit Windows
A screening visit should occur approximately 1 week 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.
Note: Subjects who at screening may require testing of pancreatic autoimmunity (ie, GAD-65 
and/or islet cell antigen [IA] antibodies) or who require a repeat of other screening procedures 
may have the duration of the screening period and/or run-in period increased by 1 to 2 weeks to 
allow sufficient time for the assessments to be obtained.
Post-randomization (from Day 1) scheduled study visits should generally occur within a 
recommended 7-day window (ie, 7 days) around the protocol-specified visit schedule (as 
provided in the Time and Events Schedule). All visits will be scheduled based on the date of 
randomization (Day 1). There may be exceptional cases where it is possible, with concurrence of 
the sponsor’s medical monitor, that certain on-site study visits may be replaced by telemedicine 
visits (a remote visit that is done by a video or phone call.).
A telephone follow-up contact (or optional study visit, at the discretion of the investigator) will 
be conducted for all subjects approximately 30 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 (or parent/guardian).
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 prematurely discontinue study drug, but don’t withdraw consent, study sites 
will be required to follow-up on subsequent scheduled visits, and to make a final contact 


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(eg, schedule the last follow-up visit). See Section 10.2.4, Comprehensive Follow-up at 
Scheduled Study Visits Following Premature Discontinuation of Study Drug, for more detail.
9.1.1.2.
Visit Reminders- Telephone Contacts 
Prior to each visit, subjects should be contacted and reminded of:

The date and time of their clinic appointment.

The requirement to fast for at least 8 hours prior to clinic visits on Day 1 (Randomization 
Visit), Week 26, Week 52, and unscheduled visit for initiation of glycemic rescue therapy.

The requirement on the morning of clinic visits at Week 12, 26, and 52 to not take blinded 
study drug prior to coming to the clinic.
Note: Non-study medications that are not AHAs should be taken as directed by the 
prescribing physician.

The requirement to bring study drugs, glucometer, hypoglycemia assessment tool(s), any 
collected SMBG measurements and ketone information to the clinic visit.
9.1.1.3.
Pregnancy Testing
A negative serum pregnancy test for females of childbearing potential is required at the
screening visit. Additionally, urine (or serum) pregnancy tests will be performed at Weeks 26 
and 52, or more frequently 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).
9.1.1.4.
Subject Diary: Collection of Self-Monitoring of Blood Glucose 
(SMBG), Ketones, and Possible Hypoglycemic Event Information
A standard, protocol-specified subject diary will be provided to each subject at Week-2 (and at 
subsequent visits, if needed). The purpose of this diary is to record routine SMBG measurements 
and those potentially leading to glycemic rescue, episodes of elevated ketone levels, and all 
episodes of possible hypoglycemia. In addition, this diary will be used to collect time and date of 
study drug administration on the days prior to PK sample collection, any missed doses of study 
drug and it may also be used to keep track of medications and/or medication changes at the 
investigator’s discretion. 
9.1.1.5.
Archive Samples for Exploratory Research and Specimen for 
Biomarker Assessment
Fasting plasma, serum, and urine archive samples will be collected (where local regulations 
permit) to allow for biomarker analyses and exploratory research related to canagliflozin or 
T2DM and obesity. 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 9.9, Exploratory Biomarker Evaluations, for further details. Additionally, refer 
to the laboratory manual for further information regarding the collection and handling of 
exploratory blood and urine samples.


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9.1.1.6.
Blood Collection
As summarized in Table 3 below, the estimated total blood volume that will be collected from a 
subject who completes the study (including all procedures outlined in the pretreatment and 
double-blind treatment phases over approximately 52 weeks) will be approximately 173 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Table 3:
Estimated Volume of Blood to be Collected from Each Subject 
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume of 
Blood (mL)a
Fasting plasma glucose
2.0
4
8.0
Hemoglobin A1c
2.0
7
14.0
C-peptide
2.0
5
10.0
Hematology
2.0
4
8.0
Serum chemistry
2.5
6
15.0
Fasting lipid panel
3.5
3
10.5
Serum -hCG pregnancy tests
2.5
1
2.5
Pharmacokinetic samples
4.0
3
12.0
Bone turnover markers 
10.0
3
30.0
Markers of calcium and phosphate homeostasis
Biomarkers (serum archived samples)c 
Biomarkers (plasma collection) 
10.0
5.0
6.0
3
3
3
30.0
15.0
18.0
Approximate Total b, c
        51.5
          45
173.0
a
Calculated as number of samples multiplied by amount of blood per sample.
b
Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
c
Approximate total volume of blood that would be collected from a subject who completed the study and had all blood tests 
performed (including Rescue and/or Down-Titration Visits). Total volume of blood collected will be lower in males, and 
in subjects who do not have a Rescue and/or Down-titration Visit during the study, or who do not consent to archive 
samples.
9.1.1.7.
Other Routine Examinations
During the study, subjects should continue to have routine screening examinations for diabetes
complications (eg, ophthalmologic and podiatric
examinations) consistent
with standard
guidelines for the care of patients with diabetes along with appropriate management, based
upon these evaluations.
9.1.2.
Pretreatment Phase
Potential subjects will be seen at a screening visit at which informed consent and assent will be 
obtained. 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 (Attachment 3, Method of Blood Pressure Measurement) and height and 
weight (Attachment 5, Guideline for Collecting Height Measurements) will be measured and 
prestudy medicines will be reviewed. For FPG, fasting C-peptide, and lipids, subjects must be 
fasting for at least 8 hours before blood sample collection, except for the screening visit when 
non-fasting blood samples may be collected.
Eligible subjects who meet all enrollment criteria (see Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria) will be scheduled to return to the investigational site at Week -2 
to begin the single-blind placebo run-in period.


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Note: Subjects who at screening may require testing of pancreatic autoimmunity (ie, GAD-65 
and/or IA antibodies) or who require a repeat of other screening procedures may have the 
duration of the screening period and/or run-in period increased by 1 to 2 weeks to allow 
sufficient time for the assessments to be obtained.
9.1.3.
Single-Blind Placebo Run-In Visit (Week -2)
At the Week -2 visit, subjects will be 1) provided with a glucose meter and testing supplies and 
instructed on the performance of SMBG, and blood and urine ketone measurement; 2) provided 
with a standard, protocol-specific subject diary (for recording of information on hypoglycemia, 
SMBG readings and ketone measurements); 3) receive counseling regarding diet and exercise 
consistent with standard diabetes guidance recommendations (eg, American Diabetes 
Association [ADA]); 4) receive counseling regarding recognition and management of 
hypoglycemia, and will be instructed to record all possible hypoglycemic episodes in the subject 
diary along with concurrent fingerstick glucose measurements, 5) receive counseling regarding 
how to recognize and monitor signs and symptoms of ketosis-related important events and 
importance of ketone monitoring and sick day management; 6) provide a first morning void urine 
sample. At this visit, potential eligible subjects who are on diet and exercise and a stable dose of 
metformin XR for at least 8 weeks prior to screening will be switched from metformin XR to 
metformin IR (at the same daily dose or nearest appropriate dose).
Subjects who meet eligibility criteria will be dispensed a single-blind placebo tablet (through 
IWRS, refer to Section 5, Treatment Allocation) and enter the 2-week single-blind placebo 
run-in period. Potential eligible subjects will be counseled to take 1 tablet of single-blind placebo 
once-daily, before the first meal of the day, for the 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 subjects that during the 
single-blind placebo run-in period subjects will receive placebo tablets. 
An assessment of the subjects’ adherence to protocol procedures during the single-blind placebo 
run-in period will be made at the end of the period (on Day 1), before randomization. 
Investigators should ensure adequate compliance with the single-blind placebo run-in period 
study procedures, including performance of the SMBG and blood ketone measurements 
(Section 9.2.1.1, Pre-specified Ketone Measurements During Run-in Period) with diary entries or 
documentation through glucose/ketone meter memory, and 80% compliance (by pill count). 
Note: If the subject does not meet the eligibility criteria related to compliance with study 
procedures during the run-in period due to unforeseeable circumstances (eg, breakage or loss of 
the meter, or intercurrent illness that prevented the subject to be compliant with single-blind 
study drug, etc), at the discretion of the investigator and with concurrence of the sponsor’s 
medical monitor, the duration of the run-in period may be extended to repeat the procedures and 
allow assessment of eligibility. In such cases, subjects may receive additional single-blind study 
drug.
Potential subjects who do not meet all entry criteria must be excluded from the study.


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9.1.4.
Double-Blind Treatment Phase
9.1.4.1.
Day 1/Day of Randomization
Eligible subjects (ie, those who have taken 80% of the scheduled single-blind placebo tablets 
during the single-blind placebo run-in period) will return for the Day 1 (baseline) visit, at which 
time they will be stratified by AHA background (ie, diet and exercise only, metformin 
monotherapy, insulin monotherapy or combination of insulin and metformin) and age group 
[10 to <15 years old; 15 to <18 years old] and will be randomly assigned to 1 of 
2 double-blind treatment groups (in a 1:1 ratio): canagliflozin 100 mg, or matching placebo. 
Those subjects who were switched from metformin XR to metformin IR at the single-blind 
placebo run-in visit will only be randomized if the metformin IR is well tolerated during the 
2-week single-blind placebo run-in period prior to Visit 3/Day 1.
The first dose of study drug will be administered at the study site on Day 1. Subjects will 
continue treatment until the study completes or the subject is prematurely withdrawn from 
double-blind study drug (refer to Section 10, Subject Completion, Premature Discontinuation of 
Treatment, or Withdrawal from the Study).
9.1.4.2.
Visits Following Randomization
Subjects will be seen in the clinic at visits as described in the Time and Events Schedule. 
Procedures and clinical laboratory assessments for each visit or contact are outlined in the Time 
and Events Schedule.
9.1.4.3.
Re-Randomization 
At Week 12, subjects’ glycemic status will be assessed by a central laboratory HbA1c. Following 
the review of the Week 12 unmasked HbA1c and eGFR results, the following will occur:

Subjects with HbA1c value <7.0% or eGFR <60 mL/min/1.73m2 will not undergo 
re-randomization and instead will continue their current treatment assignment 
(ie, canagliflozin 100 mg or matching placebo) for the remainder of the study. 

Subjects with HbA1c value 7.0% and eGFR 60 mL/min/1.73m2 will be re-randomized in a 
1:1 ratio (in a blinded fashion via the IWRS) to either

remain on their original treatment assignment (ie, canagliflozin 100 mg or matching 
placebo) or 

up-titrate canagliflozin 100 mg to 300 mg (or matching placebo). In order to keep the 
study blind, subjects randomized to the placebo group will undergo a mock up-titration.
For subjects with a Week 12 HbA1c 7.0% and who are on insulin and have experienced 
recurrent (ie, at least 2 episodes within a 7-day period) episodes of hypoglycemia after 
randomization, consideration should be given to down-titrate insulin prior to the blinded 
up-titration (or mock up-titration) to canagliflozin 300 mg. 


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Since the unmasked central laboratory HbA1c values will not be available at the Week 12 visit, 
subjects (or their parent/legal guardian) will be informed whether the subject is eligible for 
re-randomization via phone contact. If the subject is eligible for re-randomization, the subject 
and/or parent/legal guardian will return to the site, preferably within 1 week from Week 12, to 
return any unused study drug and obtain new blinded study drug according to the IWRS 
assignment. Although no additional study or laboratory procedures will occur at this visit, and 
the subject is not required to be physically present, the subject’s attendance is highly encouraged 
to allow the site to provide new dosing instructions related to the double-dummy treatment.
Management of double-blind study drug based on renal function 

Subjects who have undergone re-randomization and subsequently have a confirmed eGFR 
<60 mL/min/1.73m2 will undergo down-titration (or mock down-titration) of blinded study 
drug at an unscheduled down-titration visit; only those who were up-titrated previously to 
the canagliflozin 300 mg dose will actually titrate down (in a blinded fashion via the IWRS). 
Subjects randomized to canagliflozin 100 mg or placebo will undergo a mock down-titration 
and continue their randomized treatment. 

If at any time during the study, a subject has a confirmed eGFR of <45 mL/min/1.73m2, the 
subject must be discontinued from study drug as described in Section 10.2, Study Drug 
Treatment Premature Discontinuation, Reinstitution and Follow-up. Subjects discontinued 
from study drug and who do not withdraw consent will remain in the study and followed as 
described in Section 10.2. Study Drug Treatment Premature Discontinuation, Reinstitution, 
and Follow-up.

Prior to down-titrating or discontinuing canagliflozin due to confirmed eGFR 
<60 mL/min/1.73m2 or <45 mL/min/1.73m2, respectively, a repeat determination should be 
performed within 1 week and study drug down-titrated or discontinued if the repeat 
determination confirms that the value still meet the criteria (unless a reversible acute cause 
is identified [eg, short-term illness or transient volume depletion] in which case an 
additional repeat determination can be performed after resolution of the illness).

All subjects will receive a new medication kit assignment through the IWRS at the 
unscheduled down-titration visit. The investigator, or qualified assigned designee, will 
provide the subject with double-blind treatment medication with updated instructions on 
dosing and a new subject diary. The subject will be instructed to continue with the diet and 
exercise regimen and the completion of the study diary.
Note: Once a subject has up-titrated to canagliflozin 300 mg, down-titration is not allowed 
unless for confirmed eGFR <60 mL/min/1.73m2. Therefore, if after up-titration to canagliflozin 
300 mg a subject experiences recurrent hypoglycemia (ie, at least 2 episodes within a 7-day 
period), consideration should be given to down-titrate background AHA(s) such as insulin (or 
metformin).
9.1.5.
Post-treatment Phase (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 to collect any serious 
adverse events and adverse events of interest that occurred since the last visit, unless the subject 
has been lost to follow-up, has withdrawn consent, or has died. If serious adverse events are 


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obtained via telephone contact, written documentation of the communication must be available 
for review in the source documents. If the subject has died, the date and cause of death will be 
collected and documented on the eCRF. 
All subjects who discontinue study drug prematurely should continue to attend all subsequent
study visits in the same way as the subjects who are still on the study drug treatment, unless the
subject (and/or the parents[s]/legal guardian[s]) has elected to withdraw his/her consent from the 
study.
Subjects who discontinue study drug early for any reason (other than withdrawal of consent for 
follow-up contacts) will be contacted according to the post-treatment visit (or more frequently if 
necessary based on the investigator’s knowledge of the subject) until completion of the overall 
study, with the goal of collecting any information on vital signs, body weight, laboratory 
assessments, serious adverse events, adverse events of interest, and adverse events of special 
interest. See Section 10.2.4, Comprehensive Follow-up at Scheduled Study Visits Following 
Premature Discontinuation of Study Drug, for more detail.
9.2.
Ketone Monitoring
Subjects will be provided with a capillary blood ketone meter and strips. It should be noted that 
capillary blood ketone testing is the preferred methodology for decision making, as it provides a 
quantitative measure of 3β-OH butyrate which accounts for approximately 75% of the ketones 
(Foster 1983) and represents a more sensitive marker to detect and monitor ketonemia. On the 
contrary, the urine ketone test provides a qualitative assessment of aceto-acetate and appears to 
be less sensitive in detecting early stages of ketosis and may be overestimating the degree of 
ketosis during its resolution phase. 
Subjects and parents/legal guardians will be counseled on various aspects of sick day 
management and ketone monitoring aiming at early identification of elevated ketone levels and 
timely intervention in order to prevent or reduce the risk of progression to ketoacidosis. In 
particular, subjects will receive counseling on 

Importance of monitoring ketones any time the subject is ill or does not feel well, or has any 
potential precipitating factors for ketone elevation or DKA;

Recognition of signs and symptoms of ketosis and DKA;

Management of insulin and food intake during illness and/or in presence of elevated ketone 
levels.
See Attachment 1, Instructions on Ketone Monitoring and Sick Day Management and 
Attachment 2, Suggested Algorithm for Ketone Monitoring and Findings of Elevated Ketones.
During the study, subjects will return the diary containing information on ketone measurements 
and if applicable, action taken by the subject to treat elevated ketone levels. Study site personnel 
will be required to review the diaries and enter only the data of elevated ketones 
(ie, 0.6 mmol/L) along with other pertinent information (concomitant blood glucose levels, 
signs/symptoms of illness, precipitating factors, etc) on a specific eCRF. In addition, upon 


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review of the diaries, findings of elevated ketones considered by the investigator to be adverse 
events should also be reported in the adverse event eCRF. In addition, any illness considered to 
be a precipitating factor of the ketone elevation should be reported as an adverse event, if 
appropriate, on the adverse event eCRF.
9.2.1.1.
Pre-specified Ketone Measurements During Run-in Period
Subjects will be required to measure and document in their study diary capillary blood ketones 
and blood glucose on a minimum of 3 days during the 2-week run-in period (to assess subject’s 
pre-dose ketone levels and compliance with ketone management procedure). The measurements 
do not have to be made on 3 consecutive days.
To avoid the confounding effect of overnight fasting on ketogenesis, for the pre-specified 
ketone assessment procedures, the blood ketone measurements should be obtained in a non-
fasting state. If non-symptomatic ketone elevations are found in the fasting state, subjects 
should be instructed to repeat the ketone measurement after breakfast.
9.2.1.2.
Ketone Measurements During Periods of Increased Risk of 
Ketonemia
It is paramount that subjects and parents/legal guardians are educated on obtaining ketone 
measurements whenever they experience potential causes of ketone elevation that might 
lead to ketoacidosis if not identified and treated in time. 
These possible precipitating factors include, but are not limited to:

Acute illness 

Significant and/or sudden reduction in insulin dose (eg, non-compliance with insulin 
treatment regimen)

Prolonged fasting or low carbohydrate diet

Dehydration and/or a marked increase in physical activity

Increased alcohol consumption 

Undergoing a minor procedure (eg, dental extraction)

Significant physiologic stress 
Subjects and parents/legal guardians will be instructed to test their ketone levels in the presence 
of these possible precipitants, regardless of the presence of symptoms of DKA (such as nausea, 
abdominal pain, dehydration, polyuria), as these are nonspecific and might be interpreted as 
gastroenteritis, or signs and symptoms of osmotic-diuresis related to the use of study drug. In 
addition, it is paramount to instruct subjects and parents/legal guardians to test ketones in such 
occasions regardless of the concomitant glucose level, as blood glucose might be incongruously 
low (<250 mg/dL [<13.9 mmol/L]) and not as high as one would expect to observe during 
ketosis and DKA.


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Ketone measurements performed during illness or periods of increased risk of ketone elevation, 
should preferably be done prior to dosing of study drug to allow prompt interruption of study 
drug, if required.
During sick days, subjects must refer to the algorithm (see Attachment 2, Suggested Algorithm 
for Ketone Monitoring and Findings of Elevated Ketones) to determine, based on severity of 
illness, degree of ketosis, and ability to increase insulin dose and food intake, the appropriate 
frequency of retesting of ketones and glucose, action with blinded study drug, need to seek 
immediate medical attention, or to contact the study site. 
Subjects are required to enter pertinent information related to elevated ketones during illness 
(eg, concomitant [or closest in time] glucose levels, insulin dose and changes in insulin dose [if 
applicable], precipitating factors) on a subject diary and the information will be captured on a 
specific eCRF. Upon review of the subject’s ketone measurements, the site will be required to 
report only the episodes of elevated ketone levels (ie, 0.6 mmol/L) and the pertinent 
information onto the specific eCRF. The concomitant illness should be reported as a separate 
adverse event and study drug treatment interruptions will be documented on the eCRF. 
Note: If subjects cannot obtain capillary blood ketone measurement, a urine ketone measurement 
should be obtained. Deviations from this process should be documented on the subject’s diary.
9.2.2.
Management of Blinded Study Drug During Ketonemia 
Subjects will be instructed to interrupt blinded study drug for the following reasons:

Surgery and invasive procedures

Subjects undergoing pre-planned major surgery (eg, requiring general anesthesia), will 
be instructed to interrupt blinded study drug at least 3 days prior to the surgery. Study 
drug may be resumed after recovery from surgery and after consultation with the 
investigational site.

Subjects undergoing minor surgical and non-surgical procedures will be instructed to 
interrupt study drug on the day of the procedure (or starting the day prior to the 
procedure if deemed appropriate, such as in preparation for a colonoscopy) and resume 
dosing on the following day if their non-fasting blood ketone level on the day following 
the procedure is <0.6 mmol/L and the subject has completely recovered from the 
procedure.

Persistent elevated ketonemia 0.6 mmol/L (with or without symptoms of ketosis, 
regardless of concomitant glucose levels)

Persistent elevated ketonemia is defined as blood ketone levels 0.6 mmol/L and 
confirmed by a repeat assessment (eg, within 1 hour or sooner, if in the presence of 
symptoms). If urine ketone is being used to assess ketone status, then a value of 
“moderate/large” urine ketone will be used.


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
In the presence of illness/symptoms, or presence of potential risk factors for ketosis 
(eg, insulin dose reduction, etc), subjects should assess ketone levels prior to dosing 
blinded study drug to allow timely interruption of study drug should ketone levels be 
elevated.
Subjects should be advised to contact the study site immediately for further instructions 
regarding management of blinded study drug, insulin dose-adjustment, and possible need 
to seek immediate medical attention.
Cause of dose interruption of blinded study drug and duration of study drug interruption will be 
captured on a specific adverse event eCRF and study drug administration eCRF, respectively.
9.3.
Self-Monitoring of Blood Glucose
Run-in Period Management
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, and to enter results into the protocol-specified study diary that will be 
provided to each subject, as described in Section 9.1.1.4, Subject Diary: Collection of 
Self-Monitoring of Blood Glucose (SMBG), Ketones, and Possible Hypoglycemic Event 
Information.
Note: During the pretreatment phase, subjects will be counseled to perform fasting SMBG 
measurements  a minimum of 3 days during the 2-week run-in period. The measurements do not 
have to be made on 3 consecutive days. Additional SMBG measurements may be performed by 
the subjects at the discretion of the investigator and per local guidelines.
Double-blind Treatment Phase Glycemic Management
During the double-blind treatment phase, investigators will counsel subjects to perform regular 
fasting SMBG determinations a minimum of 3 days per week with additional measurements 
made as considered clinically appropriate by the investigator and per local guidelines.
9.4.
Study Management: Committees
9.4.1.
Medical Safety Review Committee
An internal MSRC will be established to ensure that the safety of subjects participating in the 
study is not compromised. The MSRC will include, but will not be limited to, at least one 
medical expert and at least one statistician. The MSRC will include members from the sponsor. 
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 are documented in the MSRC charter.


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9.4.2.
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 the IDMC charter.
The IDMC will have responsibility for safety review during the study, including serious adverse 
events, adverse events of interest, and events resulting in study drug discontinuation. 
9.5.
Efficacy Evaluations
9.5.1.
Measures of Efficacy/Efficacy Endpoints 
The primary measure of efficacy is HbA1c. Secondary measures of efficacy include FPG, body 
weight, proportion of subjects with an HbA1c <7.5%, <7.0%, and <6.5%, time to rescue, and 
proportion of subjects receiving rescue therapy. 
Efficacy endpoints (ie, criteria for evaluation of efficacy measures) include the following: 
The primary efficacy endpoint will be the change in HbA1c from baseline to Week 26; only 
subjects who have both baseline and at least one post-baseline measurement will be included. 
Key secondary endpoints include the change from baseline to Week 26 and change from 
baseline to Week 52 in FPG, body weight, proportion of subjects with an HbA1c <7.5%, 
<7.0%, and <6.5%, time to rescue, and proportion of subjects receiving rescue therapy. 
Additional secondary endpoints are BMI, fasting lipid profile, systolic and diastolic blood 
pressure, and change in HbA1c from baseline to Week 12.
9.6.
Pharmacokinetic Evaluations
9.6.1.
Sample Collection and Handling
Venous blood samples of 4 mL will be collected at Week 12, Week 26, EOT (Week 52), and at 
early withdrawal visit for determination of plasma trough concentrations of canagliflozin in all 
subjects. On the days when PK blood samples are collected, subjects will be instructed to refrain 
from taking the study drug before the clinic visit and to bring the study drug to the clinic visit. 
The subject will be instructed to take the dose of study drug immediately before the subject’s 
next meal. Subjects will record the time that the study drug was taken on the day preceding the 
clinic visit in the subject diary. The exact dates and times of blood sampling must be recorded in 
the eCRF or laboratory requisition form. Refer to laboratory manual for further information
regarding the collection, handling, shipment and labeling of biological samples.
9.6.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of canagliflozin using a validated, 
specific, and sensitive liquid chromatography-dual mass spectrophotometry (LC-MS/MS) 
method under the supervision of the sponsor’s bioanalytical facility. 


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9.6.3.
Pharmacokinetic Parameters 
For each treatment, trough concentrations at each visit will be summarized by descriptive 
statistics, including arithmetic mean, standard deviation, minimum, maximum, and median. 
Population based PK modeling may be applied to the available plasma concentrations as needed.
9.7.
Biomarker Evaluations
Markers of Bone Turnover and Markers of Calcium and Phosphate Homeostasis
Bone turnover markers (serum osteocalcin and serum collagen type 1 CTx) and markers of 
calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH, 25-hydroxy 
Vitamin D, calcitonin; urinary excretion of calcium and phosphate) will be measured in this 
study. These markers will be collected on Day 1, Week 26, EOT (Week 52), and at early 
withdrawal visit.
9.8.
Safety Evaluations
Safety and tolerability evaluations, according to the time points provided in the Time and Events 
Schedule will include:

Collection/monitoring of adverse events 

Collection of potential hypoglycemic episodes (eg, from the subject diary provided to 
subjects) 

Ketone monitoring

Physical examinations

Body weight 

Vital signs (blood pressures and pulse rates) 

Safety laboratory tests (including chemistry, hematology, urinalysis) (see Attachment 7, 
Clinical Laboratory Tests)

SMBG 

Bone turnover markers (serum osteocalcin and serum collagen type 1 CTx)

Markers of calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH 
25-hydroxy Vitamin D, calcitonin, urinary excretion of calcium and phosphate) 

Urinary ACR 

Assessment of growth velocity and Tanner Staging (Refer to Attachment 6, Tanner Staging)
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. Adverse events will be followed by the investigator as 
specified in Section 12, Adverse Event Reporting. Information about all adverse events (serious 


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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.
Adverse Events of Interest and Special Interest and Collection of Additional Information 
For adverse events of interest and of special 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, and the IDMC (refer to Section 9.4.1, Medical 
Safety Review Committee, and Section 9.4.2, Independent Data Monitoring Committee, 
respectively). 
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 9.1.5, Post-Treatment 
Phase [Follow-up], for details of follow-up required).
Management of Hyperglycemia
Subjects will be asked to monitor their fasting blood glucose during the study. The number of 
SMBG measurements to be performed by the subjects will be at the discretion of the investigator 
and per local guidelines. The subjects will be asked to contact the study site in the presence of 
sustained hyperglycemia (see Section 6.2.2, Glycemic Rescue Therapy: Criteria and 
Implementation). If glycemic control does not improve despite reinforcement of background 
AHA therapy, diet and exercise counseling and after correction of potential cause leading to the 
hyperglycemia, then glycemic rescue may be initiated as outlined in Section 6.2.2, Glycemic 
Rescue Therapy: Criteria and Implementation.
Collection of Information on Possible Hypoglycemic Episodes
Subjects will be asked to collect fingerstick glucose determinations at the time of possible 
hypoglycemic episodes, and to document information on these events, including the fingerstick 
glucose results, in a subject diary. This diary will be reviewed by study-site personnel at each 
scheduled visit (see Attachment 4, Hypoglycemia: Definitions, Symptoms and Treatment). 
Information on possible hypoglycemic episodes will be collected on a separate hypoglycemia 
eCRF, and hypoglycemic episodes that are considered by the investigator to be adverse events of 
hypoglycemia should also be recorded on the adverse event eCRF. 
Collection of Information on Possible Ketone-Related Events
Information on serious and non-serious ketosis-related adverse events and related terms such as 
diabetic ketoacidotic hyperglycaemic coma, ketonuria, ketonaemia, ketosis, urine ketone body 


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present, acidosis, metabolic acidosis, blood ketone body present, blood ketone body increased 
will be collected on a separate eCRF and also recorded on the adverse event eCRF. If a 
ketosis-related adverse event meets the criteria used to define a serious adverse event (SAE), the 
event must be captured as an SAE on the Adverse Event eCRF.
Subjects will be asked to collect capillary blood ketones during periods of increased risk of 
ketonemia and to document these in a subject diary. Detailed information of episodes of elevated 
ketone levels requiring corrective actions (eg, increase in insulin dose, study drug interruption, 
etc) will be collected on the subject diary which will be reviewed by study site personnel at each 
scheduled visit. Information on episodes of elevated ketones will be collected on a separate 
eCRF, and adverse events of elevated ketone levels requiring corrective actions that are 
considered by the investigator to be adverse events of elevated ketones should also be recorded 
on the adverse event eCRF.
Clinical Laboratory Tests 
Subjects will be monitored with safety laboratory measurements as described in Attachment 7, 
Clinical Laboratory Tests. 
In addition to the laboratory reports, alerts will be provided to investigators by the central 
laboratory identifying important laboratory changes
or
key out-of-range values,
so
the 
investigator can follow-up as necessary.
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. 
The laboratory reports must be filed with the source documents.
Urine samples from first morning void on day of designated visits will be collected for urine 
albumin and creatinine determinations. This urine sample should not be collected if the subject is 
menstruating, has exercised vigorously in the past 24 hours, or had a fever or an active infection 
within the past 2 days of the clinic visit. In such cases the subject may bring a first morning void 
specimen (or the 24-hour urine collection) to the investigational site during the subsequent week. 
For subjects who have atypical sleep patterns, the collection should be made at the end of the 
subject’s usual sleep period. Note: if the subject cannot provide the morning void collection on 
the Week -2 visit, it must be provided prior to the Day 1 visit to assess whether the specimen is 
positive for protein. If the Week -2 urine sample from the first morning void shows a presence of 
proteinuria (ie, proteinuria +1 and above) based on the central laboratory urine dipstick, a 
24-hour urine collection will be required to assess albumin and creatinine. The pre-
randomization 24-hour urine sample can be collected over the 24 hours preceding the Day 1 visit 
(ie, start on the morning of Day -1 and complete on the morning of Day 1. Subjects who require 
a 24-hour urine collection prior to randomization, will be required to provide a 24-hour urine 
sample also on Week 26 and Week 52. Subjects who had a Week -2 first morning void negative 
for protein and develop a positive first morning void after randomization are not required to 
obtain 24-hour urine samples. Instead, in these subjects a first morning urine sample to assess 
albumin and creatinine will be collected for the remainder of the study. 


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Fasting plasma, serum, and urine archive samples will be collected (where local regulations 
permit) to allow for biomarker analyses and exploratory research related to canagliflozin or 
T2DM and obesity. The urine collections for exploratory analysis, as well as the routine 
urinalyses, should be obtained from a spot urine specimen in the clinic. 
For SMBG monitoring during the study, refer to Section 9.3, Self-Monitoring of Blood Glucose. 
Pregnancy Testing
Serum (-hCG) pregnancy testing will be conducted for all female subjects of childbearing 
potential during the screening visit (refer to the Time and Events Schedule). Additionally, urine 
(or serum) pregnancy tests will be performed at Week 26 and Week 52 visits, or more frequently 
as determined necessary by the investigator, or required by local regulation, to establish the 
absence of pregnancy at any time during the study. Pregnancy testing will be performed for all 
female subjects according to local procedures unless they are premenarchal or surgically sterile. 
If a post-screening urine pregnancy test is positive, study drug should be immediately interrupted 
and then permanently discontinued if the urine test is confirmed by a serum pregnancy test (see 
Section 10.3, Withdrawal from the Study and Section 12.2.3, Pregnancy).
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 a seated position for 5 minutes and before blood sample collection for 
laboratory tests. Pulse rate will be measured once at each clinic visit. For the blood pressure 
methodology, refer to Attachment 3, Method of Blood Pressure Measurement.
Body Weight
Body weight will be measured using the same calibrated scale at each visit (whenever possible). 
Subjects will be weighed at approximately the same time of day on the same scale, wearing 
underwear and a gown and without shoes; they will be instructed to empty their bladders before 
being weighed.
Note: If disrobing for weighing is logistically impossible, the subject must be dressed as lightly 
as possible, with consistency from visit to visit. The study site will be responsible for 
maintaining the scale during the study. Maintenance of the scale must be documented.
Physical Examination
A physical examination, including a review of body systems (head and neck, eyes, chest and 
lungs, cardiovascular, extremities and back, and abdomen examination), will be performed to 
assure that a subject meets entry criteria. Clinically relevant findings in physical examination 
must be documented in the source document and in the Medical History section of the eCRF.
Growth Velocity and Tanner Staging
Growth velocity will be assessed in all subjects during the study. 


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Tanner staging will be performed in order to assess the physical measurements of sexual 
development. If at any of the evaluations the subject’s sexual maturation is assessed as being 
Tanner Stage 5, no further evaluations are needed during the study (Attachment 6, Tanner 
Staging). 
9.9.
Exploratory Biomarker Evaluations
Fasting plasma, serum, and urine archive samples will be collected (where local regulations 
permit) at the time points specified in the Time and Event Schedule to allow for biomarker 
analyses and exploratory research related to canagliflozin or T2DM and obesity. Refer to the 
laboratory manual for further information regarding the collection and handling of exploratory 
blood and urine samples.
10.
SUBJECT COMPLETION, PREMATURE DISCONTINUATION OF 
TREATMENT, OR WITHDRAWAL FROM THE STUDY
10.1.
Subject Completion
A subject will be considered to have completed the treatment phase if he or she has completed 
assessments at Week 52 of the double-blind treatment phase.
Subjects who prematurely discontinue study drug for any reason before completion of the 
double-blind phase at Week 52 will not be considered to have completed the study.
End-of-treatment evaluations will be performed when the subject completes the double-blind 
treatment phase at Week 52. The EOT evaluation should be followed by a 30-day off-drug 
follow-up visit or telephone contact to collect any serious adverse events and adverse events of 
interest. 
If a subject discontinues from study drug prior to Week 52, he or she will be followed as per the 
assessments included in the Time and Events Schedule up to the Week 52 visit, without the 
requirement for the post-Week 52 follow-up (see Section 10.2.4, Comprehensive Follow-up at 
Scheduled Study Visits Following Premature Discontinuation of Study Drug, for more detail).
For details regarding the procedures performed at the EOT evaluation, refer to the Time and 
Events Schedule.
10.2.
Study Drug Treatment Premature Discontinuation, Reinstitution, and 
Follow-up 
10.2.1.
Study Drug Treatment Premature Discontinuation
A subject should discontinue study drug for any of the following reasons: 

Subject is persistently in poor compliance with study drug or procedures.

The investigator believes that for safety or tolerability reasons it is essential for the subject 
to discontinue study drug.


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
The subject experiences a serious adverse event of biochemically-confirmed DKA (eg, low 
pH in presence of elevated serum ketones or urine ketones, etc). 

The investigator formally unblinds the subject’s study treatment allocation.

The subject becomes pregnant (study therapy should be immediately interrupted based upon 
a positive urinary human chorionic gonadotropin [hCG], and permanently discontinued if 
confirmed by a serum -hCG test).

Subject requires disallowed therapy (see Section 8, Prestudy and Concomitant Therapy).

Subject has an eGFR of <45 mL/min/1.73m2, confirmed by repeat (no sooner than 7 days 
and no later than 14 days from the initial report) by the central laboratory.
Note: For subjects meeting this eGFR discontinuation criterion, a repeat determination 
should be performed between 7 and 14 days and study drug discontinued if the repeat 
determination confirms that the value still meets the criteria (unless a reversible acute cause 
is identified [eg, short-term illness or transient volume depletion] in which case an 
additional repeat determination can be performed after resolution of the illness). If the value 
is improving on repeat determination, but still meets the discontinuation criteria, an 
additional repeat measurement may be performed within 2 weeks, and the subject continued 
if they no longer meet the criterion or if improvement continues (in which case an additional 
repeat within 2 weeks may be obtained, and be used to determine subject discontinuation 
from the study).

The subject meets the rescue therapy criteria, but the AHA to be initiated as rescue 
medication is not approved for use in the country of the investigational site, or the subject 
has a contraindication to the use of any approved AHA to be used as rescue medication, 
based upon the local label.
All subjects who prematurely discontinue study drug should continue subsequent study visits and 
post-treatment follow-up evaluations (see Section 10.2.4, Comprehensive Follow-up at 
Scheduled Study Visits Following Premature Discontinuation of Study Drug and Section 9.1.5, 
Post-treatment Phase [Follow-up]). Treatment should be recommenced wherever possible and 
routinely considered at every visit following discontinuation (see Section 10.2.3, Reinstitution of 
Treatment with Study Drug That Has Been Interrupted).
Subjects and/or parents[s]/legal guardian[s] 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 subject 
who discontinued the study may not be assigned to another subject. Subjects who discontinue 
study drug will not be replaced.


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10.2.2.
EOT and 30-Day Follow-up Assessments for Subjects Who 
Prematurely Discontinue Study Drug
If a subject discontinues study drug for any reason before the end of the 52-week double-blind 
phase, EOT and 30-day post-treatment follow-up assessments should be obtained and scheduled 
assessments should be continued.
Subjects who prematurely discontinue study drug will require an immediate EOT assessment 
(either on the day of study drug discontinuation or as soon as possible following study drug 
discontinuation) as well as an off-drug follow-up assessment (ie, clinic visit or telephone contact) 
approximately 30 days after their last dose of study drug. The Time and Events Schedule 
describes the evaluation required. If for some reason the subject is unable to be seen within 
30 days after discontinuing study drug, the EOT visit may be omitted, but a 30-day off-drug 
follow-up assessment should be performed. 
If a subject discontinues from study drug prior to Week 52, he or she will be followed as per the 
assessments included in the Time and Events Schedule (see Section 10.2.4, Comprehensive 
Follow-up at Scheduled Study Visits Following Premature Discontinuation of Study Drug, for 
more detail).
10.2.3.
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, or other 
unforeseen circumstance should be encouraged to restart study drug unless there is a clear 
contraindication at the discretion of the investigator with concurrence from the sponsor’s medical 
monitor.
Study drug interruption, occurring for any reason, will be documented on the appropriate eCRF.
10.2.4.
Comprehensive Follow-up at Scheduled Study Visits Following 
Premature Discontinuation of Study Drug
It is important to note that subjects who discontinue study drug early will be required, wherever 
possible, to continue with scheduled visits for the duration of the study. Data collection required 
for subjects who discontinue study drug early will be comprehensive (as described in the Time 
and Events Schedule) and will be essential for every randomized subject. Subjects will continue 
to be followed up for specific data collection, including, vital signs, body weight, laboratory 
assessments, serious adverse events, adverse events of interest, and adverse events of special 
interest for the duration of the study. For subjects who prematurely discontinue study drug, sites 
will be required to make a final contact (eg, schedule the last follow-up visit) at what would have 
been their final scheduled visit. 
Alternate Follow-up Methods
If a subject who discontinued study drug prior to Week 52 refuses or is unable to return for their 
regularly scheduled visits, he/she will be asked to return at a reduced visit schedule including key 
visits (ie, Weeks 12, 26, 42, and 52). If the subject refuses or is unable to return to the clinic for 
follow-up visits, the subject can be contacted at Weeks 12, 26, 42, and 52 to obtain adverse 


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events, and prior/concomitant medications. At the very minimum, attempts should be made at 
Week 52 to obtain adverse events and prior/concomitant medications. These alternate follow-up 
methods should be planned to coincide with the visit times outlined in the Time and Events 
Schedule. Details regarding discussions via telephone, email, or other such contacts must be 
properly documented in source records, including responses by the subject.
10.3.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:

Death

Lost to follow-up

Withdrawal of consent or assent (either by the subject and/or the parents[s]/legal 
guardian[s])
For subjects (and/or parents[s]/legal guardian[s]) withdrawing from the study before study 
completion, an early withdrawal evaluation should be performed as soon as possible after the last 
dose of study drug is taken. Refer to the Time and Events Schedule for procedures to be 
conducted at the EOT/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/or parent(s)/legal guardian(s) and to determine the subject’s 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. Third-party vendors may be used to locate subjects lost to 
follow-up where permitted by local laws and regulations.
Subject and/or parent(s)/legal guardian(s) will be asked as a condition of entry into the study to 
agree to grant permission for the investigator to consult family members, the subject’s physicians 
and medical records, or public records, to determine the subject’s status during the study, in the 
event the subject is not reachable by conventional means (eg, office visit, telephone, email, or 
certified mail). The subject and/or parent(s)/legal guardian(s) are 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 may 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 to determine the subject’s status during the study.
10.3.2.
Withdrawal of Consent
Withdrawal of consent (either by the subject or the parents[s]/legal guardian[s]) should be a very 
unusual occurrence in a clinical trial. The investigator should make every effort to maintain a 


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good relationship with subjects and their parents[s]/legal guardian[s] to avoid this occurrence. 
Unless consent is specifically withdrawn, subjects are expected to be followed up through the 
end of the study. 
Subjects and/or parents[s]/legal guardian[s] who request to withdraw consent from the study 
should be asked if they are agreeable to be contacted to obtain post-treatment follow-up 
information, including the Week 52 post-treatment follow-up visit. Subjects and/or 
parents[s]/legal guardian[s] who are not agreeable to follow-up will be withdrawn from the study 
as “withdrawal of consent” and will not be scheduled for the Week 52 post-treatment follow-up 
visit. Subjects and/or parents[s]/legal guardian[s] who wish to discontinue study drug but agree 
to further follow-up have, by definition, not withdrawn consent to the trial and will be scheduled 
to return to the clinic for the Week 52 post-treatment follow-up visit (see Section 10.2, Study 
Drug Treatment Premature Discontinuation, Reinstitution, and Follow-up). The recording of 
withdrawal of consent in the eCRF for this study will occur after a discussion between the 
investigator and the subject along with the parents[s]/legal guardian[s] has taken place. 
For subjects and/or parents[s]/legal guardian[s] requesting to withdraw consent, it is 
recommended that the withdrawal is in writing. If the subject and/or parents[s]/legal guardian[s] 
refuses or is physically unavailable, the study site should document and sign the reason for the 
subject’s and/or parents[s]/legal guardian[s] failure to provide a request to withdraw and 
maintain this documentation in the subject’s source records.
When a subject and/or parents[s]/legal guardian[s] withdraws consent before completing the 
study, the reason for withdrawal of consent 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 consent (either per their own decision and/or by the parents[s]/legal 
guardian[s]) will not be replaced.
If a subject and/or parents[s]/legal guardian[s] had previously withdrawn consent but decides to 
retract that withdrawal, the subject and/or parents[s]/legal guardian[s] will be re-consented. The 
investigator will be responsible for making all required notifications to the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC).
10.4.
Withdrawal from the Use of Samples in Future Research
A subject who withdraws consent 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 


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requested, the investigator will receive written confirmation from the sponsor that the 
samples [has] [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. 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. Details of the sample 
retention for research are presented in the main ICF and in the separate ICF for optional research 
samples.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP). 
11.1.
Analysis Sets
The full analysis set (FAS) population includes all subjects who are randomly assigned to a 
treatment group, have received at least 1 dose of study drug and have a baseline HbA1c
measurement. 
The safety analysis set will include randomized subjects who take at least 1 dose of study drug.
The per protocol (PP) analysis set consists of all FAS subjects who complete the 26-week 
double-blind treatment phase and have no major protocol deviations that may affect the 
interpretation of the primary efficacy endpoint. Major protocol deviations will be defined in the 
SAP.
The primary efficacy analyses, to demonstrate the superiority of canagliflozin compared with 
placebo, will be based on the FAS population. Supportive analyses in the PP analysis set will 
also be performed for the primary endpoint of HbA1c. 
Efficacy data will be analyzed according to the initial randomization assignment, regardless of 
the actual treatment received. Safety data will be analyzed according to the predominant 
treatment received, in the event that subjects received a treatment other than that to which they 
were randomly assigned to receive. The approaches used to handle study deviations will be 
detailed in the SAP.


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11.2.
Sample Size Determination
The primary hypothesis of the study is that canagliflozin is superior to placebo in glycemic 
control, as measured by the change from baseline to Week 26 in HbA1c. 
The sample size calculation is based on the 2-stage randomization design using a 2-sample, 
2-sided t-test with Type 1 error rate of 0.05. Based on the following assumptions on treatment 
effect (0.4% to 0.5%) and an associated common standard deviation of 0.9% and assuming 50% 
of the subjects will meet the re-randomization criteria at Week 12, it is estimated that at least 
66 subjects per group will be required to achieve approximately 85% power. To account for 
attrition due to study discontinuation in a longitudinal analysis (to be described below), a 10% 
sample size inflation factor is employed (Lu 2008), and a total of at least 146 subjects (73 per 
arm) will be randomized in this study. 
Treatment group
Meeting re-
randomization 
criteria at Week 12
Placebo-subtracted group difference in 
change in HbA1c from baseline to Week 
26
canagliflozin 100 mg to canagliflozin 100 mg
No
0.5%
canagliflozin 100 mg to canagliflozin 100 mg
Yes
0.4%
canagliflozin 100 mg to canagliflozin 300 mg
Yes
0.5%
For subjects who are on background metformin (with or without insulin), it is estimated that at 
least 33 subjects per group (after accounting for attrition due to study discontinuation) will be 
required to achieve approximately 85% power to assess the efficacy of canagliflozin on a 
background of metformin. 
Treatment group (add-on to metformin)
Meeting re-
randomization 
criteria at Week 12
Placebo-subtracted group difference in 
change in HbA1c from baseline to Week 
26
canagliflozin 100 mg to canagliflozin 100 mg
No
0.75%
canagliflozin 100 mg to canagliflozin 100 mg
Yes
0.65%
canagliflozin 100 mg to canagliflozin 300 mg
Yes
0.75%
The assumed treatment effect above is based on a subgroup analysis of subjects with baseline 
eGFR of 90 mL/min/1.73m2 from the add-on to metformin study of canagliflozin in adults 
(ie, Study DIA3006).
11.3.
Efficacy Analyses 
11.3.1.
Primary Efficacy Endpoint 
11.3.1.1.
Definition
The primary efficacy endpoint will be the change in HbA1c from baseline at Week 26.
Estimand
The primary efficacy estimand is described according to the following attributes:

Population: children and adolescents (≥10 to <18 years) with T2DM who have an HbA1c
≥6.5% to ≤11.0%


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
Variable: change in HbA1c from baseline to Week 26

Treatments: canagliflozin vs placebo

Intercurrent event (events that preclude observation of the variable or affects its 
interpretation): treatment discontinuation or initiation of rescue medication, variable is used 
regardless of early treatment discontinues or initiation of rescue medication

Treatment policy strategy: the measurements of the variable of interest are used regardless 
of the occurrence of the intercurrent event

Population-level summary for the variable: the placebo-subtracted difference (ie, 
canagliflozin versus placebo) in least-squares mean change of HbA1c from baseline at Week 
26 along with the 2-sided 95% CI
This estimand targets the effect of canagliflozin on the variable measured and follows an “ITT 
principle” strategy.
The main analysis of the primary efficacy outcome will be based on all HbA1c measurements 
(regardless of the occurrence of treatment discontinuation or initiation of rescue medication) and 
will employ pattern mixture modelling using multiple imputation methods. The imputed datasets 
will be analyzed using analysis of covariance (ANCOVA) with terms for treatment, stratification 
factors, and baseline HbA1c. Additional details will be specified in the SAP.
The following sensitivity analyses will also be performed using the primary estimand:

The primary efficacy endpoint will be analyzed using a mixed model for repeated measures 
(MMRM) based on restricted maximum likelihood. The analysis will use the observed data
and will include the fixed, categorical effects of treatment, stratification factors (ie, 
background AHA and age group), visit, and treatment-by-visit interaction, as well as the 
fixed, continuous covariates of baseline and baseline-by-visit interaction. An unstructured 
covariance will be used to model the within-patient errors. This sensitivity analysis will 
constitute the primary analysis based on a specific health authority request.

The change from baseline in HbA1c will be analyzed using an ANCOVA model with 
treatment and the stratification factors as fixed effects and baseline HbA1c value as a 
covariate. The treatment differences in the least-squares means and the 2-sided 95% CI will 
be estimated based on this model. The last observation carried forward (LOCF) method will 
be applied when the Week 26 values are missing.
The following supplementary analysis will be performed using the primary estimand:

A re-randomization test (Proschan 2011) (utilizing the MMRM as described above) will be 
used to determine the p-value for the primary efficacy comparison (ie, comparing all 
subjects who are randomized to canagliflozin to all subjects who are randomized to
placebo). The re-randomization test will fix the observed HbA1c data, regenerate treatment 
assignments for the entire study using the same minimization algorithm employed in the 
study and compute the test statistics corresponding to the primary efficacy comparison. This 
process will be repeated at least 1,000 times. The p-value for the primary efficacy 
comparison will be defined as the proportion of re-randomized studies whose test statistic 
for that comparison is at least as extreme as that of the original treatment assignment. 


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The primary efficacy endpoint will also be performed in the subset of FAS subjects on a 
background of metformin (with or without insulin) using the main analysis methods described 
above. Analyses for the other AHA subgroups in the FAS may also be performed.
Additional details on the data handling rules (including the definition of data windows used for 
analysis) will be described in the SAP.
11.3.2.
Multiplicity Adjustment
To strongly control the family-wise error rate at the 5% significance level, a sequential testing 
procedure as illustrated in Figure 2 below will be applied. The primary endpoint will be first 
tested  in all subjects (ie, FAS), and if the results are significant (2-sided alpha level of 0.05), it 
will then proceed to test the subset of subjects on a background of metformin (with or without 
insulin).
Figure 2:
Testing Sequence
Canagliflozin 
superiority vs placebo
HbA1c reduction
(All subjects)
=0.05
↓
Canagliflozin 
superiority vs placebo
HbA1c reduction
(Add-on to metformin)
The formal hypothesis testing above will be based on all randomized subjects in the FAS.
The comparisons by canagliflozin dose to placebo will also be presented and analyzed using the 
weights in the analyses described below. 

When comparing subjects who initially receive canagliflozin 100 mg with no dose increase 
to 300 mg to placebo: All subjects start with a weight of 1. After Week 12, subjects with an 
HbA1c ≥7.0% and eGFR ≥60 mL/min/1.73m2 who are re-randomized to continue 
canagliflozin 100 mg will have a weight of 2. The subjects who are re-randomized to 
up-titrate to canagliflozin 300 mg will have a weight of 0. 

When comparing subjects who initially receive canagliflozin 100 mg followed by a dose 
increase to 300 mg to placebo: All subjects start with a weight of 1. After Week 12, subjects 
with an HbA1c ≥7.0% and eGFR ≥60 mL/min/1.73m2 who are re-randomized to continue 
canagliflozin 100 mg will have a weight of 0 and those who are re-randomized to up-titrate 
to canagliflozin 300 mg will have a weight of 2.
As the secondary efficacy endpoints listed in Section 11.3.3, Secondary Efficacy Endpoints, are 
supportive in nature, no corresponding hypothesis testing will be performed, and therefore they 
are not included in the testing sequence above. 


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11.3.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints at Week 26 and Week 52 include:

Change from baseline in FPG

The proportion of subjects with HbA1c <7.5%, <7.0%, and <6.5%

Time to rescue and proportion of subjects receiving rescue therapy 

Percent change from baseline in body weight

Change from baseline in BMI

Percent change from baseline in lipids

Change from baseline in systolic and diastolic blood pressure
The secondary efficacy endpoint at Week 12 and Week 52:

Change from baseline in HbA1c
The estimands for the analysis of the secondary endpoints are the same as for the primary 
efficacy endpoint.
The categorical secondary efficacy endpoint of maintaining HbA1c <7.0% (and HbA1c <6.5% and 
HbA1c <7.5%) will be analyzed longitudinally using a generalized linear mixed model in the 
FAS population. The model will include the fixed, categorical effects of treatment, stratification 
factors (ie, background AHA and age group), visit, and treatment-by-visit interaction, as well as 
the fixed, continuous covariates of baseline and baseline-by-visit interaction. An unstructured 
covariance will be used to model the within-subject errors. The odds ratio and 2-sided 95% CI 
for the treatment comparisons at Week 26 (canagliflozin compared to placebo) will be estimated 
based on this model. 
Continuous endpoints (except for triglycerides) will be analyzed with an MMRM model as 
described before in the FAS population. For the endpoints with post-baseline assessments taken 
only at Week 26 and Week 52, an analysis of covariance (ANCOVA) model similar to the 
primary efficacy endpoint will be used at Week 26. The least-squares means for the treatment 
comparisons and their 2-sided 95% confidence intervals will be estimated based on this model. 
The analysis of percent change in triglycerides may be based on nonparametric methods (given 
the anticipated skewed nature of this parameter) or alternative methods, to be further described in 
the SAP. 
11.4.
Pharmacokinetic Analyses 
Concentrations will be reported for all subjects at all visits. Concentrations below the lower limit 
of quantification or missing will be labeled as such in the concentration database. Descriptive 
statistics, including arithmetic mean, SD, coefficient of variation, median, minimum, and 
maximum will be calculated and provided by treatment arm, and by treatment and background 
treatment. Population based PK modeling may be applied to the available plasma concentrations 
as needed.


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11.5.
Biomarker Analyses 
Changes in serum osteocalcin and serum collagen type 1 CTx over time will be summarized by 
treatment group. Associations between baseline levels and changes from baseline in select 
markers and clinical response at 26 and 52 weeks of treatment will be explored. Biomarker 
analyses will be summarized in separate technical reports.
Biomarker results will be presented in a separate report.
11.6.
Safety Analyses
Subjects in the safety analysis set (defined as subjects who are randomized and take at least 
1 dose of study drug) will be included in the denominators for the summaries of adverse event, 
exposure, and concomitant medication data. There will be no imputation of missing values for 
clinical safety laboratory test results and vital sign measurements, in the safety analyses. 
Descriptive statistics for clinical laboratory test results and vital sign measurements will be 
presented based on measurements on study drug, including up to a maximum of 2 days after the 
last dose of study drug, as well as all measurements regardless of the time of the last dose of 
double-blind study drug. All safety analyses (except hypoglycemia) will be summarized 
regardless of the use of rescue medication; given the potential confounding due to rescue 
medication, analyses related to hypoglycemia will only be presented prior to rescue medication.
Adverse Events
The terms used in the eCRFs by investigators to identify adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events with onset 
during the treatment phase (ie, treatment-emergent adverse events) will be included in the 
analysis. Additionally, a summary of all reported adverse events (regardless of whether 
treatment-emergent) will also be provided.
For each adverse event, the percentage of subjects who experienced at least 1 occurrence of the 
given event will be summarized by treatment group. The percentage of subjects with specific 
treatment-emergent adverse events will be summarized by severity and relationship to study 
drug, as classified by the investigator, by treatment group. 
Special attention will be given to those subjects who died, or who discontinued treatment due to 
an adverse event, or who experienced a severe or a serious adverse event (eg, summaries, 
listings, and narrative preparation may be provided, as appropriate).
Further analyses, to be described in the SAP for this study, will be conducted on the 
pre-specified adverse events for which additional information is collected from the investigators 
(refer to Section 9.8, Safety Evaluations), and on other adverse events. 
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (to be specified in the SAP) will be referred to in the summary. Descriptive 


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statistics will be reported for each laboratory analyte at baseline and at each scheduled time point 
and for change from baseline.
Laboratory analyses will include percent change in lipids (ie, LDL-C, non-HDL-C and total 
cholesterol) from baseline at Week 26, and percent change in the ratio of LDL-C to HDL-C and 
non-HDL to LDL-C from baseline at Week 26, and change from baseline in bone turnover 
markers (serum osteocalcin and serum collagen type 1 CTx) and markers of calcium and 
phosphate homeostasis (calcium, magnesium, phosphate, PTH, 25-hydroxy Vitamin D, 
calcitonin; urinary excretion of calcium and phosphate). Additional laboratory parameters (listed 
in Attachment 7, Clinical Laboratory Tests) will also be analyzed.
Hypoglycemic Episodes
Hypoglycemic episodes are collected on a separate eCRF and are also collected on the adverse 
event eCRF (for all such events considered as adverse events by the investigator). The primary 
analysis of hypoglycemia will be based upon data from the hypoglycemia eCRF (and not from 
the adverse event database). No reconciliation of hypoglycemia data from the adverse event 
eCRF and the hypoglycemic eCRF will be performed (except to assure that all adverse events of 
hypoglycemia are also recorded on the hypoglycemia eCRF).
Hypoglycemic episodes will be classified as either biochemically documented (ie, a 
hypoglycemia episode with a concurrent reported glucose value of 70 mg/dL [3.9 mmol/L]) 
and/or severe. The primary hypoglycemic analysis of interest will be all biochemically 
documented hypoglycemic episodes regardless of the presence of symptoms plus all severe 
hypoglycemic episodes. For each type of hypoglycemia, the percentage of subjects with at least 
one event will be summarized by treatment group. The hypoglycemic episode rate per subject 
year exposure, based on the number of episodes adjusted by exposure duration, will be reported 
by treatment group for each classification of hypoglycemia. (See Attachment 4, Hypoglycemia: 
Definitions, Symptoms, and Treatment).
Vital Signs
Descriptive statistics for pulse and sitting blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized at each scheduled time point. The percentage of 
subjects with values beyond clinically important limits will be summarized.
Physical Examination
Physical examination findings will not be summarized except when reported as an adverse event.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures 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.


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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, and pregnancy. 
The following adverse events have been designated as adverse events 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. These adverse events must be reported using a 
supplemental reporting form, to complement standard information collected on the Adverse 
Event/SAE eCRF, together with the SAE report for serious events.

Diabetic ketoacidosis and adverse events related to DKA, ketoacidosis, metabolic acidosis 
or acidosis

Amputations

Pancreatitis

Serious adverse events of UTIs including urosepsis and pyelonephritis
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.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH].)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.2.1, All Adverse Events, for time of last adverse event recording).


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Serious Adverse Event
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:

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 other outcomes listed in the definition above. 
These should usually be considered serious.
A serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity 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 IB.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the study 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.


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Possible
An adverse event that might be due to the use of the study drug. An alternative explanation, eg, 
concomitant drug(s) or disease(s), is inconclusive. The relationship in time is reasonable; thus, 
the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the study drug. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
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 severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Procedures
12.2.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the study 
(including subjects who discontinue study drug treatment). 
Data will be collected in source documents and on the eCRF for all adverse events.
All deaths will also be recorded.
For adverse events of interest (see Section 9.8, Safety Evaluations) a supplemental eCRF 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.


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Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported 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 sponsor will evaluate any safety information that is spontaneously 
reported by an investigator beyond the time frame specified in the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. 
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 sponsor 
instructions.
Study research staff should make study subjects aware of potential signs and symptoms of DKA 
such as difficulty breathing, nausea, vomiting, abdominal pain, feeling confused, fruity-smelling 
breath, and unusual fatigue or sleepiness. Study subjects should be instructed to contact the site if 
they experience such symptoms. If the investigator suspects these symptoms may be related to 
DKA (even if the subject’s blood glucose levels are <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 Day 1, Week 26, and Week 52 visits) to 
identify risk factors for ulcers and amputations. The examination should include inspection 
of the skin, assessment of foot deformities, neurological assessment including pinprick or 
vibration testing or assessment of ankle reflexes, and vascular assessment including pulses 
in the legs and feet. 

Subjects who have a history of prior lower-extremity complications, loss of protective 
sensation, structural abnormalities, or peripheral arterial disease should be referred to foot 
care specialists for ongoing preventative 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. 


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The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate IEC/IRB that 
approved the protocol unless otherwise required and documented by the IEC/IRB. A SUSAR 
will be reported to regulatory authorities unblinded. Participating investigators and IEC/IRB will 
receive a blinded SUSAR summary, unless otherwise specified. 
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.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local Sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.2.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site 
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).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
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
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)

Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of 
hospitalization) that occurs during the course of a subject's participation in a study must be 
reported as a serious adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social 
reasons such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). 
The cause of death of a subject in a study within 30 days of the last dose of study drug, whether 
or not the event is expected or associated with the study drug, is considered a serious adverse 
event.
12.2.3.
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, 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 discontinue further treatment with study drug. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequel in the 
infant will be required. 
12.3.
Hypoglycemia
In accordance with the ADA Workshop on Hypoglycemia and as outlined in the February 2008 
FDA draft guidance on developing drugs for the treatment of diabetes, hypoglycemic episodes 
will be classified as: severe, documented symptomatic (symptoms consistent with hypoglycemia 
with concurrent biochemical hypoglycemia), probable symptomatic (symptoms consistent with 
hypoglycemia with no concurrent glucose measurement), or asymptomatic (low measured 
glucose [ie, 70 mg/dL (3.9 mmol/L)], without symptoms). Refer to Attachment 4, 
Hypoglycemia: Definitions, Symptoms, and Treatment for additional information.
Information on events of possible hypoglycemia will be collected on a separate hypoglycemia 
eCRF and will also be recorded on the adverse event eCRF if considered an adverse event by the 
investigator. If a hypoglycemic episode meets the criteria used to define a serious adverse event, 
the event must be captured on the serious adverse event eCRF page.
12.4.
Diabetic Ketoacidosis 
Diabetic ketoacidosis, ketoacidosis, metabolic acidosis and acidosis events have occurred at a 
low and relatively stable frequency over time in subjects participating in canagliflozin T2DM 


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clinical trials. The incidence and incidence rates of these events are within the range expected 
based on comparisons to existing observational data. While more cases have occurred with 
canagliflozin, relative to comparator, the majority of the cases are confounded by co-existing 
medical conditions (eg, T1DM, LADA) known to cause DKA or ketoacidosis. Given the 
potential in routine clinical practice for misdiagnosis of T2DM for more ketosis-prone types of 
diabetes (eg, T1DM and LADA) and the possibility of low pancreatic beta-cell reserve and 
associated insulinopenia in some patients with T2DM, an increased risk of DKA with 
canagliflozin in patients diagnosed with T2DM cannot be excluded. If present, this increased risk 
is small and would not change the overall benefit/risk profile of canagliflozin. Information on
events of possible DKA will be collected on a separate DKA eCRF and will also be recorded on 
the adverse event eCRF if considered an adverse event by the investigator. If a DKA meets the 
criteria used to define a serious adverse event, the event must be captured on the serious adverse 
event eCRF. Test for ketones in any subject who presents with signs and symptoms of 
ketoacidosis, such as difficulty breathing, nausea, vomiting, abdominal pain, feeling confused, 
fruity-smelling breath, and unusual fatigue or sleepiness even if blood glucose levels are 
<250 mg/dL (<13.9 mmol/L).
12.5.
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, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from 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 studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the 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 12.2.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.


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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 100 mg and 300 mg tablets with matching placebo tablets for each dose strength 
will be supplied for this study. 
Study drug will be manufactured and provided under the responsibility of the sponsor. Refer to 
the IB for a list of excipients. (IB JNJ-28431754 2020)
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.
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 59°F to 86°F (15°C to
30°C) and kept out of reach of children.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects or their legally acceptable representatives 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 


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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 or 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 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

Study binder with all other necessary documentation (Investigator Brochure, Protocol, 
Clinical Trial Agreement)

The IWRS Manual and worksheets

Template ICF

eCRF completion guidelines

Home blood glucose and ketone monitoring system, glucose strips, ketone strips (blood and 
urine), alcohol wipes, lancets, and calibration solution (optional by country/region)

Materials to promote healthy dietary and exercise habits

Subject diaries

Laboratory operations manual, requisition forms, sampling supplies, and equipment, if 
necessary

Computer, if the study site is assessed to require a laptop computer to enter eCRF data
for the study.
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The primary ethical consideration in the study is the investigational use of canagliflozin in 
children and adolescents in a non-approved indication for pediatric population.
Potential subjects and their parents/legal guardians will be fully informed of the risks and 
requirements of the study and, during the study, subjects and/or their parents[s]/legal guardian[s] 
will be given any new information that may affect their decision to continue participation. They 
will be told that their consent or their child’s assent 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 and/or their parents[s]/legal guardian[s] 


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who are fully able to understand the risks, benefits, and potential adverse events of the study, and 
provide their consent/assent voluntarily will be enrolled.
Hypoglycemia is a common adverse event in patients with T2DM. Treatment with canagliflozin 
may lead to an increase risk of hypoglycemia when administered with insulin or insulin 
secretagogues (eg, SU). During this study, subjects will be instructed on how to recognize and 
treat hypoglycemia, and subjects will be routinely monitored with fingerstick glucose levels, and 
reports of potential events of hypoglycemia will be carefully collected and evaluated. Subjects 
will be provided with a glucose meter and will provide fasting SMBG assessments. Furthermore, 
in the presence of recent history of recurrent episodes of hypoglycemia investigators are 
instructed to consider down-titration of insulin prior to up-titration of blinded study drug, and 
clinical judgment should be applied in managing background AHAs in the presence of increased 
risk of hypoglycemia.
This study design includes the use of a placebo group, which is of key importance in helping to 
characterize both the safety and efficacy of canagliflozin. A study without a placebo arm cannot 
properly determine the glucose-lowering efficacy of an AHA, given the impact of co-
interventions, and the natural history of the disease, on the course of glucose over time. 
Similarly, given background occurrence of adverse events in this population are relatively 
common, without a placebo, it is not possible to precisely define the safety and tolerability 
profile of a new AHA. Given the continuing need for new medications to improve the care of 
patients with T2DM, providing a thorough evaluation of a medication such as canagliflozin that 
may provide good efficacy and other useful benefits, is important. However, the importance of 
the placebo group must be balanced with the increased risk that subjects allocated to placebo will 
not achieve glycemic control consistent with current diabetes guidances during their participation 
in this study. As described above, all subjects will receive diet and exercise counseling, and will 
have regular fingerstick glucose monitoring, glycemic rescue therapy will be implemented with 
progressively lower glucose cutpoints for the first 6 months, and HbA1c goal thereafter.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each subject, his or her parent(s) (preferably both parents, if 
available) or a legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has 
been fully explained and before the performance of any study-related assessments. Assent must 
be obtained from all subjects. For the purposes of this study, all references to subjects who have 
provided consent (and assent as applicable) refers to the subjects and his or her parent(s) or the 
subject's legal guardian(s) or legally acceptable representative(s) who have provided consent 
according to this process. Minors who assent to a study and later withdraw that assent should not 
be maintained in the study against their will, even if their parents still want them to participate.
For a subject who completes the study (including all procedures outlined in the pretreatment and 
double-blind treatment phases) the total blood volume to be collected is considered to be an 
acceptable amount of blood to be collected over this time period from this pediatric population 


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based upon the standard of the World Health Organization. 
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on 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 study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
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 ICF (and any other written materials to be provided to the subjects)

IB (or equivalent information) and amendments/addenda

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 the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation.
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:


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
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF 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

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF 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 study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution). 
16.2.3.
Informed Consent/Pediatric Assent
Subject’s parent(s) or legally accepted representative(s) must give written consent, granting 
permission for his/her child to participate in the study according to local requirements after the 
nature of the study has been fully explained. Children (minors) or subjects who are unable to 
comprehend the information provided for this study can be enrolled only after obtaining consent 
of a parent(s) or legally accepted representative(s). Assent must be obtained from children 
(minors) capable of understanding the nature of the study, typically subjects 7 years of age and 
older, depending on institutional policies. Written assent should be obtained from subjects who 


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are able to write. A separate assent form written in language that the subject can understand 
should be developed based on the age of the treated population.
Parental permission must be given by signing the consent document. Minors will be asked to 
provide assent and sign an informed assent document. During the assent process, an explanation 
of the study, its purposes and requirements will be given to the child, verbally, in language 
appropriate to the child’s developmental and functional status.
The requirement of reconsenting pediatric subjects who become adults is determined by the 
applicable local regulations and the IRB/IEC requirements. 
The ICF(s)/pediatric assent must be signed before performance of any study-related activity. The 
ICF(s) and assent form that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent/assent 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 and their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects and parents/legally acceptable representatives will 
be informed that their participation is voluntary and that they may withdraw consent to 
participate at any time. They will be informed that choosing not to participate will not affect the 
care the subject will receive for the treatment of his or her disease. Subjects will be told that 
alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
ID register for the purposes of long-term follow-up if needed and that their records may be 
accessed by Health Authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF/pediatric assent the subject and parent or legally acceptable representative are 
authorizing such access, including permission to obtain information about his or her survival 
status, 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, and subsequent disease-related 
treatment, or to obtain information about his or her survival status.
The subject and parent or legally acceptable representative will be given sufficient time to read 
the ICF and the opportunity to ask questions. After this explanation and before entry into the 
study, consent should be appropriately recorded by means of either the subject's or his or her 
legally acceptable representative's personally dated signature. After having obtained the consent 
and assent, a copy both must be given to the subject and parent or legally acceptable 
representative.
If the subject and parent or legally acceptable representative are unable to read or write, an 
impartial witness should be present for the entire informed consent/pediatric assent process 


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(which includes reading and explaining all written information) and should personally date and 
sign the ICF/assent after the oral consent of the subject and parent or legally acceptable 
representative is obtained.
When prior consent of the subject is not possible and the subject's parent or legally acceptable 
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and 
well-being of the subject and to ensure compliance with applicable regulatory requirements. The 
subject and parent or legally acceptable representative must be informed about the study as soon 
as possible and give consent/assent to continue.
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 fulfill the objectives of the 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 subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker and PK 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.


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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 (or according to local 
regulations) for additional research. Samples will only be used to understand canagliflozin, to 
understand T2DM in the pediatric population, and to understand differential drug responders. 
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 10.4, Withdrawal from the Use of Samples in Future 
Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. 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. 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 (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.


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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 assent/consent forms, 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 sub-investigators.

Documentation of sub-investigator qualifications (eg, curriculum vitae).

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable.

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable.
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject ID and enrollment log to permit easy ID of each 
subject during and after the study. This document will be reviewed by the sponsor study-site 
contact for completeness.
The subject ID 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 ID and date of birth. In 


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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 ID, eligibility, and study ID; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 
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 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-site personnel from the source documents onto an eCRF and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
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 
subject's 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. Study-site personnel must 
complete the eCRF 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 study-site personnel must adjust the eCRF (if applicable) and complete the query.


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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 sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory written instructions will be 
provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site 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 study database they will be verified for 
accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.


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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site 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 data entered into the eCRFs with the hospital or clinic records (source 
documents); a sample may be reviewed. 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 study-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.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit/follow-up contact for 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 at that study site, 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 
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.


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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 he or she has 
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 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 accomplish this study and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of canagliflozin, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of exploratory biomarker 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 


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report and will not require a revision of the Clinical Study Report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such 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 Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
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REFERENCES
1.
American Heart Association (AHA) Council on High Blood Pressure 2005.
2.
Canagliflozin Investigator’s Brochure. Janssen Research and Development. Edition 18. May 2020.
3.
Centers for Disease Control (CDC) and Prevention. Measuring children’s height and weight accurately at 
home. http://www.cdc.gov/healthyweight/assessing/bmi/childrens_bmi/measuring_children.html. Accessed 
01 July 2015. 
4.
Clinical Study Report 28431754DIA1055. Open-Label, Multicenter, Multiple Oral Dose Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics and Safety of Canagliflozin in Older Children and Adolescents 10 to 
<18 Years of Age with Type 2 Diabetes Mellitus and Currently on a Stable Dose of Metformin; Janssen 
Research & Development (29 Jun 2016).
5.
Clinical Study Report 28431754DIA4004. A Randomized, Double-blind, Placebo-Controlled, 2-arm, Parallel-
group, 26-week, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in the 
Treatment of Subjects with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Metformin and 
Sitagliptin Therapy; Document ID No: EDMS-ERI-118976965; Janssen Research & Development (23 Feb 
2016).
6.
Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus 
(T2DM) in children and adolescents. Pediatrics 2013;131:364–382.
7.
Foster DW, Mcgarry JD. The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med. 
1983;309(3):159-169.
8.
Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and 
American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic 
Ketoacidosis. Endocr Pract. 2016;22(6):753-762.
9.
ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials Step 5, 17 February 2020, EMA/CHMP/ICH/436221/2017, Committee for 
Medicinal Products for Human Use. Inagaki N, Kondo K, Yoshinari T, Kuki H. Efficacy and safety of 
canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 
diabetes: A 52-week open-label study. J Diabetes Investig. 2015;6(2):210-218.
10.
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. 
Diabetes Metab Res Rev. 1999;15(6):412-426.
11.
Lu K, Devan M, Liu G. Sample size determination for constrained longitudinal data analysis. Statistics in 
Medicine, Dec 2008;28(4):679-699.
12.
Nadeau KJ, Klingensmith G, Zeitler P. Type 2 diabetes in children is frequently associated with elevated 
alanine aminotransferase. J Pediatr Gastroenterol Nutr. 2005;41(1):94-98.
13.
Newton KP, Hou J, Crimmins NA, et al. Prevalence of type 2 diabetes and prediabetes in children with 
nonalcoholic fatty liver disease. JAMA Pediatr. 2016 October 03; 170(10): e161971.
14.
Proschan M, Brittain E, Kammerman L. Minimize the use of minimization with unequal allocation. 
Biometrics. 2011;67(3):1135-1141.
15.
Tamborlane WV, Haymond MW, Dunger D, et al. Expanding treatment options for youth with type 2 diabetes: 
Current problems and proposed solutions: A White Paper from the NICHD Diabetes Working Group. Diabetes 
Care. 2016;39(3):323-329.
16.
Tahara Y, Shima K (1993) The response of GHb to stepwise plasma glucose over time in diabetic patients. 
Diabetes Care. 1993;9:1313–1314.


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Attachment 1: Instructions on Ketone Monitoring and Sick Day Management 
The guidelines for ketone measurement during illness or in the presence of other possible risk factors for 
DKA and the interventions presented here are aimed at early identification of elevated ketone levels and 
timely intervention in order to prevent or reduce the risk of progression to ketoacidosis and:

limit risk of emergency room visits/hospitalization

allow outpatient management, either by subject alone or with healthcare provider over the phone

allow prompt study drug interruption
It is paramount that subjects receive detailed counseling on various aspects of sick day management and 
ketone monitoring with particular focus on the following aspects:
Importance of monitoring ketones any time the subject is ill or does not feel well, or has any 
potential precipitating factors for DKA
During illness or stress, or any time a possible cause for ketonemia (eg, skipping an insulin dose, 
increased alcohol consumption, strenuous physical exercise, etc), has occurred regardless of symptoms 
(subjects are requested to assess blood ketones (or urine ketones) to determine the absence or presence of 
ketones, degree of ketonemia (or ketonuria), and response to treatment (ie, interrupting study drug, 
increasing insulin, carbohydrate and fluid intake and monitoring blood glucose). As DKA can occur with 
blood glucose levels <250 mg/dL (<13.9 mmol/L), it is extremely important that the subject does NOT 
rely on blood glucose levels as a trigger to measure ketone levels.
Recognition of signs and symptoms of DKA 
The study site personnel must ensure that the subject and parents/guardians are educated on recognizing 
signs and symptoms of DKA (ie, nausea, vomiting, abdominal pain, increased urination and thirst, 
fruity-smelling breath, rapid, deep respirations, headache, somnolence, etc). It is fundamental that in the 
presence of these signs/symptoms concomitant ketone levels are obtained to determine the proper actions 
and course of treatment, given that many of the signs/symptoms of DKA are nonspecific 
(eg, gastrointestinal symptoms) and may vary with degree of ketone elevation. 
Generally,

thirst, frequent urination, and sweet breath may occur with blood ketones <1.0 mmol/L 
(small/moderate urine ketones), 

dry mouth, nausea, stomach cramps, and/or vomiting may occur with blood ketones from 1.0 to 3.0 
mmol/L (moderate/large urine ketones), 

labored deep breathing, extreme weakness, confusion, and eventually unconsciousness (coma) may 
occur with blood ketones >3.0 mmol/L (large urine ketones) 
The study site personnel must also educate the subject on the importance of measuring capillary blood 
ketone (or urine ketones) regardless of the concomitant glucose levels, as these may be not as elevated 
(ie, >250 mg/dL [>13.9 mmol/L]) as usually observed during DKA.
Also, the subject must be instructed when to call the study site and what action to take while awaiting 
further instructions and when to seek immediate medical attention. In particular, in the presence of blood 
ketones ≥0.6 mmol/L (repeated and confirmed), subjects are required to:

contact the study site to receive further instructions based on the clinical assessment of the 
investigator or delegate

interrupt study drug


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
increase insulin if subject is on insulin (without increasing risk of hypoglycemia)

increase carbohydrate and fluid intake

seek immediate medical attention if appropriate increases in insulin and fluid intake cannot be 
managed by the subject (due to hypoglycemia, vomiting etc) and/or the subject shows 
signs/symptoms of DKA such as nausea, vomiting, abdominal pain, dehydration, or rapid breathing
Management of insulin and food intake during illness and/or in presence of elevated ketone levels
Subjects who are on insulin must be instructed to NOT reduce or interrupt insulin treatment during sick 
days and/or in the presence of ketone elevations, even if they are vomiting and unable to eat. Subjects 
should be educated on the importance of increasing insulin and carbohydrates in the presence of elevated 
ketones, unless there is increased risk of hypoglycemia (eg, reduced glucose levels in subject who is 
vomiting). If the subject is unable to increase insulin in the presence of elevated ketones due to fear of 
hypoglycemia, the subject should seek immediate medical attention.
Subjects should be instructed to eat small meals and to eat more frequently when they are ill. Soft foods 
or liquids are often tolerated best. Fluid intake is essential during illness. If vomiting, diarrhea, or fever is 
present, the subject should be instructed to take small quantities of liquids every 15 to 30 minutes. Clear 
broth, tea, or other fluids can supplement liquids containing carbohydrate. Eating about 10 to 15 g 
carbohydrate every 1 to 2 hours is usually sufficient. Foods and beverages containing about 15 g 
carbohydrate that can be considered for subjects include:
½ cup (~ 125 mL) regular gelatin
½ cup (~ 125 mL) regular soft drink
½ cup (~ 125 mL) ice cream
½ cup (~ 125 mL) orange or apple juice
½ cup (~ 125 mL) custard
1 cup (~ 250 mL) Gatorade
1 regular double Popsicle
1 cup (~ 250 mL) creamed soup
¾ cup (~ 200 mL) regular ginger ale


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Attachment 2: Suggested Algorithm for Ketone Monitoring and Findings of Elevated Ketones
Subjects will be instructed to measure capillary blood ketone levels:

any time the subject is ill or does not feel well

subject has undergone a minor procedure (eg, dental extraction)

anytime a possible cause for ketonemia has occurred that would predispose the subject to DKA 
(eg, skipping insulin dose, strenuous physical exercise, reduced carbohydrate intake)
Ketone measurements during periods of increased risk of ketonemia/ketonuria must be obtained 
regardless of the concomitant blood glucose values; ketone measurements should preferably be done 
prior to dosing to allow prompt interruption of study drug, if required. Ketone should be measured until 
the etiology for measuring ketones has abated (eg, illness has subsided).
Instructions for Elevated Ketone Findings

If blood ketone 0.6 mmol/L (with or without symptoms, regardless of concomitant glucose levels) 
confirmed by repeat assessment (suggested repeat measurement one hour later or sooner if in 
presence of symptoms), the subject should be instructed to:

contact the investigator or qualified assigned designee immediately (if possible)

if dose of study drug has not yet been taken, skip that dose and resume, with the permission of 
the investigator or qualified site personnel, once blood ketone levels are <0.6 mmol/L and 
precipitating cause (if identified) has resolved

if subject is on prandial insulin, increase insulin every 2 to 3 hours until the blood ketones have 
decreased to <0.6 mmol/L 

continue monitoring blood glucose

increase carbohydrate and fluid intake to allow increased insulin dosing if on insulin treatment

continue monitoring blood ketones at least every 4 to 6 hours until ketone levels reach levels 
0.2 mmol/L
The investigator or qualified assigned designee should review the potential precipitating factors with the 
subject, and correct if necessary

Illness/infection 

Reduction or missed insulin dose 

Reduction in carbohydrate intake or fasting 

Alcohol consumption

Strenuous exercise 

Significant stress

In female subjects, phase of menstrual cycle
Subjects are to be instructed to SEEK IMMEDIATE MEDICAL ATTENTION in the presence of 
blood ketones 0.6 mmol/L, regardless of blood glucose levels, IF:

appropriate increases in insulin and/or fluid intake cannot be managed by subject (due to 
hypoglycemia, vomiting etc) 


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
the subject shows signs/symptoms of DKA such as nausea, vomiting, abdominal pain, 
dehydration, or rapid breathing
It should be noted that these recommendations are provided as guidance to subjects and investigators. 
Investigators are expected to use their clinical judgment and knowledge of the subject’s medical history 
and assessment of present condition.
Whenever possible, the management should be based on capillary blood ketone levels. Only in those rare 
instances in which capillary blood ketones cannot be obtained, a urine ketone levels may be used. A urine 
ketone level of moderate/large may be considered an approximation of blood ketone level of 0.6 mmol/L. 
It should be noted however, that in the presence of dehydration, urinary ketone measurements may be 
difficult to obtain and may not provide reliable readings. 
For any confirmed ketone level 0.6 mmol/L that triggers the above actions, the subject will be requested 
to enter detailed information in the subject diary, including (but not limited to) ketone and glucose values, 
precipitating factors (eg, changes in insulin dose regimen, illness), and treatment received.


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Attachment 3: Method of Blood Pressure Measurement
Subject Preparation
The subject should remove all clothing that covers the location of cuff placement. (The sleeve should not 
be rolled up so that it has a tourniquet effect.)
The subject should be comfortably seated with legs uncrossed, and back and arm supported, so that the 
upper arm is at the level of the right atrium (midpoint of the sternum).
The subject should be instructed to relax and not talk; approximately 5 minutes should pass before the 
first reading is taken.
Blood Pressure Measurement Device
Blood pressure readings should be taken manually with a mercury sphygmomanometer or an automated 
blood pressure monitor. 
Cuff Size
Correct blood pressure measurement in children requires the use of a cuff that is appropriate for the size 
of the child’s upper arm A technique that can be used to select a blood pressure cuff size of appropriate 
size is to select a cuff that has a bladder width that is at least 40% of the arm circumference midway 
between the olecranon and the acromion. This will usually be a cuff bladder that will cover 80% to 100% 
of the circumference of the arm.
Arm Circumference (cm)
Size
<22
Older Child (9 x 18 cm)
22-26
Small Adult (12 x 22 cm)
27-34
Adult (16 x 30 cm)
Cuff Placement
Palpate the brachial artery in the antecubital fossa.
Place the midline of the bladder of the cuff so that it is over the arterial pulse on the subject’s bare upper 
arm. The lower end of the cuff should be 2 to 3 cm above the antecubital fossa to allow space for the 
stethoscope. 
Pull the cuff snugly around the bare upper arm. 
Neither the observer nor the subject should talk.
Inflation/Deflation
Inflate the cuff to at least 30 mmHg above the point at which the radial pulse disappears.
Deflate the mercury column at 2 to 3 mmHg per second. 
The first and last audible sounds should be taken as systolic and diastolic pressure.
Number of Measurements
Three readings should be taken at intervals of at least 1 minute apart, and the results recorded.
Blood pressure should be measured at the screening visit in both arms. If there is an inter-arm difference 
of more than 10 mmHg in either the systolic or diastolic pressure, it is recommended to use the arm with 
the higher pressure for all subsequent blood pressure measurement during the study.
If possible, if the blood pressure is measured manually, it should be taken by the same individual, using 
the same equipment, at each visit so as to reduce inter-observer variability. (AHA 2005)


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Attachment 4: Hypoglycemia: Definitions, Symptoms, and Treatment
Hypoglycemia is defined and classified as follows:
Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are 
accompanied by a measured plasma glucose (PG) concentration 70 mg/dL (3.9 mmol/L) 
Asymptomatic hypoglycemia is defined as an event not accompanied by typical symptoms of 
hypoglycemia but with a measured PG concentration 70 mg/dL (3.9 mmol/L) 
Probable symptomatic hypoglycemia is defined as an event during which symptoms of hypoglycemia are 
not accompanied by a PG determination. 
Severe hypoglycemia is defined as an event requiring the assistance of another person to actively 
administer a carbohydrate, glucagon, or other resuscitative actions. A subject is considered to "require 
assistance" if he/she is unable to help himself/herself. An act of kindness to assist a subject when it is not 
necessary does not qualify as "requiring assistance". These episodes may be associated with sufficient 
neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during 
such an event, but neurologic recovery attributable to the restoration of PG to normal is considered 
sufficient evidence that the event was induced by a low PG concentration. 
The classification of hypoglycemic episodes will determine how the event is captured in the eCRF. Refer 
to Section 12.3, Hypoglycemia, for further details.
Symptoms
Subjects will receive counseling regarding the symptoms of and treatment for hypoglycemia. Signs and 
symptoms of hypoglycemia and other specific details will be captured in the subject diary, which will be 
returned to the study center for review by study-site personnel at each visit. The following list of 
symptoms is not meant to be exhaustive but represents the more common symptoms associated with 
hypoglycemia:

Seizure

Loss of consciousness

Headache

Tremor

Hunger 

Sweating 

Nervousness

Palpitations

Light headedness

Blurred vision 

Disorientation

Dizziness

Feeling faint
Treatment
The treatment of hypoglycemia requires the ingestion of glucose- or carbohydrate-containing foods. The 
acute glycemic response correlates better with the glucose content than with the carbohydrate content of 
the food. Therefore, glucose (15 to 20 g) is the preferred treatment for hypoglycemia. Although pure 
glucose may be the preferred treatment, any form of carbohydrate that contains glucose will raise blood 
glucose (BG) and may be used. Adding protein to a carbohydrate does not affect the glycemic response 
and does not prevent subsequent hypoglycemia. However, adding fat may retard and then prolong the 
acute hypoglycemic response. Treatment effects should be apparent within 15 minutes although the 
effects may only be temporary. Therefore, PG should be retested in approximately 15 minutes, as 
additional treatment may be necessary.


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Attachment 5: Guideline for Collecting Height Measurements (CDC 2015)
Height
Standing height will be measured without shoes using a stadiometer. The stadiometer must be calibrated
when mounting it to the wall, and according to the manufacturer’s instructions thereafter.
To measure height accurately:
1.
Remove the subject’s shoes, bulky clothing, and hair ornaments, and unbraid hair that interferes with 
the measurement.
2.
Take the height measurement on flooring that is not carpeted and against a flat surface such as a wall 
with no molding.
3.
Have the subject stand with feet flat, together, and against the wall. Make sure legs are straight, arms 
are at sides, and shoulders are level.
4.
Make sure the subject is looking straight ahead and that the line of sight is parallel with the floor.
5.
Take the measurement while the subject stands with head, shoulders, buttocks, and heels touching 
the flat surface (wall). (See Figure 2.) Depending on the overall body shape of the child or teen, all 
points may not touch the wall.
6.
Use a flat headpiece to form a right angle with the wall and lower the headpiece until it firmly 
touches the crown of the head.
7.
Make sure the measurer's eyes are at the same level as the headpiece.
8.
Lightly mark where the bottom of the headpiece meets the wall. 
9.
Accurately record the height to the nearest 1/8th inch or 0.1 centimeter.
Figure 2


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Attachment 6: Tanner Staging
Tanner Staging must be performed by the investigator or site staff and not by the subject and parent or legally acceptable representative. 
Female – Breast development
The drawings on this page show different stages of development of the breasts. A female passes through each of the 5 stages shown by these sets of 
drawings. Please look at each set of drawings and read the sentences under the drawing. Then choose the set of drawings closest to the subject’s stage of 
breast development and mark it as “1” on the line above that drawing. Then choose the drawing that is the next closest to the subject’s stage of breast 
development and mark it as “2”. 
1.     Drawing A
2.  Drawing B
3.  Drawing C
4.  Drawing D
5.  Drawing E
        ________
         _______
           _______
       _______
______
The nipple is raised a little in 
this stage. The rest of the 
breast is still flat.  
This is the breast bud 
stage. In this stage, the 
nipple is raised more than 
in Stage 1. The breast is 
small and round. The 
areola is larger than in 
Stage 1.  
The areola and the breast are 
both larger than in Stage 2. 
The areola does not stick out 
away from the breast.  
The areola and the nipple 
make up a mound that sticks 
up above the shape of the 
breast. (Note: This stage may 
not happen at all for some 
female. Some female develop 
from Stage 3 to Stage 4).
This is the mature adult stage. 
The 
breasts 
are 
fully 
developed. Only the nipple 
sticks out in this stage. The 
areola has moved back to the 
general shape of the breast.  


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Female – Pubic hair
The drawings on this page show different amounts of female pubic hair. A female passes through each of the 5 stages shown by these drawings. Please 
look at each drawing and read the sentences under the drawing. Then choose the drawing closest to the subject’s stage of hair development and mark it as 
“1” on the line above that drawing. Then choose the drawing that is next closest to the subject’s stage of hair development and mark it as “2”.  
1.     Drawing A
2.  Drawing B
3.  Drawing C
4.  Drawing D
5.  Drawing E
        ________
    _______
           _______
     _______
           ______
There is no pubic hair.
There is a little long, 
lightly, colored hair. This 
hair might be straight or a 
little curly. 
The hair is darker in this 
stage. It is coarser and more 
curled. It has spread out and 
thinly covers a larger area.
The hair is now as dark, 
curly, and coarse as that of 
an adult female. However, 
the area that the hair 
covers is not as large as 
that of an adult female. 
The hair has not spread 
out to the thighs. 
The hair now is like that of 
an adult female. It also covers 
the same area as that of the 
adult female. The hair usually 
forms a triangle (∆) pattern as 
it spreads out to the thighs. 


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Male – Pubic hair
The drawings on this page show different amounts of male pubic hair. A male passes through each of the 5 stages shown by these drawings. Please look 
at each drawing and read the sentences under the drawing. Then choose the drawing closest to the subject’s stage of hair development, mark it as “1” on 
the line above that drawing. Then choose the drawing that is next closest to the subject’s stage of hair development and mark it as “2”. In choosing the 
right picture, look only at the pubic hair and not at the size of the testes, scrotum, and penis.
1.     Drawing A
2.  Drawing B
3.  Drawing C
4.  Drawing D
5.  Drawing E
            ________
         _______
       _______
            _______
          ______
There is no pubic hair at 
all.
There is a little soft, long, 
lightly curled hair. Most of 
the hair is at the base of 
the penis. This hair may be 
straight or a little curly.
The hair is darker in this 
stage. It is coarser and more 
curled. It has spread out and 
thinly covers a somewhat 
larger area. 
The hair is now as dark, 
curly, and coarse as that 
of 
an 
adult 
male. 
However, the area that 
the hair covers is not as 
large as that of an adult 
male. The hair has not 
spread out to the thighs. 
The hair has spread out 
to the thighs. The hair 
is now like that of an 
adult male. It covers 
the same area as that of 
an adult male. 


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Male – Development of external genitalia
The drawings on this page show different stages of development of the testes, scrotum, and penis. A male passes through each of the 5 stages shown by 
these drawings. Please look at the drawings and read the sentences under the drawing. Then choose the drawing closest to the subject’s stage of 
development and mark it as “1” on the line above that drawing. Then choose the drawing that is next closest to the subject’s stage of development and 
mark it as “2”. In choosing the right picture, look only at the stage of development, not at pubic hair.  
1.     Drawing A
2.  Drawing B
3.  Drawing C
4.  Drawing D
5.  Drawing E
           ________
_______
        _______
  _______
          ______
The testes, scrotum, and 
penis are about the same 
size and shape as they 
were when you were a 
child.
The testes and scrotum 
have gotten a little larger. 
The skin of the scrotum 
has changed. The scrotum, 
the sack holding the testes, 
has lowered a bit. The 
penis has gotten only a 
little larger. 
The penis has grown 
mainly in length. The 
testes and scrotum have 
grown 
and 
dropped 
lower than in Stage 2. 
The penis has grown 
even larger. It is wider. 
The glans (the head of 
the penis) is bigger. The 
scrotum is darker than 
before. 
It 
is 
bigger 
because the testes have 
gotten bigger. 
The penis, scrotum, and 
testes are the size and 
shape of that of an adult 
male. 


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Attachment 7: Clinical Laboratory Tests
Blood samples for serum chemistry and hematology, and a urine sample for urinalysis will be collected. 
The investigator must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the adverse event section of the eCRF and take appropriate 
action (eg, repeating abnormal laboratory result or further evaluation as considered clinically appropriate). 
The following tests will be performed by the central laboratory.

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential

Serum Chemistry Panel 
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
-phosphate
-aspartate aminotransferase (AST)
-albumin
-alanine aminotransferase (ALT)
-total protein
-gamma-glutamyltransferase (GGT)
-magnesium
-total bilirubin

Fasting serum lipid profile (low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-
cholesterol [HDL-C], total cholesterol, non-HDL-C, LDL-C to HDL-C ratio, non-HDL-C to LDL-C 
ratio, and triglycerides). 

HbA1c

FPG

C-peptide (random and fasting)

Blood ketones

Bone turnover markers (serum osteocalcin and serum collagen type 1 carboxy-telopeptide [CTx])

Markers of calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH, 25-hydroxy 
Vitamin D, calcitonin; urinary excretion of calcium and phosphate)

Urinalysis 
Dipstick done at central laboratory
-specific gravity
-pH
-glucose
-protein
-blood
-ketones
-bilirubin
-urobilinogen
-nitrite


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-leukocyte esterase
If dipstick result is abnormal, microscopic examination will be performed.

First morning void urine for Urinary ACR

Subject who have a Week -2 first morning void showing a presence with proteinuria (ie, proteinuria 
+1 and above) based on the central laboratory urine dipstick, will require a 24-hour urine collection 
prior to randomization and thereafter.

Serum (β-human chorionic gonadotropin [β-hCG] pregnancy testing will be conducted for all female 
subjects of childbearing potential at screening visit. Additional urine (or serum) 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.

Testing for pancreatic autoimmunity (GAD and islet cell antigen 2 [IA2] antibody) will be conducted 
in subjects with no available documentation at time of screening.

Subjects must be fasting for at least 8 hours before collection of blood samples that require fasting 
(eg, glucose, lipid panel, etc).
Central laboratory will report the estimated glomerular filtration rate (eGFR) at study visits when
serum creatinine is measured as specified below:

Estimated Glomerular Filtration Rate (eGFR)

eGFR will be calculated using Schwartz formula:
o
eGFR (mL/min/1.73m2) = (0. 55 × height in cm) / serum creatinine in mg/dL for girls from 
10 to <18 years of age and boys from 10 to 12 years of age
o
eGFR (mL/min/1.73m2) = (0.70 × height in cm) / serum creatinine in mg/dL for boys from 
13 to <18 years of age


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Attachment 8: Maturity-Onset Diabetes of the Young (MODY)
SOURCE: National Diabetes Information Clearinghouse (NDIC) https://www.niddk.nih.gov/health-
information/diabetes/overview/what-is-diabetes/9.  
Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes that usually first occurs 
during adolescence or early adulthood and it accounts for 1% to 5% of all cases of diabetes in the United 
States. Many different gene mutations have been shown to cause MODY, all of which limit the ability of 
the pancreas to produce insulin (see Table below). This process leads to the high BG levels characteristic 
of diabetes. Patients with MODY may have only mild or no symptoms of diabetes and their 
hyperglycemia may only be discovered during routine blood tests. Patients with MODY are generally not 
overweight and do not have other risk factors for type 2 diabetes, such as hypertension or hyperlipidemia. 
While both T2DM and MODY can run in families, patients with MODY typically have a family history 
of diabetes in multiple successive generations. MODY can be diagnosed by genetic testing.
Type
Affected 
gene
Affected proteinIncidence
Age at diagnosis
Inheritance 
pattern
Overweight/
Obesity
Transient/
Permanent
Treatment
MODY
1
HNF4A
hepatocyte 
nuclear factor 4ɑ
(alpha)
Rare
Adolescence or early 
adulthood
Autosomal 
dominant
No
Permanent For most, oral 
sulfonylureas; some 
patients may need 
insulin
MODY
2
GCK
glucokinase
MODY 2 and 
MODY 3 
account for 
about two-thirds 
of all cases of 
MODY
MODY 2 is the 
second-most 
common form 
of MODY
Mild hyperglycemia 
may be present at 
birth; otherwise, early 
childhood
Autosomal 
dominant
Lower than 
normal birth-
weight can 
occur
Permanent Diet modification and 
physical activity; 
medications usually not 
required; some patients 
do not require any 
treatment during 
childhood
MODY
3
TCF1
hepatic nuclear 
factor
1ɑ(alpha) or 
HNF1ɑ
(alpha) or
HNF1A
MODY 3 is the
most common 
form of MODY
Adolescence or early 
adulthood
Autosomal 
dominant
No
Permanent Initially, treat with diet 
modification; can be 
treated with oral 
sulfonylureas; some 
patients may need 
insulin
MODY
4
IPF1; also 
known as 
PDX1
insulin promoter 
factor 1
Rare
Early adulthood; can 
present later
Autosomal 
dominant
No
Permanent Oral sulfonylureas; some 
patients may need 
insulin
MODY
5
TCF2
hepatic nuclear 
factor
1β (beta) or
HNF1B
Rare
Adolescence or early 
adulthood
Autosomal 
dominant
No
Permanent Insulin; patients also 
may need treatment for 
related conditions such 
as kidney failure or cysts
MODY
6
NeuroD1,
or
BETA2
neurogenic 
differentiation 
factor 1
Rare
In the fourth decade 
of life
Autosomal 
dominant
No
Permanent Insulin
Patients who are suspected to have MODY should first undergo genetic testing and only after exclusion of MODY 
can be considered for enrollment into the study.


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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Research & Development
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User
Date
Reason
14-Aug-2020
17:21:22
(GMT)
Document Approval
PPD


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Status: Approved,  Date: 26 May 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
A Randomized, Multicenter, Double-Blind, Parallel-Group, Placebo-Controlled Study to 
Investigate the Efficacy and Safety of Canagliflozin in Children and Adolescents (≥10 to 
<18 years) with Type 2 Diabetes Mellitus
Protocol 28431754DIA3018; Phase 3
AMENDMENT 3
JNJ-28431754  (canagliflozin)
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved
Date:
26 May 2020
Prepared by:
Janssen Research & Development, LLC
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
CCI
CCI
NCT03170518


COVID-19 Appendix
JNJ-28431754 (canagliflozin)
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Status: Approved,  Date: 26 May 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If at any time a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed 
remotely/virtually or delayed until such time that on-site visits can be resumed. At each contact, 
participants will be interviewed to collect safety data. Key efficacy endpoint assessments should 
be performed if required and as feasible. Participants will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted after consultation takes place between the participant and investigator, and with the 
agreement of the sponsor. Missed assessments/visits will be captured in the clinical trial 
management system for protocol deviations. Discontinuations of study interventions and 
withdrawal from the study should be documented with the prefix “COVID-19-related” in the 
electronic case report form (eCRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study and any 
changes (eg, delay or discontinuation in recruitment, site monitoring and audits) will be 
communicated to the sites and health authorities according to local guidance. If a participant has 
tested positive for COVID-19, the adverse event (AE) should be reported on the Adverse Event 
eCRF and the investigator should contact the sponsor’s responsible medical officer to discuss plans 
for study intervention and follow-up. Modifications made to the study conduct as a result of the 
COVID-19 pandemic should be summarized in the clinical study report.


COVID-19 Appendix
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Clinical Protocol 28431754DIA3018
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3
Status: Approved,  Date: 26 May 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL:
Study Visits and Assessments:
Pre-Randomization:

For sites located in areas under travel restrictions due to the COVID-19 outbreak, screening 
visits for new subjects should be temporarily discontinued and Site Managers should be 
notified. If subjects are actively in Screening and/or Run-In period, the Site Manager should 
be contacted to determine the best course of action for each subject. As a reminder, the visit 
window for single-blind Run-In Period is +/- 4 days.

Once in the Run-In period, if a subject is not able to return to the site for their next scheduled 
visit (ie, Randomization Visit) within the allowable visit window, the Site Manager must be 
contacted, and the subject should be registered as a Screen-failure. The subject should be re-
screened when conditions permit after consultation with the Study Responsible Physician (see 
Protocol Section 4.4 for further guidance).  
Post-Randomization:

All subjects should return for scheduled in-clinic visits when possible. As a reminder, the 
double-blind treatment phase provides a +/-7 day window around each visit for scheduling. 

For subjects who are unable to return to complete a scheduled in-clinic visit, the scheduled in-
clinic visit should be changed to a virtual contact (eg, via telephone, video-conferencing, or 
other channels) to collect information on the subject’s current health status, medication 
compliance, and any new or ongoing AEs as well as changes in concomitant medications. The 
virtual method used for contacting the subject must be allowable per local regulations and 
documented in the subject’s source record as well as entered in the Comments eCRF clearly 
designating the contact as “COVID-19-related”. Additional virtual contacts may be conducted 
in between scheduled visits if deemed clinically appropriate by the Investigator and all virtual 
contacts must be recorded as outlined above. 

All subjects should continue to have protocol-specified central laboratory assessments when 
possible. If central laboratory tests cannot be performed or ambient samples cannot be 
collected by courier due to local restrictions and regulations relating to the COVID-19 
outbreak, the use of an accredited local laboratory is permitted for all visits and all protocol-
specified laboratory assessments, especially those outlined for Weeks 12, 26, and 52 and for 
essential laboratory measurements related to safety/efficacy (eg, HbA1c, eGFR, etc) as 
outlined in the Protocol’s Time and Events Schedule. Additional guidance on the recording 
of local laboratory assessments in the clinical database can be found in the eCRF Completion 
Guidelines. Site Managers must be informed of all local laboratory assessments performed. 

Every effort should be made to keep subjects on treatment as deemed clinically appropriate. 
For subjects who cannot attend scheduled in-clinic visits and run out of study drug as a result, 
a direct-to-subject shipment program may be available as local regulations allow (see Study 
Drug Resupply section below). If it is not possible to resupply subjects with study drug, the 
protocol allows for study drug to be temporarily interrupted. Any changes in study drug 
administration must be documented in the subject’s source record and the Study Drug 
Administration eCRF using the “COVID-19-related” prefix. When conditions improve, travel 
restrictions are lifted, and the subjects are willing and able to come to the clinic, subjects 


COVID-19 Appendix
JNJ-28431754 (canagliflozin)
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Status: Approved,  Date: 26 May 2020
should be evaluated and encouraged to restart study drug unless there is a clear 
contraindication at the discretion of the Investigator and with concurrence from the Study 
Responsible Physician (see Protocol Section 10.2.3 for further guidance).

All subjects and parents/legal guardians should be reminded of the instructions pertaining to 
sick day management, glucose/ketone monitoring, timely intervention of diabetic ketoacidosis 
(DKA), and when to seek medical attention for any urgent conditions that were provided to 
each subject and parent/legal guardian at the time of study enrollment. 

All protocol deviations (eg, missed, delayed or modified visits/laboratory assessments, 
adjustments to study procedures, missed doses of study drug, etc) occurring as a result of 
restrictions relating to the COVID-19 outbreak must be documented in detail within the 
subject’s source records and on the Comments eCRF using the “COVID-19-related” prefix.  
Study Drug and Clinical Supplies: 

Continue to check that all clinical supplies, such as study drug kits, laboratory kits, and 
ancillary supplies (eg, glucometers, glucose strips, ketone strips and control solution, etc) are 
available (and within expiry) in sufficient quantities to accommodate the next 2 study visit for 
each subject enrolled. Site Managers should be contacted with any questions or concerns 
relating to clinical supplies.  
Study Drug Resupply

For subjects who are not able to return to the site for their next scheduled visit, a caregiver or 
family member may be permitted to receive study drug on behalf of the subject if first 
discussed and agreed to by the subject or parents/legal guardians. Identification of the 
individual who is granted permission to receive the study drug on behalf of the subject must 
be confirmed and documented in the subject’s source records and on the study drug 
accountability forms. The site staff must confirm that the study drug is provided to the 
appropriate individual while ensuring the proper chain of custody for the study drug and 
maintaining subject privacy.  

The site staff may deliver study drug directly to subject’s home with approval from the 
IRB/EC overseeing the trial and in accordance with site approved procedures. The chain of 
custody for the study drug and transit conditions must be documented within the subject’s 
source records.  

If no other alternative is feasible, the Site Manager should be contacted to confirm if local 
regulations allow for direct-to-subject study drug shipments. Permission from the subject or 
parents/legal guardians and the Sponsor is required prior to implementing a direct-to-subject 
study drug shipment and all permissions must be recorded in the subject’s source record and 
on the Comments eCRF using the “COVID-19-related” prefix.  
Data Entry and Site Monitoring: 

The regular assessment and reporting of adverse events and changes in concomitant 
medications should continue as outlined in the eCRF Completion Guidelines.  

If on-site monitoring is not possible as a result of the COVID-19 outbreak, site monitoring 
will be performed remotely. Site Managers will schedule on-site or remote monitoring visits 
as conditions dictate. 


COVID-19 Appendix
JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DIA3018
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 26 May 2020
To ensure the safety of subjects and their families as well as site staff, the guidance offered in this 
Appendix is to be followed on a temporary basis at those sites impacted by the COVID-19 outbreak 
in order to enable continuity of treatment and the continuation of protocol-specified assessments 
outlined in the Protocol’s Time and Events Schedule. Every effort should be made to complete all 
protocol-required assessments when possible.  


COVID-19 Appendix
JNJ-28431754 (canagliflozin)
Clinical Protocol 28431754DIA3018
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 26 May 2020
INVESTIGATOR AGREEMENT
PPD
PPD
PPD

SAP_003.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 22 September 2023
Janssen Research & Development 
Statistical Analysis Plan
A Randomized, Multicenter, Double-Blind, Parallel-Group, Placebo-Controlled Study to 
Investigate the Efficacy and Safety of Canagliflozin in Children and Adolescents (≥10 to 
<18 years) with Type 2 Diabetes Mellitus
Protocol JNJ-28431754DIA3018; Phase 3
JNJ-28431754 (canagliflozin)
Amendment 3
Status:
Approved
Date:
22 September 2023
Prepared by:
Janssen Research & Development, LLC
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
CCI
NCT03170518


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
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2
Status: Approved, Date: 22 September 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
AMENDMENT HISTORY.............................................................................................................................. 5
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 9
1.4.
Sample Size Justification ................................................................................................................. 9
1.5.
Randomization and Blinding .......................................................................................................... 10
2.
GENERAL ANALYSIS DEFINITIONS ..............................................................................................11
2.1.
Visit Windows................................................................................................................................. 11
2.2.
Analysis Sets.................................................................................................................................. 12
2.2.1.
Efficacy Analysis Set(s) .............................................................................................................. 12
2.2.2.
Safety Analysis Set..................................................................................................................... 13
2.3.
Definition of Subgroups.................................................................................................................. 13
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 13
4.
SUBJECT INFORMATION................................................................................................................ 13
4.1.
Demographics and Baseline Characteristics ................................................................................. 13
4.2.
Disposition Information................................................................................................................... 14
4.3.
Treatment Compliance................................................................................................................... 15
4.4.
Extent of Exposure......................................................................................................................... 15
4.5.
Protocol Deviations ........................................................................................................................ 15
4.6.
Prior and Concomitant Medications ............................................................................................... 16
5.
EFFICACY ......................................................................................................................................... 16
5.1.
Analysis Specifications................................................................................................................... 16
5.1.1.
Level of Significance................................................................................................................... 16
5.1.2.
Data Handling Rules................................................................................................................... 17
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 17
5.2.1.
Definition..................................................................................................................................... 17
5.2.2.
Estimand..................................................................................................................................... 17
5.2.3.
Analysis Methods........................................................................................................................ 18
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 20
5.3.1.
Definition..................................................................................................................................... 20
5.3.2.
Analysis Methods........................................................................................................................ 21
5.4.
Other Efficacy Variable(s) .............................................................................................................. 22
5.4.1.
Definition..................................................................................................................................... 22
5.4.2.
Analysis Methods........................................................................................................................ 22
6.
SAFETY............................................................................................................................................. 22
6.1.
Adverse Events .............................................................................................................................. 23
6.1.1.
Selected Adverse Events for Additional Analysis....................................................................... 24
6.1.2.
Hypoglycemia ............................................................................................................................. 25
6.2.
Clinical Laboratory Tests................................................................................................................ 26
6.3.
Vital Signs and Physical Examination Findings .............................................................................26
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 27
REFERENCES............................................................................................................................................ 28


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
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Status: Approved, Date: 22 September 2023
ATTACHMENTS......................................................................................................................................... 29
Attachment 1:
Prestudy and Concomitant Medications Classified by ATC Code and/or Other 
Conditions...................................................................................................................29
Attachment 2:
List of Preferred Terms for Selected AEs of Interest.................................................. 30
Attachment 3:
Clinical Laboratory Tests............................................................................................ 34
Attachment 4:
Criteria for Pre-defined Limit of Change (PDLC) and Abnormal Values .................... 36


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
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Status: Approved, Date: 22 September 2023
ABBREVIATIONS
ACR
albumin/creatinine ratio
AE
adverse event
AHA
antihyperglycemic agent
ANCOVA
analysis of covariance
ATC
anatomical therapeutic chemical 
BMI
body mass index
CI
confidence interval
CSR
clinical study report
CTx
carboxy-telopeptide
DBP
diastolic blood pressure
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOT/EW
end-of-treatment/early withdrawal
FAS
Full analysis set
FOIA
Freedom of Information Act
FPG
fasting plasma glucose
GCP
Good Clinical Practice
HbA1c
Hemoglobin A1c
HDL-C
high-density lipoprotein-cholesterol
IDMC
Independent Data Monitoring Committee
IWRS
interactive web response system
KM 
Kaplan-Meier
LDL-C
low-density lipoprotein-cholesterol
LLN
Lower Limit of Normal
LOCF
last observation carried forward
LS mean
least-squares mean 
MAR
missing at random
MCMC
Monte Carlo Markov chains
MI
multiple imputation
MH
medical history
MedDRA
medical dictionary for regulatory activities
MMRM
mixed model for repeated measures
PDLC
pre-defined limit of change
PD
pharmacodynamics 
PK
pharmacokinetic(s)
PMM
pattern mixture model
PP
per protocol
PT
preferred term
PTH
parathyroid hormone 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SE
standard error
SGLT2
sodium-glucose co-transporter 2
SOC
System Organ Class
SPERT
Safety, Planning, Evaluation, and Reporting Team 
TEAE
Treatment-Emergent Adverse Event
T2DM
Type 2 Diabetes Mellitus
ULN
Upper Limit of Normal
UTI
urinary tract infection 
WHODD
World Health Organization Drug Dictionary


JNJ-28431754  (canagliflozin)
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Status: Approved, Date: 22 September 2023
AMENDMENT HISTORY
Amendment 1 (17 July 2018)
Applicable Section(s)
Description of Change
Rationale: The reason for this amendment is to include analyses of the primary efficacy endpoint in an 
independently powered subset of subjects on a background of diet and exercise only. Clarifying text is added and 
minor typographical errors are also addressed.
Section 1.1. Major Secondary Objectives
Major secondary objectives have been updated to reflect the 
change above.
Section 1.3. Statistical Hypotheses for Trial 
Objectives, (Secondary Hypotheses)
Secondary hypotheses have been updated to reflect the change 
above.
Section 1.4. Sample Size Justification
The details of the assumptions for the sample size justification 
have been updated based on adult data from Stenlöf (2013).
Section 3. Interim Analysis and Data 
Monitoring Committee Review
Section streamlined with reference to the IDMC Charter for 
further details.    
Section 5.1.1. Level of Significance 
Text and figure describing the multiplicity adjustment have been 
updated to accommodate the hypothesis testing for the subset of 
subjects on a background of diet and exercise only.
Section 5.2.3. Analysis Methods
Text to address the additional analyses of the change in HbA1c in 
AHA subsets has been added.
References
The following reference has been added:
Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of 
canagliflozin monotherapy in subjects with type 2 diabetes 
mellitus inadequately controlled with diet and exercise. Diabetes 
Obes Metab. 2013;15(4):372-382.
Amendment 2 (11 May 2023)
Applicable Section(s)
Description of Change
The purpose of this amendment is to make this document consistent with Protocol Amendment 4 in terms of the 
analysis specifications and other pertinent details including the primary efficacy analysis based on the pattern 
mixture model. An additional analysis of primary efficacy endpoint using informative Bayesian Prior is added 
due to revised estimates of the treatment effect and the standard deviation specified in the Written Request 
Amendment 5. This analysis will be performed in the event that the study on its own does not yield significant 
results based on primary efficacy analysis. Two additional sensitivity analyses of the primary efficacy endpoint 
are also included. Clarifying text is added as applicable and minor typographical errors are also addressed.
Section 1.4. Sample Size Justification
This section is updated to make it consistent with Protocol 
Amendment 4
Section 5.1.1. Level of Significance 
Text and figure describing the multiplicity adjustment have been 
updated to reflect the deletion of the hypothesis testing for the 
subset of subjects on a background of diet and exercise only and 
make it consistent Protocol Amendment 4.
Section 5.2.2 Estimand 
Section updated to be consistent with Protocol Amendment 4
Section 5.2.3. Analysis Methods
Details of the primary and secondary efficacy analyses of the 
primary efficacy endpoint using pattern mixture model have been 
added. Text added to mention that Bayesian analysis of primary 
efficacy endpoint will be performed in the event the primary 
efficacy analysis does not yield significant results. Analysis of the 
primary efficacy endpoint based on copy reference multiple 
imputation (MI) as well as tipping point analysis have been added 
as sensitivity analyses. Additionally, supportive analyses have 
been placed together for further clarity. Other minor editorial 
changes have been made to provide clarity.
Section 5.3 Secondary Efficacy Endpoints
Section updated to be consistent with Protocol Amendment 4
References
The following reference has been deleted as it is no longer 
applicable:


JNJ-28431754  (canagliflozin)
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Status: Approved, Date: 22 September 2023
Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of 
canagliflozin monotherapy in subjects with type 2 diabetes 
mellitus inadequately controlled with diet and exercise. Diabetes 
Obes Metab. 2013;15(4):372-382.
Amendment 3 (22 September 2023)
Applicable Section(s) 
Description of Change
The purpose of this amendment is to correct minor inconsistencies at few places in the description of the 
supportive analyses and subgroup analyses. Additionally, clarifying text is added to the description of the 
sensitivity analysis based on mixed model for repeated measures (MMRM).
Section 5.2.3. Analysis Methods
Changes in the description of the sensitivity analysis based on 
MMRM.
In the description of the sensitivity analysis of the primary 
efficacy endpoint based on mixed model for repeated measures 
(MMRM), the following sentence is added to consider other 
covariance structures in case the model does not converge using 
the unstructured covariance:
“In case the model does not converge using the unstructured 
covariance then alternative covariance structures (such as 
compound symmetry and AR (1)) will be considered.”
Furthermore, since MMRM is not the primary efficacy analysis, 
the following sentence has been deleted:
“This sensitivity analysis will constitute the primary analysis 
based on a specific health authority request.”
Changes in the description of re-randomization test
Since MMRM will be utilized to perform the re-randomization 
test, to be consistent, the phrase “primary efficacy comparison” 
have been replaced with “treatment comparison” as applicable at 
couple of places since primary efficacy comparison is based on 
Pattern Mixture Model (PMM) and not MMRM.
Changes in the description of subgroup analyses
In the paragraph describing the subgroup analyses, the phrase
‘primary efficacy analysis’ is replaced with ‘primary efficacy 
endpoint’ to be consistent since subgroups will be analyzed based 
on MMRM.


JNJ-28431754  (canagliflozin)
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Status: Approved, Date: 22 September 2023
1.
INTRODUCTION
This statistical analysis plan (SAP) contains the definitions of analysis sets, derived variables, and 
statistical methods for the analyses of efficacy and safety data from the canagliflozin study 
28431754DIA3018.
1.1.
Trial Objectives
In children and adolescents (!10 to <18 years) with type 2 diabetes mellitus (T2DM) who have 
inadequate glycemic control (ie, hemoglobin A1c [HbA1c] of !6.5% to ∀10.5%), either on diet and 
exercise only, or on diet and exercise and metformin monotherapy, or on diet and exercise and 
insulin monotherapy, or on diet and exercise and combination therapy with metformin and insulin.
Primary Objectives
#
To assess the effect of canagliflozin relative to placebo on HbA1c after 26 weeks of treatment.
#
To assess the overall safety and tolerability of canagliflozin.
Major Secondary Objectives
#
After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on HbA1c
in the subset of subjects on a background of metformin (with or without insulin).
#
After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on HbA1c
in the subset of subjects on a background of diet and exercise only.
#
After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:
∃
Fasting plasma glucose (FPG).
∃
Proportion of subjects with HbA1c <7.5%, <7.0%, and <6.5%.
∃
Time to rescue therapy and proportion of subjects receiving rescue therapy.
∃
Body weight.
#
After 52 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:
∃
HbA1c and FPG.
∃
Proportion of subjects with HbA1c <7.5%, <7.0%, and <6.5%.
∃
Time to rescue therapy and proportion of subjects receiving rescue therapy.
∃
Body weight.
Additional Secondary Objectives
#
After 12 weeks of treatment to assess the effects of canagliflozin relative to placebo on HbA1c.
#
After 26 weeks of treatment, to assess the effect of canagliflozin 100 mg relative to placebo 
on HbA1c.
#
After 26 weeks of treatment, to assess the effect of canagliflozin 100 mg followed by a dose 
increase to 300 mg relative to placebo on HbA1c.


JNJ-28431754  (canagliflozin)
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Status: Approved, Date: 22 September 2023
#
After 26 weeks and 52 weeks of treatment, to assess the effect of canagliflozin relative to 
placebo on:
∃
Body mass index (BMI).
∃
Fasting plasma lipids (ie, low-density lipoprotein-cholesterol [LDL-C], high-density 
lipoprotein-cholesterol [HDL-C], total cholesterol, non-HDL-C, LDL-C to HDL-C ratio, 
non-HDL-C to LDL-C ratio, and triglycerides).
∃
Systolic blood pressure (SBP) and diastolic blood pressure (DBP).
∃
Growth velocity and Tanner Staging.
∃
Markers of calcium and phosphate homeostasis, (calcium, magnesium, phosphate, 
parathyroid hormone [PTH], 25-hydroxy Vitamin D, calcitonin; urinary excretion of 
calcium and phosphate).
∃
Bone turnover markers (serum osteocalcin and serum collagen type 1 carboxy-telopeptide 
[CTx]).
∃
Urinary albumin/creatinine ratio (ACR).
1.2.
Trial Design
This is a 52-week randomized, double-blind, placebo-controlled, parallel-group study, consisting 
of a 26-week core double-blind treatment period followed by a 26-week extension double-blind 
treatment period. Eligible subjects will be either on diet and exercise alone, on diet and exercise 
and a stable dose of metformin monotherapy, on diet and exercise and a stable insulin monotherapy 
regimen, or on diet and exercise and a stable combination therapy with metformin and insulin.
Eligible subjects will go directly into a 2-week single-blind placebo run-in period and may then be 
randomized if they meet all other enrollment criteria. The goal is to have at least 30% of 
randomized subjects that will be !10 to <15 years of age, 30% to 75% of participants will be 
female, and at least 20% in both age subsets (10 to <15 years, and ≥15 to <18 years) will be male,
and 30% of participants that will have ethnicity and life-style comparable to Europe (these include 
Greece, Poland, Russia, Brazil and Mexico).
Subjects who meet all enrollment criteria will be randomly assigned in a 1:1 ratio to once-daily 
administration of canagliflozin 100 mg or placebo and enter a 52-week double-blind 
placebo-controlled treatment phase consisting of a 26-week core double-blind treatment period, 
followed by a 26-week double-blind extension treatment period. Randomization will be stratified 
by antihyperglycemic agent (AHA) background (ie, diet and exercise only, metformin 
monotherapy, insulin monotherapy, or combination of insulin and metformin) and age group 
[!10 to <15 years old, !15 to <18 years old]. Subjects who at Week 12 have an HbA1c of !7.0% 
and an estimated glomerular filtration rate (eGFR) !60 mL/min/1.73 m2 will be re-randomized in 
a 1:1 ratio to either remain on double-blind canagliflozin 100 mg (or matching placebo) or to up-
titrate to double-blind canagliflozin 300 mg (or matching placebo).


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
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Status: Approved, Date: 22 September 2023
The total duration of the study, including the 1-week screening phase, the 2-week single-blind
placebo run-in period, the 52-week double-blind placebo-controlled treatment phase, and the
30-day follow-up post-treatment phase is approximately 59 weeks for each subject.
1.3.
Statistical Hypotheses for Trial Objectives
In children and adolescents (!10 to <18 years) with T2DM who have inadequate glycemic control 
(ie, HbA1c of !6.5% to ∀10.5%), either on diet and exercise only, or on diet and exercise and 
metformin monotherapy, on diet and exercise and insulin monotherapy or on diet and exercise and 
combination of metformin and insulin:
Primary Hypothesis
#
After 26 weeks of treatment, canagliflozin reduces HbA1c relative to placebo.
Secondary Hypotheses
#
After 26 weeks of treatment, canagliflozin reduces HbA1c relative to placebo in the subset of 
subjects on background of metformin (with or without insulin).
#
After 26 weeks of treatment, canagliflozin reduces HbA1c relative to placebo in the subset of 
subjects on a background of diet and exercise only.
1.4.
Sample Size Justification
The primary hypothesis of the study is that canagliflozin is superior to placebo in glycemic control, 
as measured by the change from baseline to Week 26 in HbA1c. 
The sample size calculation is based on the 2-stage randomization design using a 2-sample, 2-sided 
t-test with Type 1 error rate of 0.05. Based on the following assumptions on treatment effect (0.4% 
to 0.5% change in HbA1c) and an associated common standard deviation (SD) of 0.9% and 
assuming 50% of the subjects will meet the re-randomization criteria at Week 12, it is estimated 
that at least 66 subjects per group will be required to achieve approximately 85% power. To 
account for attrition due to study discontinuation in a longitudinal analysis (to be described below), 
a 10% sample size inflation factor is employed (Lu 2008), and a total of at least 146 subjects (73 
per arm) will be randomized in this study. 
Treatment group
Meeting re-
randomization 
criteria at 
Week 12
Placebo-subtracted group 
difference in change in HbA1c
from baseline to Week 26
canagliflozin 100 mg to canagliflozin 
100 mg
No
0.5%
canagliflozin 100 mg to canagliflozin 
100 mg
Yes
0.4%
canagliflozin 100 mg to canagliflozin 
300 mg
Yes
0.5%


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For subjects who are on background metformin (with or without insulin), it is estimated that at 
least 33 subjects per group (after accounting for attrition due to study discontinuation) will be 
required to achieve approximately 85% power to assess the efficacy of canagliflozin on a 
background of metformin.
Treatment group (add-on to 
metformin)
Meeting re-
randomization 
criteria at Week 
12
Placebo-subtracted group 
difference in change in HbA1c
from baseline to Week 26
canagliflozin 100 mg to 
canagliflozin 100 mg
No
0.75%
canagliflozin 100 mg to 
canagliflozin 100 mg
Yes
0.65%
canagliflozin 100 mg to 
canagliflozin 300 mg
Yes
0.75%
The assumed treatment effect above is based on a subgroup analysis of subjects with baseline 
eGFR of !90 mL/min/1.73m2 from the add-on to metformin study of canagliflozin in adults 
(ie, Study DIA3006).
1.5.
Randomization and Blinding
Stratification
Dynamic randomization (ie, covariate-adjusted randomization) will be used to maintain balance 
between treatment groups with respect to the following stratification factors: AHA background 
(ie, diet and exercise only, metformin monotherapy, insulin monotherapy, or combination of 
metformin and insulin) and age group [!10 to <15 years old, !15 to <18 years old]. The 
stratification process will be handled after logging on to the IWRS being used for the study.
Randomization
In dynamic randomization, a new subject is sequentially assigned to a particular treatment group 
by taking into account the specific covariates and previous assignments of subjects. This approach 
uses the method of minimization by assessing the imbalance of sample size among the covariates 
listed above. On Day 1, subjects will be randomized to 1 of 2 treatment groups based on a 
computer-generated dynamic randomization algorithm prepared by or under the supervision of the 
sponsor before the study. This approach seeks to maintain balance between treatment groups with 
respect to the AHA background and age group. The goal is to have at least 30% of randomized 
subjects that will be !10 to <15 years of age, 30% to 75% of participants will be female, and at 
least 20% in both age subsets (10 to <15 years, and ≥15 to <18 years) will be male, and 30% of 
participants that will have ethnicity and life-style comparable to Europe.
Re-randomization
At Week 12, subjects’ glycemic status will be assessed by a central laboratory HbA1c. Following 
the review of the Week 12 unmasked HbA1c results and the Week 12 eGFR value, the following 
will occur:


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#
Subjects with HbA1c value <7.0% or eGFR <60 mL/min/1.73 m2 will not be undergoing 
re-randomization and instead will be continuing their current treatment assignment 
(ie, canagliflozin 100 mg or matching placebo) for the remainder of the study.
#
Subjects with HbA1c value !7.0% and eGFR !60 mL/min/1.73 m2 will be re-randomized in 
a 1:1 ratio (in a blinded fashion via IWRS) to either.
∃
remain on their original treatment assignment (ie, canagliflozin 100 mg or matching 
placebo) or
∃
up-titrate canagliflozin 100 mg to 300 mg (or matching placebo). In order to keep the 
study blind, subjects randomized to the placebo group will undergo a mock up-titration.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
The double-blind treatment phase will begin with the day when the first dose of double-blind study 
medication (either canagliflozin or placebo) is taken, which will be denoted as study Day 1. All 
efficacy and safety measurements at each visit will be assigned a study day relative to this date. 
All data collected on or after study Day 1 up to and including the End-of-treatment/Early 
Withdrawal (EOT/EW) visit will be considered within the double-blind treatment phase 
(ie, baseline through endpoint).
While the Time and Events Schedule of the protocol indicates the visit timing and procedures for 
each visit, the timing of a subject’s actual visit may not be exactly as per the protocol indicated 
target day / visit window (note that the protocol does not indicate required visit windows, but rather 
provides clear guidance for visit timing). Consequently, for the purpose of analysis, 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 day is study Day 1.
Baseline will be defined as the pre-dosing measure closest to or including Day 1 (prior to dose 
administration). If the pre-dosing measure on Day 1 is missing, the latest available measurement 
prior to Day 1 will be used.
If a subject has two or more actual visits in one analysis visit window, the visit closest to the target 
day will be used as the study visit for that analysis visit window. However, results from all visits 
will be included in the safety analyses (eg, pre-defined limits of change analysis) to assure that all 
on-treatment results are included. If two 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 


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day. Even though all visits will be allocated an analysis visit window, only planned protocol visits 
for each variable will be included in the by-visit analyses.
Table 1 summarizes the analysis visit windows for laboratory, vital signs, physical examination, 
and other key safety variables.
Table 1: 
Time Intervals for Analysis Visit Windows – Double-Blind Treatment Period
Scheduled Visit Time
(label on output)
Time Interval (Day)a
Target Time Point (Day)
Baseline
∀1b
1
Week 6
1c to 64
43
Week 12
65 to 113
85
Week 20
114 to 162
141
Week 26
163 to 211
183
Week 34
212 to 267
239
Week 42
268 to 330
295
Week 52
! 331
365
a
Relative to the day of the first dose of double-blind study medication.
b 
Up to the first dose of double-blind study 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.
2.2.
Analysis Sets
Unless otherwise specified, all analyses will use the Full Analysis set (FAS), which is defined 
below. If additional subjects need to be excluded from the analysis sets, the subjects will be 
identified before database lock, and the reasons for the exclusion will be documented in the clinical 
study report.
2.2.1.
Efficacy Analysis Set(s)
The FAS includes all subjects who are randomly assigned to a treatment group, have received at 
least one dose of study drug and have a baseline HbA1c measurement.
The 26-week per protocol (PP) analysis set consists of all FAS subjects who complete the 26-week 
double-blind treatment period and have no major protocol deviations that may affect the 
interpretation of the primary efficacy endpoint (including but not limited to initiation of glycemic 
rescue therapy) within the 26 weeks of core double-blind treatment period.
The subjects who complete the 26-week core double-blind treatment period are defined as those 
subjects who receive study drug and have non-missing HbA1c measurement at Week 26. In the 
case that the subjects discontinue from the treatment or have drug interruption at Week 26, the 
HbA1c measurement needs to be taken no later than the last dose of study drug at Week 26 plus 
7 days and the subjects’ last dose date needs to be on or after Day 163 based on the visit windows 
in Table 1.
The 52-week PP analysis set consists of all FAS subjects who complete the 52-week double-blind 
treatment period (ie, documented in the eCRF by the investigator that the subject complete 
treatment in the study through the Week 52 visit) and have no major protocol deviations that may 


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affect the interpretation of the efficacy endpoint (including but not limited to initiation of glycemic 
rescue therapy) within the 52 weeks of treatment.
Major protocol deviations are defined in Section 4.5.
2.2.2.
Safety Analysis Set
The safety analysis set consists of the subjects who are randomized and take at least 1 dose of 
study drug.
2.3.
Definition of Subgroups
Subgroups are defined as follows:
#
AHA subgroups: diet and exercise only; metformin monotherapy; insulin monotherapy; 
combination of metformin and insulin.
#
Age: !10 to <15 years of age; !15 to <18 years.
#
Sex: female; male.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An Independent Data Monitoring Committee (IDMC) will be established to monitor safety data 
on an ongoing basis. A separate IDMC Charter will include an overview of the proposed summary 
tables/figures/listings to be provided to the IDMC by the Statistical Support Group. No interim 
analysis will be performed.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Baseline anthropometric and demographic characteristics will be summarized by treatment group 
and overall (all treatments pooled together) for the FAS and PP analysis sets. Descriptive statistics 
(N, mean, SD, median, and range) will be provided by treatment group 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 treatment group:
#
Age group: 10 to <15, !15 to <18 years old
#
Sex: male, female.
#
Race: White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, Multiple, Not reported.
#
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported.
#
AHA background: diet and exercise only, metformin monotherapy, insulin monotherapy,
combination of metformin and insulin.
Descriptive statistics (N, mean, SD, median, and range) will also be provided by treatment group
for baseline disease characteristics such as:


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#
HbA1c
#
FPG
#
Body weight
#
BMI
#
Fasting plasma lipids (ie, LDL-C, HDL-C, total cholesterol, non-HDL-C, LDL-C to HDL-C 
ratio, non-HDL-C to LDL-C ratio, and triglycerides).
#
SBP and DBP.
#
Growth velocity and Tanner Staging.
#
Markers of calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH, 
25-hydroxy Vitamin D, calcitonin; urinary excretion of calcium and phosphate).
#
Bone turnover markers (serum osteocalcin and serum collagen type 1 CTx).
#
Urinary ACR.
The number and percentage of subjects with history of medical conditions by SOC and preferred 
term (based upon the general medical history [MH] eCRF) will be summarized by treatment group 
and overall.
4.2.
Disposition Information
Subject disposition for all randomized subjects will be summarized by treatment group and overall 
using the following:
#
Subjects who are randomized;
#
Subjects who are randomized but not dosed (subjects excluded from the FAS);
#
Subjects in the FAS;
#
Subjects who complete the 26-week core double-blind treatment period (defined in 
Section 2.2.1);
#
Subjects in the 26-week PP analysis set;
#
Subjects who receive rescue therapy during the 26-week core double-blind treatment period;
#
Subjects who complete the 52-week double-blind treatment phase (ie, investigator indicates 
on the eCRF [treatment disposition page] that the subject completed treatment);
#
Subjects who receive rescue therapy during the 52-week double-blind treatment phase;
#
Subjects in the 52-week PP analysis set;
#
Subjects in the FAS who discontinue from treatment before the Week 52 visit (ie, investigator 
indicates on the eCRF [treatment disposition page] that the subject discontinued from the 
treatment prior to the Week 52 visit);
#
Subjects in the safety analysis set.
For subjects who discontinue after randomization, the corresponding reasons for discontinuation 
from the treatment and discontinuation from the study will be summarized. Listings will be 


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provided for subjects whose predominant treatment differs from their randomized treatment and 
for subjects who temporarily take the wrong study medication.
For time to early discontinuation, Kaplan-Meier (KM) curves will be plotted by treatment group 
for the 52-week double-blind treatment phase. Descriptive analyses for the time to early 
termination will be provided.
4.3.
Treatment Compliance
Treatment compliance will be based on the information from drug compliance eCRF page. The 
number and percent of subjects who have at least 75% study drug compliance from Baseline will 
be presented for Week 26 and Week 52 separately.
4.4.
Extent of Exposure
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. If the end 
date of the medication intake is not known (e.g., subject is lost to follow-up), it will be imputed as 
the earlier of the disposition date (i.e., date of last contact with subject) or 28 days from the date 
that the last medication kit was dispensed.
Descriptive statistics (N, mean, SD, median, and range) will be presented by treatment group for 
treatment duration. The number of subjects with duration in each of the following categories 
(<2 weeks, 2 to <6 weeks, 6 to <12 weeks, 12 to <18 weeks, 18 to <26 weeks, 26 to <34 weeks, 
34 to <42 weeks, 42 to <52 weeks, and !52 weeks) will also be presented by treatment group as 
well as overall.
For subjects who discontinue from treatment prematurely (i.e., before Week 52), exposure will be 
summarized through the last day of dosing of double-blind study medication for that subject.
4.5.
Protocol Deviations
The following list of protocol deviations may affect the interpretation of the primary efficacy 
endpoint and therefore, subjects with any of these protocol deviations will be excluded from the 
PP analysis set. The complete list of subjects with these protocol deviations will be identified prior 
to database lock and a summary of reasons for exclusion will be provided in the CSR.
#
Subject has taken a prohibited medication including other SGLT2 inhibitors, or other AHAs 
that are not approved for use in pediatric population (including commercially available 
canagliflozin) for > 7 consecutive days within the last 90 days prior to the study’s primary 
endpoint at Week 26 (excluding from 26-week PP analysis set) or at Week 52 (excluding from 
52-week PP analysis set).
#
Subject has had a change in his/her dose of background therapy during the double-blind period 
for !2 consecutive weeks within the last 90 days prior to the study’s primary endpoint at 
Week 26 (excluding from 26-week PP analysis set) or at Week 52 (excluding from 52-week 
PP analysis set).


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#
Subject has taken pharmacologic (non-replacement) dose of a corticosteroid agent (oral or 
parenteral) for !2 consecutive weeks during the last 90 days prior to the study’s primary 
endpoint at Week 26 (excluding from 26-week PP analysis set) or at Week 52 (excluding from 
52-week PP analysis set).
#
Subject has received study drug other than the one to which he/she was randomized for 
!2 consecutive weeks during the last 90 days prior to the study’s primary endpoint at Week 26 
(excluding from 26-week PP analysis set) or at Week 52 (excluding from 52-week PP analysis 
set).
#
Subject has taken less than 75% of their double-blind study medication of either canagliflozin 
or placebo during the core double-blind treatment period (excluding from 26-week PP analysis 
set) or during the 52-week double-blind treatment phase (excluding from 52-week PP analysis 
set).
4.6.
Prior and Concomitant Medications
Prestudy (i.e., medications taken before initiation and stopped prior to initiation of double-blind 
study medication) and concomitant medications (i.e., medications taken after initiation of 
double-blind study medication that were either started prior or after initiation of double-blind study 
medication) including antihyperglycemic agents (AHAs) and all other medications are collected 
(prestudy AHAs taken in the 6 months prior to study enrollment and other medications taken 
30 days prior to enrollment).
All prestudy and concomitant medications are coded using World Health Organization Drug 
Dictionary (WHODD) and Anatomical Therapeutic Chemical (ATC) codes (Attachment 1).
Prestudy and concomitant medications will be summarized by the number of subjects taking 
pre-specified categories of medications by treatment group and overall.
5.
EFFICACY
The efficacy analysis of the primary and secondary efficacy endpoints will be performed based on 
the FAS (Section 2.2.1). Assessment of the primary efficacy endpoint (i.e., change from baseline 
in HbA1c) on the 26-week PP analysis set will be conducted as supportive analyses.
Regardless of the actual treatments the subjects receive, efficacy data will be analyzed according
to the randomization assignment.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Unless otherwise specified, all statistical tests will be interpreted at a 2-sided significance level of 
5% and all confidence intervals at a 2-sided confidence level of 95%.
To strongly control the family-wise error rate at the 5% significance level, a sequential testing 
procedure as illustrated in Figure 1 below will be applied. The primary endpoint will be first tested 
in all subjects (i.e., FAS), and if the results are significant (2-sided alpha level of 0.05), it will then 
proceed to test the subset of subjects on a background of metformin (with or without insulin).


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Figure 1:
Testing Sequence
Canagliflozin
superiority vs. placebo
HbA1c reduction
(All subjects)
%=0.05
↓
Canagliflozin 
superiority vs. placebo
HbA1c reduction
(Add-on to metformin)
As the secondary efficacy endpoints listed in Section 5.3 are supportive in nature, no 
corresponding hypothesis testing will be performed and therefore they are not included in the 
testing sequence above.
5.1.2.
Data Handling Rules
For the endpoints at Week 12 and Week 26, data collected after Week 26 will be excluded from 
the statistical model. For the endpoints at Week 52, data collected up to Week 52 will be included 
in the statistical model.
For subjects who will be undergoing re-randomization, data collected during the Week 12 window 
will be considered in the statistical analysis only if the measurements are taken prior to the re-
randomization date.
Unlike other assessments which were scheduled to be collected once at each visit, three 
consecutive readings of the SBP and DBP were taken (at intervals of at least 1 minute apart) and 
recorded. The average of the multiple measurements will be computed at each visit for all subjects 
and this averaged value will be used in all the analyses and summaries of blood pressure.
Unless otherwise stated, all efficacy analyses and summaries will be performed using the treatment 
groups assigned by Interactive Web Response System (IWRS).
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Definition
The primary efficacy endpoint will be the change in HbA1c from baseline at Week 26.
5.2.2.
Estimand
The clinical scientific question of interest is: 
What is the mean treatment difference at Week 26 on change from baseline in HbA1c expected 
from treatment assignment to either canagliflozin or placebo in children and adolescents with 
T2DM who have inadequate glycemic control, regardless of treatment discontinuation or 
initiation of rescue medication?


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The primary efficacy estimand is described according to the following attributes:
#
Population: children and adolescents (≥10 to <18 years) with T2DM who have an HbA1c
≥6.5% to ≤11.0%.
#
Variable: change in HbA1c from baseline to Week 26.
#
Treatment: canagliflozin (100 mg or 300 mg) vs placebo.
#
Intercurrent events (ICEs) (events that preclude observation of the variable or affect its 
interpretation): treatment discontinuation or initiation of rescue medication; ICEs are 
addressed with the treatment policy strategy, targeting the effect of treatment assignment, 
regardless of the occurrence of ICE.
#
Population-level summary: difference in means versus placebo.
5.2.3.
Analysis Methods
Primary Analysis
The primary analysis is based on the FAS dataset, including all HbA1c measurements collected 
from randomization to Week 26, including the measurements collected after treatment 
discontinuation or initiation of rescue medication. 
The primary analysis will be based on pattern mixture model (PMM), as described below:
#
Any intermediate missing data will be multiply imputed using Monte Carlo Markov Chains 
(MCMC), under a Missing at Random (MAR) assumption.
#
Then the participants with ICEs and missing Week 26 HbA1c values will be multiply imputed 
using a multiple imputation (MI) model based on the participants with ICEs and non-missing 
Week 26 HbA1c values. An MI regression will be applied to impute all monotone missing 
values, using treatment group, stratification factors, baseline HbA1c and the change from 
baseline in HbA1c at Weeks 6, 12 and 20. If this MI model does not converge then a Copy 
Reference MI model will be used instead, as described in the sensitivity analysis section.
#
Any Week 26 missing values for change from baseline in HbA1c in participants without ICEs 
will be imputed based on the MI regression (see description above) applied to all participants.
#
A total of 1000 multiple imputations will be performed. A seed equal to 345 will be used in 
all MI models.
#
After MI, each of the multiply imputed datasets will be analyzed using analysis of covariance 
(ANCOVA) with terms for treatment, stratification factors, and baseline HbA1c.
#
Rubin’s rules will be applied to combine the ANCOVA results across the imputed datasets, 
including the Week 26 LS Means for each treatment group and the difference vs placebo in 
LS Means.
Secondary analysis of the primary efficacy endpoint
The secondary analysis is based on a subset of subjects on background metformin (with or without 
insulin) from the FAS dataset, including all HbA1c measurements collected from randomization 
to Week 26, including the measurements collected after treatment discontinuation or initiation of 


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rescue medication. The attributes of estimand for this analysis is the same as the primary efficacy 
estimand except the population is a subset of subjects with background metformin (with or without 
insulin).  The same analysis based on PMM will be performed as described above.
Bayesian analysis of the primary efficacy endpoint
Bayesian Analysis of the Primary Efficacy Endpoint for overall study and subset of subjects with 
metformin (with or without insulin) will be performed in the event that the study on its own yields 
non-significant result based on primary efficacy analysis. Full details of the Bayesian analysis will 
be included in a separate supplemental SAP.
Sensitivity and supportive Analyses
The following sensitivity analyses will also be performed, all aligned with the primary estimand:
#
A Copy Reference MI model will be performed (Ratitch 2013). After any intermediate 
missing data will be imputed based on MCMC, monotone missing data will be imputed as 
following:
∃
For the canagliflozin group, imputation will be performed using an imputation model 
based on the placebo/reference group, conditional on the stratification factors, baseline 
HbA1c and the observed change from baseline values at previous time points relative to 
the mean of the model for the placebo group.  Participants in the canagliflozin group will 
be imputed as if they had always been members of the placebo group.
∃
For the placebo group, imputation will assume Missing at Random.
∃
A total of 1000 multiple imputations will be performed. A seed equal to 345 will be used 
in all MI models.
∃
After MI, each of the multiple imputed datasets will be analyzed using ANCOVA with 
terms for treatment, stratification factors, and baseline HbA1c.
∃
Rubin’s rules will be applied to combine the ANCOVA results across the imputed 
datasets.
#
A tipping point analysis will also be performed. This analysis starts with a MAR MI model 
(intermediate missing imputed with MCMC and monotone missing imputed with a MI 
regression model, using treatment group, stratification factors, baseline HbA1c and the change 
from baseline in HbA1c at Weeks 6, 12 and 20). Then each imputed value for monotone 
missing in the canagliflozin group will be made worse by a difference Delta. Each imputed 
dataset will be analyzed using ANCOVA and Rubin’s rules will be applied to combine the 
ANCOVA results across the imputed datasets. A sequence of Delta worsening adjustments 
will be applied, starting with zero with increments of 0.1 until the results reach statistical non-
significance. The results corresponding to all applied Delta adjustments will be plotted 
together with the results from the primary analysis, Copy Reference MI analysis and the other 
sensitivity analyses.
#
The primary efficacy endpoint will be analyzed using a mixed model for repeated measures 
(MMRM) based on restricted maximum likelihood. The analysis will use the observed data 
and will include the fixed, categorical effects of treatment, stratification factors (ie, 
background AHA and age group), visit, and treatment-by-visit interaction, as well as the fixed, 


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continuous covariates of baseline and baseline-by-visit interaction. An unstructured 
covariance will be used to model the within-patient errors. In case the model does not 
converge using the unstructured covariance then alternative covariance structures (such as 
compound symmetry and AR(1)) will be considered.
#
The change from baseline in HbA1c will be analyzed using an ANCOVA model with treatment 
and the stratification factors as fixed effects and baseline HbA1c value as a covariate. The 
treatment differences in the least-squares means and the 2-sided 95% CI will be estimated 
based on this model. The last observation carried forward (LOCF) method will be applied 
when the Week 26 values are missing.
In addition, based on the FAS with the data collected up to Week 26, the following supportive 
analysis will be performed:
#
A re-randomization test (Proschan 2011) (utilizing the MMRM) will be used to determine the 
p-value for the treatment comparison of the primary efficacy endpoint (ie, comparing all 
subjects who are randomized to canagliflozin to all subjects who are randomized to placebo).
The re-randomization test will fix the observed HbA1c data, regenerate treatment assignments 
for the entire study using the same minimization algorithm employed in the study and compute 
the test statistics corresponding to the treatment comparison. This process will be repeated at 
least 1,000 times. The p-value for the treatment comparison will be defined as the proportion 
of re-randomized studies whose test statistic for that comparison is at least as extreme as that 
of the original treatment assignment.
#
A supportive analysis of the primary endpoint will be conducted based on the 26-week PP 
analysis set using the same mixed model with repeated measures as in the sensitivity analysis.
Subgroup Analyses
Additional analyses of the primary efficacy endpoint in the FAS will be performed to examine if 
the treatment effect is different for the subgroups defined in Section 2.3. The interaction of 
treatment with each of the subgroups will be analyzed based on the MMRM model for the primary 
efficacy endpoint with the addition of the interaction term. If an interaction is observed 
(significance<0.10), then further evaluations will be performed to assess and explain the nature of 
the interaction [quantitative or qualitative interaction]. The LS mean change from baseline and the 
95% CI for the LS means differences between canagliflozin compared to placebo will be presented 
for the subgroups.
In the event of small subgroups, descriptive statistics may be provided in lieu of model-based 
estimates.
5.3.
Secondary Efficacy Endpoints
5.3.1.
Definition
The secondary efficacy endpoints at Week 26 and Week 52 include:
#
Change from baseline in FPG.
#
The proportion of subjects with HbA1c <7.5%, <7.0%, and <6.5%.
#
Time to rescue and proportion of subjects receiving rescue therapy.


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#
Percent change from baseline in body weight.
#
Change from baseline in BMI.
#
Percent change from baseline Fasting plasma lipids (ie, LDL-C, HDL-C, total cholesterol, 
non-HDL-C, LDL-C to HDL-C ratio, non-HDL-C to LDL-C ratio, and triglycerides).
#
Change from baseline in SBP and DBP.
The secondary efficacy endpoint at Week 12 and Week 52:
#
Change from baseline in HbA1c.
The analysis of the above endpoints will use the same attributes of the primary estimand except 
that the population level summary for the categorical endpoints will be difference in proportions.
5.3.2.
Analysis Methods
The estimands for the secondary endpoints are the same as for the primary efficacy endpoint except 
for the variable.
Continuous endpoints (except for triglycerides) will be analyzed with an MMRM model as 
described before in the FAS population. For the endpoints with post-baseline assessments taken 
only at Week 26 and Week 52, an analysis of covariance (ANCOVA) model similar to the primary 
efficacy endpoint will be used at Week 26. The least-squares means for the treatment comparisons 
and their 2-sided 95% confidence intervals will be estimated based on this model. The analysis of 
percent change in triglycerides may be based on nonparametric methods (given the anticipated 
skewed nature of this parameter) or alternative methods.
The categorical secondary efficacy endpoint of maintaining HbA1c <7.0% (and HbA1c <6.5% and 
HbA1c <7.5%) will be analyzed longitudinally using a generalized linear mixed model in the FAS 
population. The model will include the fixed, categorical effects of treatment, stratification factors 
(ie, background AHA and age group), visit, and treatment-by-visit interaction, as well as the fixed, 
continuous covariates of baseline and baseline-by-visit interaction. An unstructured covariance 
will be used to model the within-subject errors. The odds ratio and 2-sided 95% CI for the treatment 
comparisons at Week 26 (canagliflozin compared to placebo) will be estimated based on this 
model. It is possible that the generalized linear mixed model may fail to converge for the binary 
secondary efficacy endpoint of the proportion of subjects with HbA1c <7.0% (and HbA1c <6.5% 
and HbA1c <7.5%) due to few subjects meeting the threshold. In this case, a logistic regression 
model will be used. The model will include treatment and stratification factor as fixed effects, and 
baseline HbA1c value as a covariate. This alternative approach will be applied on the LOCF data 
at Week 26/Week 52 and the observed data by visit. Odds ratios and the 2-sided 95% CIs for the 
treatment comparisons will be derived from the model.
The time to event data (e.g., time to receiving rescue therapy or discontinuing due to need for 
rescue therapy) will be plotted using the KM method. The difference in proportion of subjects 
receiving rescue therapy or discontinuing due to need for rescue therapy between canagliflozin 
and placebo with 95% confidence intervals will be provided.


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5.4.
Other Efficacy Variable(s)
5.4.1.
Definition
Additional endpoints of interest include the following:
#
Change from baseline in HbA1c at Week 26 between canagliflozin 100 mg and placebo.
#
Change from baseline in HbA1c at Week 26 between canagliflozin 100 mg followed by a 
dose increase to 300 mg and placebo.
#
Percent change from baseline in lipids at Week 26 and at Week 52 between canagliflozin 
and placebo.
#
Change from baseline in SBP and DBP at Week 26 and at Week 52 between canagliflozin 
and placebo.
5.4.2.
Analysis Methods
The comparisons by dose (canagliflozin 100 mg without up-titration after Week 12 and 
canagliflozin 100 mg up-titrate to 300 mg after Week 12) to placebo will be tested for reference 
purpose by using the weights in the analyses described below.
#
When comparing the subjects who initially receive canagliflozin 100 mg with no dose increase 
to 300 mg to placebo: All subjects start with a weight of 1. After Week 12, subjects with an 
HbA1c !7.0% and eGFR !60 mL/min/1.73m2 who are re-randomized to continue canagliflozin 
100 mg will have a weight of 2. The subjects who are re-randomized to up-titrate to 
canagliflozin 300 mg will have a weight of 0.
#
When comparing the subjects who initially receive canagliflozin 100 mg followed by a dose 
increase to 300 mg to placebo: All subjects start with a weight of 1. After Week 12, subjects 
with an HbA1c !7.0% and eGFR !60 mL/min/1.73m2 who are re-randomized to continue 
canagliflozin 100 mg will have a weight of 0 and those who are re-randomized to up-titrate to 
canagliflozin 300 mg will have a weight of 2.
Given that lipids are only collected at baseline, Week 26 and Week 52, the percent change in lipid 
parameters (except for triglycerides) will be analyzed using an analysis of covariance at Week 26 
and at Week 52 with LOCF applied when the Week 26 or Week 52 values are missing. The model 
will be similar to the supportive approach listed in Section 5.2.3. The percent change in 
triglycerides will be analyzed using nonparametric methods as outlined below given its skewed 
nature. A Wilcoxon rank sum test will be performed to compare canagliflozin to placebo. 
Additionally, the Hodges-Lehman estimator for the difference in the medians and the distribution-
free confidence intervals based on the Wilcoxon rank sum test (Hollander 2013) will also be 
provided.
The change from baseline in SBP and DBP will be analyzed using an MMRM model similar to 
the one used to analyze the primary efficacy endpoint.
6.
SAFETY
All safety analyses and summaries will be based on the safety analysis set (Section 2.2.2). Safety 
data will be analyzed according to the predominant treatment received, in the event that a subject 


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received a treatment other than that to which they were randomly assigned to receive. The 
predominant treatment is defined as the treatment to which the subject was exposed for the greatest 
duration during the double-blind treatment phase.
There will be no imputation of missing values for clinical laboratory test results, vital signs
measurements in the safety analyses and there will be no hypothesis testing for results from safety 
analyses.
6.1.
Adverse Events
Adverse events will be summarized for the 26-week core double-blind treatment period and for 
the 52-week double-blind treatment phase separately. 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 updated 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. 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. Treatment-emergent AEs before the initiation of 
rescue therapy and TEAEs regardless of rescue therapy will be summarized separately for the 26-
week core double-blind treatment period and for the 52-week double-blind treatment phase.
The overall incidence (ie, number and percent of subjects with one or more AE in each category) 
of AEs, AEs leading to discontinuation of study medication, drug-related AEs, drug-related AEs 
leading to discontinuation of study medication, serious AEs, serious AEs leading to 
discontinuation of study medication, serious drug-related AEs, serious drug-related AEs leading 
to discontinuation of study medication and deaths, will be summarized by treatment group.
AEs by SOC (ie, number and proportion of subjects with one or more AEs within a SOC) will be 
summarized by treatment group.
For each AE, the percentage of subjects who experienced at least one occurrence of the given event 
will be provided by preferred term, grouped by SOC, and presented by treatment group. In 
addition, the incidence of 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 AEs leading to discontinuation.
As a screening tool, the 95% CIs for 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. 


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Four (rule-of-4) was chosen based on the recommendation from the Safety, Planning, Evaluation, 
and Reporting Team (SPERT) (Crowe 2009) for studies with less than 400 subjects in each 
treatment group. No multiplicity adjustment will be applied. The exclusion of “0” in the 95% CI
around the difference in incidence (canagliflozin compared to placebo) 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 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 drug, investigator assessed intensity of AE.
2.
Time to AE relative to start of double-blind study medication, duration of AE, action taken on 
study drug/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.
All hypoglycemic events will be reported on an eCRF page specific for hypoglycemia. If the 
hypoglycemia event is considered to be an AE/SAE in the opinion of the investigator, the event 
was 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 analysis of hypoglycemia events 
(Section 6.1.2) will be based on results collected using the hypoglycemia eCRF. Reconciliation 
will be conducted to assure that all hypoglycemia events reported as AEs are also recorded on the 
hypoglycemia eCRF form; however, hypoglycemia events reported on the hypoglycemia eCRF do
not have to be reported as an AE of hypoglycemia as this determination is left to the investigator’s 
clinical judgement.
6.1.1.
Selected Adverse Events for Additional Analysis
To support the additional assessment of particular categories of AEs, such as vulvovaginal 
candidiasis, balanitis or balanoposthitis, urinary tract infections (UTIs), volume depletion, hepatic 
injury, renal impairment/renal failure, hypersensitivity, venous thromboembolic event, 
photosensitivity, and malignancy, groupings of selected preferred terms will be created. A blinded 
review prior to database lock will be performed to assure that no reported term suggestive of the 
AE of interest is omitted. The list of preferred terms that are to be combined for assessment of 
each of the pre-specified AEs is provided in Attachment 2. Given the planned sample size of the 
study (ie, 146 subjects overall), listings may be provided instead of summary tables for any 
selected AEs below that are reported with low incidence (ie, <5%).
Fracture events identified by the investigator or the sponsor for meeting the criteria pre-specified 
in the charter will be sent to an independent fracture adjudication committee to confirm that events 
were fractures, to determine fracture location (anatomic region) and type (low trauma or not). 
Summary of the fracture events will be based on the adjudicated events of fracture.


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Diabetic ketoacidosis (DKA) identified by investigator or the sponsor for meeting the criteria pre-
specified in the charter will be sent to an independent DKA adjudication committee. Summary of 
the DKA events will be based on the adjudicated events of DKA.
Pancreatitis identified by investigator or the sponsor for meeting the criteria pre-specified in the 
charter will be sent to an independent pancreatitis adjudication committee. Summary of the 
pancreatitis events will be based on the adjudicated events of pancreatitis.
Lower extremity amputation will be recorded on a dedicated amputation case report form page. 
Summary of the lower extremity amputation will be based on the case report form page.
6.1.2.
Hypoglycemia
Hypoglycemia episodes are collected by a specific, dedicated eCRF. Investigators are also asked 
to report episodes of hypoglycemia as an adverse event if they evaluate the episode as such. 
Analyses discussed below are based upon events reported through the hypoglycemia eCRF. Note 
that reconciliation will be performed to assure that all events reported as AEs are also recorded on 
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 episode is 
associated with symptoms (symptomatic hypoglycemia) or not (asymptomatic hypoglycemia)
#
Severe hypoglycemia episode: a hypoglycemia episode that has
∃
the answer “Yes” for “Convulsions/Seizure” or “Loss of consciousness/Coma” to the 
question “Any signs/symptoms present?”, or
∃
check “Subject was not Capable of Treating Self and Required Assistance” to the question 
“If treatment given indicate assistance needed.”
Only treatment-emergent hypoglycemia episodes, reported on the eCRF for hypoglycemia, will be 
summarized. Treatment-emergent is defined the same way as treatment-emergent AEs (defined in 
Section 6.1). Given the potential confounding of rescue medication to the treatment effect, 
treatment-emergent hypoglycemia episodes before the initiation of rescue therapy will also be 
summarized.
Because the background AHA may affect the risk of hypoglycemia, treatment-emergent 
hypoglycemia episodes will be summarized for both 26-week core double-blind treatment period 
and 52-week double-blind treatment phase by the following background AHA groups at 
randomization before the initiation of rescue therapy and regardless of rescue therapy.
#
Diet and exercise only; or metformin monotherapy.
#
On insulin (with or without metformin).


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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 2 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 summarized (this includes events without concurrent fingerstick glucose reported and 
events with fingerstick glucose >70 mg/dL [3.9 mmol/L]) by treatment group.
6.2.
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, SD, 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 from 
baseline. The descriptive statistics will be presented based on measurements on study medication, 
including up to a maximum of 2 days after the last dose of study medication, as well as all 
measurements regardless of the time of the last dose of double-blind study drug. Summaries based 
on both standard units (SI) and conventional units will be provided.
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 compared to 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.
6.3.
Vital Signs and Physical Examination Findings
Descriptive statistics (N, mean, SD, median, and range) will be reported for SBP and DBP and 
pulse at each scheduled time point for absolute value and for change from baseline, including the 
95% CI for the change from baseline. The descriptive statistics will be presented based on 
measurements on study medication, including up to a maximum of 2 days after the last dose of 
study medication, as well as 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.


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A treatment-emergent vital sign abnormality is defined as a change from baseline and subsequent 
post-baseline value that satisfies the criteria listed in the PDLC list (Attachment 4). For each vital 
sign parameter, the proportion of subjects with a treatment-emergent abnormality will be tabulated 
by treatment group.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Concentrations will be reported for all subjects at all visits. Concentrations below the lower limit 
of quantification or missing will be labeled as such in the concentration database. Descriptive 
statistics, including arithmetic mean, SD, coefficient of variation, median, minimum, and 
maximum will be calculated and provided by treatment arm, and by treatment and background 
treatment. No population-based PK modeling is planned for this study.


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REFERENCES
Crowe BJ (2009), Xia HA, Berlin JA, et al. Recommendations for safety planning, data collection, evaluation and 
reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting 
team. Clin Trials. 2009;6(5):430-440.
Hollander M (2013), Wolfe DA, Chichen E. Nonparametric Statistical Methods, Third edition. John Wiley and
Sons, Inc., 2013.
Lu K (2008), Devan M, Liu G. Sample size determination for constrained longitudinal data analysis. Statistics in 
Medicine. 2008;28(4):679-699.
Proschan M (2011), Brittain E, Kammerman L. Minimize the use of minimization with unequal allocation. 
Biometrics. 2011;67(3):1135-1141.
Ratitch B (2013), O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to statistical 
analysis using pattern mixture models. Pharm Stat. 2013;12(6):337-347.


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ATTACHMENTS
Attachment 1: Prestudy and Concomitant Medications Classified by ATC Code and/or Other 
Conditions
Antihyperglycemic 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 ‘A10BD’ (combinations of oral blood 
glucose lowering drugs)
Antimicrobial Therapies
Antifungals: ATC Codes start with ‘D01’ (Antifungals for dermatological use), ‘J02’ 
(Antimycotics for systemic use), ‘G01AF’ (Imidazole derivatives), and ‘G01AG’ (Triazole 
derivatives).
Antibacterials: ATC Codes start with ‘D06’ (Antibiotics and chemotherapeutics for 
dermatological use), ‘J01’ (Antibacterials for systemic use), ‘G01AA’ (Antibiotics), ‘G01AB’ 
(Arsenic compounds), ‘G01AC’ (Quinoline derivatives), ‘G01AD’ (Organic acids), and ‘G01AE 
(Sulfonamides)’
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’


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Attachment 2: List of Preferred Terms for Selected AEs of Interest
Vulvovaginal Candidiasis
Genital candidiasis; Genital infection; Genital infection female; Genital infection fungal; 
Urogenital infection fungal; Vaginal infection; Vaginal Inflammation; Vulvitis; Vulvovaginal 
candidiasis; Vulvovaginal mycotic infection; Vulvovaginitis.
Balanitis or Balanoposthitis
Acquired phimosis; Balanitis; Balanitis candida; Balanoposthitis; Balanoposthitis infective; 
Erosive balanitis; Gangrenous balanitis; Genital candidiasis; Genital infection; Genital infection 
fungal; Genital infection male; Penile infection; Phimosis; Posthitis.
Urinary Tract Infections
Bacterial pyelonephritis; Bacterial ureteritis; Bacterial urethritis; Bladder candidiasis; Cystitis; 
Cystitis bacterial; Cystitis escherichia; Cystitis gonococcal; Cystitis haemorrhagic; Cystitis 
interstitial; Cystitis klebsiella; Cystitis pseudomonal; Emphysematous cystitis; Emphysematous 
pyelonephritis; Escherichia urinary tract infection; Fungal cystitis; Funguria; Genitourinary tract 
infection; Kidney infection; Perinephric abscess; Pyelocystitis; Pyelitis; Pyelonephritis; 
Pyelonephritis acute; Pyelonephritis chronic; Pyelonephritis fungal; Pyelonephritis mycoplasmal; 
Pyelonephritis viral; Pyonephrosis; Renal abscess; Renal cyst infection; Streptococcal urinary tract 
infection; Ureter abscess; Ureteritis; Uretheritis; Urethral abscess; Urethral carbuncle; Urethral 
stricture post infection; Urinary bladder abscess; Urinary tract abscess; Urinary tract infection; 
Urinary tract infection bacterial; Urinary tract infection enterococcal; Urinary tract infection 
fungal; Urinary tract infection pseudomonal; Urinary tract infection staphylococcal; Urosepsis; 
Urethritis; Urethritis noninfective.
Volume Depletion
Blood pressure decreased; Blood pressure orthostatic decreased; Dehydration; Diastolic 
hypotension; Dizziness postural; Hypotension; Hypovolaemia; Hypovolemic shock; Orthostatic 
hypotension; Orthostatic intolerance; Postural orthostatic tachycardia syndrome; Presyncope; 
Shock; Shock symptom; Syncope; Urine output decreased.
Renal Impairment/Renal Failure
Acute kidney injury; Acute phosphate nephropathy; Acute prerenal failure; Anuria; Azotaemia; 
Blood creatinine increased; Blood urea increased; Continuous haemodiafiltration; Dialysis; 
Glomerular filtration rate decreased; Haemodialysis; Haemofiltration; Hypercreatinaemia; 
Neonatal anuria; Nephritis; Nephropathy toxic; Oliguria; Peritoneal dialysis; Prerenal failure; 
Renal failure; Renal failure acute; Renal failure neonatal; Renal impairment; Renal impairment 
neonatal.


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Hypersensitivity
Anaphylactic reaction; Anaphylactic shock; Anaphylactoid reaction; Anaphylactoid shock; 
Angioedema; Laryngeal oedema; Laryngotracheal oedema; Oropharyngeal swelling; Pharyngeal 
oedema; Rash; Rash erythematous; Rash generalized; Rash generalized; Rash macular; Rash 
maculopapular; Rash maculo-papular; Rash papular; Rash pruritic; Rash pustular; Rash vesicular; 
Small bowel angioedema; Swollen tongue; Tongue oedema; Urticaria.
Venous Thromboembolic Event
Deep vein thrombosis; Deep vein thrombosis postoperative; Embolism venous; Iliac vein 
occlusion; Inferior vena cava syndrome; Inferior vena caval occlusion; Jugular vein occlusion; 
Mesenteric 
vein 
thrombosis; 
Mesenteric 
venous 
occlusion; 
Obstructive 
shock; 
Portosplenomesenteric venous thrombosis; Post procedural pulmonary embolism; Postpartum 
venous thrombosis; Pulmonary embolism; Pulmonary infarction; Pulmonary microemboli; 
Pulmonary oil microembolism; Pulmonary thrombosis; Renal vein embolism; Renal vein 
occlusion; Subclavian vein thrombosis; Vascular occlusion; Venous thrombosis; Venous 
thrombosis in pregnancy; Venous thrombosis limb; Visceral venous thrombosis.
Photosensitivity
Actinic elastosis; 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.
Hepatic Injury
Acute graft versus host disease in liver; Acute hepatic failure; Acute yellow liver atrophy; Allergic 
hepatitis; Ammonia increased; Ascites; Asterixis; Autoimmune hepatitis; Bacterascites; Biliary 
ascites; Biliary cirrhosis; Biliary cirrhosis primary; 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; 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;


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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.
Malignancy Renal Cell Cancer
Clear cell renal cell carcinoma, Clear cell sarcoma of the kidney, Denys-Drash syndrome, 
Hereditary leiomyomatosis renal cell carcinoma, Hereditary papillary renal carcinoma, Metastatic 
renal cell carcinoma, Nephroblastoma, Non-renal cell carcinoma of kidney, Papillary renal cell 
carcinoma, Renal cancer, Renal cancer metastatic, Renal cancer recurrent, 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.
Malignancy Bladder Cancer
Bladder adenocarcinoma recurrent, Bladder adenocarcinoma stage 0, Bladder adenocarcinoma 
stage I, Bladder adenocarcinoma stage II, Bladder adenocarcinoma stage III, Bladder 
adenocarcinoma stage IV, Bladder adenocarcinoma stage unspecified, Bladder cancer, Bladder 
cancer recurrent, Bladder cancer stage 0, with cancer in situ, Bladder cancer stage 0, without cancer 
in situ, Bladder cancer stage I, with cancer in situ, Bladder cancer stage I, without cancer in situ, 
Bladder cancer stage II, Bladder cancer stage III, Bladder cancer stage IV, Bladder squamous cell 
carcinoma recurrent, Bladder squamous cell carcinoma stage 0, Bladder squamous cell carcinoma 
stage I, Bladder squamous cell carcinoma stage II, Bladder squamous cell carcinoma stage III, 
Bladder squamous cell carcinoma stage IV, Bladder squamous cell carcinoma stage unspecified, 
Bladder transitional cell carcinoma, Bladder transitional cell carcinoma metastatic, Bladder 
transitional cell carcinoma recurrent, Bladder transitional cell carcinoma stage 0, Bladder 
transitional cell carcinoma stage I, Bladder transitional cell carcinoma stage II, Bladder transitional 
cell carcinoma stage III, Bladder transitional cell carcinoma stage IV, Metastases to bladder, 
Metastatic carcinoma of the bladder, Neuroendocrine carcinoma of the bladder, Transitional cell 
carcinoma.
Malignancy Phaeochromocytoma
Phaeochromocytoma,
Phaeochromocytoma 
crisis, 
Phaeochromocytoma 
excision, 
Phaeochromocytoma malignant.
Malignancy Breast Cancer
Apocrine breast carcinoma, Breast angiosarcoma, Breast angiosarcoma metastatic, Breast cancer, 
Breast cancer female, Breast cancer in situ, Breast cancer male, Breast cancer metastatic, Breast 


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved, Date: 22 September 2023
cancer recurrent, Breast cancer stage I, Breast cancer stage II, Breast cancer stage III, Breast cancer 
stage IV, Breast neoplasm, Breast sarcoma, Breast sarcoma metastatic, Breast sarcoma recurrent,
Contralateral breast cancer, HER-2 positive breast cancer, Hormone refractory breast cancer, 
Inflammatory carcinoma of breast recurrent, Inflammatory carcinoma of breast stage III, 
Inflammatory carcinoma of breast stage IV, Inflammatory carcinoma of the breast, Intraductal 
papillary breast neoplasm, Intraductal proliferative breast lesion, Invasive breast carcinoma, 
Invasive ductal breast carcinoma, Invasive lobular breast carcinoma, Invasive papillary breast 
carcinoma, Lobular breast carcinoma in situ, Malignant nipple neoplasm, Malignant nipple 
neoplasm female, Malignant nipple neoplasm male, Medullary carcinoma of breast, Metaplastic 
breast carcinoma, Metastases to breast, Mucinous breast carcinoma, Neuroendocrine breast 
tumour, Nipple neoplasm, Oestrogen receptor positive breast cancer, Paget's disease of nipple, 
Phyllodes tumour, Triple negative breast cancer, Tubular breast carcinoma.
Malignancy Testicular
Benign neoplasm of testis, Leydig cell tumour of the testis, Sertoli cell testicular tumour, 
Spermatocytic seminoma, Testicle adenoma, Testicular cancer metastatic, Testicular neoplasm, 
Testicular papilloma, Testis cancer.


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
34
Status: Approved, Date: 22 September 2023
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
blood urea nitrogen (BUN)
o
calcium
o
creatinine
o
phosphate
o
aspartate aminotransferase (AST)
o
albumin
o
alanine aminotransferase (ALT)
o
total protein
o
gamma-glutamyltransferase (GGT)
o
magnesium
o
total bilirubin
#
Fasting serum lipid profile (low-density lipoprotein-cholesterol [LDL-C], high-density 
lipoprotein-cholesterol [HDL-C], total cholesterol, non-HDL-C, LDL-C to HDL-C ratio, non-
HDL-C to LDL-C ratio, and triglycerides)
#
HbA1c
#
FPG
#
C-peptide (random and fasting)
#
Blood ketones
#
Bone turnover markers (serum osteocalcin and serum collagen type 1 carboxy-telopeptide 
[CTx])
#
Markers of calcium and phosphate homeostasis (calcium, magnesium, phosphate, PTH, 
25-hydroxy Vitamin D, calcitonin; urinary excretion of calcium and phosphate)
#
Urinalysis
Dipstick done at central laboratory
-specific gravity
-pH
-glucose
-protein
-blood
-ketones
-bilirubin


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
35
Status: Approved, Date: 22 September 2023
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, microscopic examination will be performed.
#
First morning void urine for Urinary ACR
Subject who have a Week -2 first morning void showing a presence with proteinuria 
(ie, proteinuria +1 and above) based on the central laboratory urine dipstick, will require a 24-hour 
urine collection prior to randomization and thereafter.
#
Serum (β-human chorionic gonadotropin [β-hCG] pregnancy testing will be conducted for all 
female subjects of childbearing potential at screening visit. Additional urine (or serum) 
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.
#
Testing for pancreatic autoimmunity (GAD and islet cell antigen 2 [IA2] antibody) will be 
conducted in subjects with no available documentation at time of screening.
#
Subjects must be fasting for at least 8 hours before collection of blood samples that require 
fasting (eg, glucose, lipid panel, etc).
Central laboratory will report the estimated glomerular filtration rate (eGFR) at study visits
when serum creatinine is measured as specified below:
#
Estimated Glomerular Filtration Rate (eGFR)
∃
eGFR will be calculated using Schwartz formula:
o
eGFR (mL/min/1.73 m2) = (0. 55 × height in cm) / serum creatinine in mg/dL for 
girls from 10 to <18 years of age and boys from 10 to 12 years of age
o
eGFR (mL/min/1.73 m2) = (0.70 × height in cm) / serum creatinine in mg/dL for 
boys from 13 to <18 years of age


JNJ-28431754  (canagliflozin)
Statistical Analysis Plan JNJ-28431754DIA3018
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
36
Status: Approved, Date: 22 September 2023
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: >2X ULN
Bicarbonate
Absolute Value: <16 mEq/L
Calcium
Composite: >ULN and >10% increase from BL
Magnesium
Composite: >ULN and >25% increase from BL
Phosphorus
Composite: >ULN and >25% increase from BL
Potassium 
Composite: <LLN and >15% decrease from BL
Composite: >ULN and >15% increase from BL
Absolute Value: ≥6.5 mEq/L
Sodium 
Composite: <LLN and decrease >5 mEq/L or more from BL
Composite: >ULN and increase>5 mEq/L or more from BL
Urate
Composite: <LLN and >25% decrease from BL
Hematology
Hemoglobin
Change: ≥ 2 g/dL decrease from BL
Change: ≥ 2 g/dL 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
ULN = Upper Limit of Normal; LLN = Lower Limit of Normal; BL = Baseline