Clinical trial NCT04288778
Conditions: Diabetes Mellitus
Sponsor: Johnson & Johnson Private Limited
Start date: 2020-11-25; Completion date: 2022-07-26
Enrollment: 276 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess safety of canagliflozin + metformin hydrochloride immediate Release (IR) fixed-dose combination.

Detailed description:

Arms: arm 1: Participants will receive canagliflozin + metformin hydrochloride IR fixed-dose combination, 50 milligram (mg) + 500 mg or 50 mg + 1000 mg, will be provided as tablets for oral administration.
Interventions: intervention 1: Canagliflozin + Metformin hydrochloride (Fixed Dose Combination)
Intervention descriptions: intervention 1: Participants will receive canagliflozin + metformin hydrochloride IR fixed-dose combination, 50 milligram (mg) + 500 mg or 50 mg + 1000 mg, will be provided as tablets for oral administration. The study Treatment duration will be of 24 weeks.

Protocol documents:
Prot_000.pdf: 
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1
Status: Approved,  Date: 4 February 2021
Johnson & Johnson Private Limited
Clinical Protocol
Protocol Title
A prospective, multi-centric, open-label, single-arm, phase 4 study to evaluate the safety 
and efficacy of canagliflozin + metformin hydrochloride IR fixed-dose combination as an 
adjunct to diet and exercise to improve glycemic control in Indian adult patients with type 
2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate
Short Title
A study to evaluate the safety and efficacy of canagliflozin + metformin hydrochloride IR 
fixed-dose combination in Indian adults with type 2 diabetes
Protocol 28431754DIA4032; Phase 4
AMENDMENT 1
Protocol Version 2.0
JNJ-28431754  (canagliflozin)
Status:
Approved
Date:
4 February 2021
Prepared by:
Johnson & Johnson Private Limited
EDMS number:
EDMS-ERI-181652461, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT04288778


JNJ-28431754  (canagliflozin)
Clinical Protocol 28431754DIA4032 Amendment 1
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Approved, Date: 4 February 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
4-Feb-2021
Original Protocol
31-Oct-2018
Amendment 1 (4 February 2021)
Overall Rationale for the Amendment:  Incorporating changes in the treatment for overdose part and 
certain important one’s in exclusion criteria & SoA
Section Number
and Name
Description of Change
Brief Rationale
1.1 Dose Regimens
“Local Prescribing Information” instead of 
“Prescribing Information”
More Specific
1.3 Schedule of Activities (SoA)
Added a window period of 7 days after 28 days
To ensure more 
maximum follow up 
completion
1.3 Schedule of Activities (SoA)
Added Serum beta HCG test for eligible females at 
screening 
To rule out pregnancy at 
screening
1.3. Schedule of Activities 
(SoA) 
“Urine Pregnancy Test” instead of “Pregnancy 
Test’
More Specific
1.3 Schedule of Activities (SoA)
Removed UPT for females at screening 
Since Serum beta HCG 
is done at screening
1.3 Schedule of Activities (SoA)
Added a row “Patient Diary Dispensing & 
Review”
For efficient recording 
of adverse events, if any 
4.2 Scientific Rationale for 
Study Design
“To be dispensed” instead of “selected”
More Specific
4.2. Scientific Rationale for 
Study Design
“Local Prescribing Information” instead of 
“Prescribing Information”
More Specific
4.2 Scientific Rationale for 
Study Design
Added “For dispensing details please refer to 
section 6.1”
For detailed information
4.3. Justification for Dose
“Local Prescribing Information” instead of 
“Prescribing Information”
More Specific
4.3. Justification for Dose
Added “and available commercialized strengths in 
India”
More Specific
4.4 End of study definition
Removed “Study completion” Added “Wk 24 of 
the Treatment Phase”
More Specific
4.4 End of study definition
Added “early withdrawal evaluation visit/ EOT 
Visit”
More Specific
5.1. Inclusion Criteria (3)
Added “Willing to Adhere” Instead of “adhering”
More Specific
5.1. Inclusion Criteria (7)
Corrected typo from 2 to 6
Correction
5.1. Inclusion Criteria (7)
Removed “urine” & added “serum beta HCG test 
at screening 
Correction
5.1. Inclusion Criteria (7)
Added “negative UPT” at baseline
Correction


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Section Number
and Name
Description of Change
Brief Rationale
5.2. Exclusion Criteria 
“Local Prescribing Information” instead of 
“Prescribing Information”
More Specific
Added canagliflozin & metformin separately along 
with canagliflozin+metformin
For more detailed 
exclusion criteria for 
hypersensitivity 
reactions
Deleted individual SGLT2i names (dapagliflozin 
and empagliflozin)
To avoid future update 
if any new drug is 
approved
6.1. Study Interventions 
Administered
“Local Prescribing Information” instead of 
“Prescribing Information”
More Specific
6.6. Study Interventions 
Administered
“Local Prescribing Information” instead of 
“Prescribing Information”
More Specific
6.6. Study Interventions 
Administered
“Local Prescribing Information” instead of 
“Prescribing Information”
More Specific
7.2.
Participant 
Discontinuation/ Withdrawal 
From the Study
Added 24 weeks for non compliance duration 
Additional information
8. STUDY ASSESSMENTS
AND PROCEDURES
Specified about urine pregnancy test and removed 
serum
To maintain consistency
8.1 Efficacy Assessments
Deleted 26 weeks & replaced with 24 weeks
Correction
8.2.1 Vital Signs
Extra steps deleted
To facilitate ease of 
measurement
8.4. Treatment of Overdose
Provided detailed plan for management of 
accidental overdose
Provided as per 
prescribing information
Removed the clause of PK analysis
As per recommendation 
in prescribing 
information
10.3 Appendix 3: Clinical 
Laboratory Tests
Other Screening Tests: Deleted Urine Pregnancy 
& added serum beta HCG test
More Specific
10.11 Appendix 11: Protocol 
Amendment History
Instead of “original”, protocol with amendment 1
Unlisted (Unexpected) Adverse 
Event/Reference Safety
Information
Removed the term “investigators brochure” 
To maintain consistency
Sponsor's Responsible Medical 
Officer
Change of personal 
(Administrative change)
PPD


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
DOCUMENT HISTORY ................................................................................................................................ 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1.
PROTOCOL SUMMARY ..................................................................................................................... 7
1.1.
Synopsis........................................................................................................................................... 7
1.2.
Schema .......................................................................................................................................... 10
1.3.
Schedule of Activities (SoA)........................................................................................................... 11
2.
INTRODUCTION................................................................................................................................ 13
2.1.
Study Rationale.............................................................................................................................. 13
2.2.
Background .................................................................................................................................... 13
2.3.
Benefit/Risk Assessment ............................................................................................................... 15
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 16
4.
STUDY DESIGN ................................................................................................................................ 17
4.1.
Overall Design................................................................................................................................ 17
4.2.
Scientific Rationale for Study Design............................................................................................. 18
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 18
4.3.
Justification for Dose...................................................................................................................... 18
4.4.
End of Study Definition................................................................................................................... 19
5.
STUDY POPULATION ...................................................................................................................... 19
5.1.
Inclusion Criteria ............................................................................................................................ 19
5.2.
Exclusion Criteria ........................................................................................................................... 20
5.3.
Lifestyle Considerations................................................................................................................. 21
5.4.
Screen Failures .............................................................................................................................. 21
6.
STUDY INTERVENTION................................................................................................................... 22
6.1.
Study Interventions Administered .................................................................................................. 22
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 22
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 23
6.4.
Study Intervention Compliance...................................................................................................... 23
6.5.
Concomitant Therapy..................................................................................................................... 23
6.5.1.
Rescue Medication ..................................................................................................................... 23
6.6.
Dose Modification........................................................................................................................... 23
6.7.
Intervention After the End of the Study.......................................................................................... 24
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 24
7.1.
Discontinuation of Study Intervention ............................................................................................ 24
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 24
7.3.
Lost to Follow-up............................................................................................................................ 25
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 25
8.1.
Efficacy Assessments .................................................................................................................... 26
8.2.
Safety Assessments....................................................................................................................... 26
8.2.1.
Vital Signs................................................................................................................................... 27
8.2.2.
Electrocardiogram (ECG) ........................................................................................................... 27
8.2.3.
Clinical Safety Laboratory Assessments .................................................................................... 27
8.2.4.
Hypoglycemia Episodes ............................................................................................................. 27
8.3.
Adverse Events and Serious Adverse Events ............................................................................... 27


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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 28
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 28
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 29
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 29
8.3.5.
Pregnancy................................................................................................................................... 29
8.3.6.
Disease-Related Events and Disease-Related Outcomes not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 29
8.4.
Treatment of Overdose .................................................................................................................. 29
8.5.
Pharmacokinetics........................................................................................................................... 30
8.6.
Pharmacodynamics........................................................................................................................ 30
8.7.
Genetics ......................................................................................................................................... 30
8.8.
Biomarkers ..................................................................................................................................... 30
8.9.
[Health Economics] [Medical Resource Utilization and Health Economics] .................................. 30
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 30
9.1.
Statistical Hypotheses.................................................................................................................... 30
9.2.
Sample Size Determination ........................................................................................................... 30
9.3.
Populations for Analyses................................................................................................................ 31
9.4.
Statistical Analyses ........................................................................................................................ 31
9.4.1.
Safety Analyses .......................................................................................................................... 31
9.5.
Interim Analysis.............................................................................................................................. 32
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 33
10.1.
Appendix 1: Abbreviations and Trademarks.................................................................................. 34
10.2.
Appendix 2: Anticipated Events ..................................................................................................... 35
10.3.
Appendix 3: Clinical Laboratory Tests ........................................................................................... 36
10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations......................................... 37
REGULATORY AND ETHICAL CONSIDERATIONS .......................................................................... 37
FINANCIAL DISCLOSURE .................................................................................................................. 39
INFORMED CONSENT PROCESS ..................................................................................................... 39
DATA PROTECTION ........................................................................................................................... 40
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA........................................... 41
DATA QUALITY ASSURANCE ............................................................................................................ 42
CASE REPORT FORM COMPLETION ............................................................................................... 42
SOURCE DOCUMENTS ...................................................................................................................... 43
MONITORING ...................................................................................................................................... 44
ON-SITE AUDITS................................................................................................................................. 44
RECORD RETENTION ........................................................................................................................ 45
STUDY AND SITE CLOSURE ............................................................................................................. 45
10.5.
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................... 47
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS.............................................................. 47
ATTRIBUTION DEFINITIONS.............................................................................................................. 48
SPECIAL REPORTING SITUATIONS ................................................................................................. 48
PROCEDURES .................................................................................................................................... 49
CONTACTING SPONSOR REGARDING SAFETY............................................................................. 50
PRODUCT QUALITY COMPLAINT HANDLING.................................................................................. 50
10.6.
Appendix 6: Contraceptive and Barrier Guidance and Collection of Pregnancy Information........ 52
10.7.
Appendix 7: Genetics..................................................................................................................... 54
10.8.
Appendix 8: Liver Safety: Suggested Actions and Follow-up Assessments.................................. 54
10.9.
Appendix 9: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting............................................................................................ 54
10.10.
Appendix 10: .................................................................................................................................. 54
10.11.
Appendix 11: Protocol Amendment History ................................................................................... 54
11.
REFERENCES................................................................................................................................... 55


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INVESTIGATOR AGREEMENT ................................................................................................................. 56
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Subjects from India in Efficacy Analysis ................................................................................... 14
Table 2:
Subjects from India in Safety Analysis (ISS Phase 3 Broad Dataset 3)................................... 15
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 10


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A prospective, multi-centric, open-label, single-arm, phase 4 study to evaluate the safety and efficacy of 
canagliflozin + metformin hydrochloride IR fixed-dose combination as an adjunct to diet and exercise to 
improve glycemic control in Indian adult patients with type 2 diabetes mellitus when treatment with both 
canagliflozin and metformin is appropriate
Canagliflozin + metformin hydrochloride IR is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and 
biguanide combination product which combines two oral antihyperglycemic agents with complementary 
mechanisms of action to improve glycemic control in patients with type 2 diabetes. By inhibiting SGLT2, 
canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), 
and thereby increases urinary glucose excretion (UGE). Metformin decreases hepatic glucose production, 
decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose 
uptake and utilization (Fleming JW 2015).
OBJECTIVES AND ENDPOINTS
Objectives
Primary Objective
In adult Indian patients with type 2 diabetes mellitus when treatment with both canagliflozin and metformin 
is appropriate:
The primary objective is to assess safety of canagliflozin + metformin hydrochloride IR fixed-dose 
combination
Secondary Objective
In adult Indian patients with type 2 diabetes mellitus when treatment with both canagliflozin and metformin 
is appropriate:
The secondary objective is to assess efficacy of canagliflozin + metformin hydrochloride IR fixed-dose 
combination. 
Tertiary/Exploratory Objectives
In adult Indian patients with type 2 diabetes mellitus when treatment with both canagliflozin and metformin 
is appropriate:
The tertiary/exploratory objectives are to assess other efficacy parameters like FPG, PPG, body weight, 
waist circumference, BP, and proportion of patients achieving HbA1c goal of below 7%.
Endpoints
Primary Endpoint
The percentage (%) of adverse events (AEs), serious adverse events (SAEs), unexpected adverse events or 
adverse drug reactions [Time Frame: 24 weeks].
Secondary Endpoint
Change from baseline in Glycosylated Haemoglobin (HbA1c) % [Time Frame: 12 and 24 weeks]


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Tertiary/Exploratory Endpoints
Change from baseline in fasting plasma glucose (FPG) in mg/dL [Time Frame: 12 and 24 weeks]
Change from baseline in 2-hr post-prandial plasma glucose (PPG) in mg/dL [Time Frame: 12 and 24 weeks]
Proportion of patients achieving HbA1c goal of below 7% [Time Frame: 12 and 24 weeks]
Change from baseline in blood pressure (BP) in mmHg [Time Frame: 12 and 24 weeks]
Change from baseline in body weight in Kg [Time Frame: 12 and 24 weeks]
Change from baseline in waist circumference in cm [Time Frame: 12 and 24 weeks].
Hypothesis
The study will be descriptive in nature to assess safety and efficacy of canagliflozin + metformin 
hydrochloride IR fixed-dose in Indian patients with type 2 diabetes mellitus.
OVERALL DESIGN
This is a prospective, multi-center, open-label, single-arm, phase 4 study in Indian adult patients with type 
2 diabetes mellitus to evaluate the safety and efficacy of canagliflozin + metformin hydrochloride IR fixed-
dose combination as an adjunct to diet and exercise to improve glycemic control when treatment with both 
canagliflozin and metformin is appropriate.
The study will be conducted in 3 phases: a 7-day screening phase, a 24 weeks treatment phase extending 
from Day 1 (baseline) to completing at the Week 24 visit (or the end-of-treatment [EOT] visit for subjects 
discontinuing study treatment early), and a 28 days post-treatment phase- Telephone follow-up contact (or 
optional study visit, at the discretion of the investigator) approximately 28 days after the last dose of study 
drug. The duration of individual participation will be approximately 29 weeks.
Key safety assessments include adverse events (AEs), serious adverse events (SAEs), unexpected adverse 
events or adverse drug reactions. Key efficacy assessments include HbA1C, FPG, PPG, blood pressure, 
body weight, and waist circumference. 
NUMBER OF PARTICIPANTS
A total of 276 participants will be enrolled in this study.
INTERVENTION GROUPS AND DURATION
Study phases:

Pretreatment phase
o
Screening period

Screening visit (week -1)

Treatment phase 
o
Starting at the baseline (Day 1) visit and completing at the Week 24 visit (or the end-of-
treatment [EOT] visit for subjects discontinuing study treatment early)

Posttreatment phase (28 days follow-up contact)
o
Telephonic follow-up contact (or optional study visit, at the discretion of the investigator) 
approximately 28 days after the last dose of study drug


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Study duration: 
Screening period will be of 1 week, during which study participants will be evaluated for eligibility criteria. 
Study participants will be followed up for study duration period of 24 weeks. The total duration of the 
study, including the 1-week screening period, the 24-week treatment phase and the 4-week post-treatment 
phase is approximately 29 weeks for each subject.
Dose Regimens:
Study participants will receive canagliflozin + metformin hydrochloride IR fixed-dose combination tablets 
at a dose determined by the investigator. Study participants will be asked to take one tablet orally twice 
daily with meals throughout the study period. Dosing can be adjusted based on effectiveness and tolerability 
while not exceeding the maximum recommended daily dose of metformin 2000 mg and canagliflozin 
300 mg in patients with an eGFR of 60 mL/min/1.73 m2 or greater. Dose initiation and dose adjustment 
will be done as per local prescribing information of canagliflozin + metformin hydrochloride IR, as 
determined by the investigator.
SAFETY EVALUATIONS
Safety evaluations, according to the time points provided in the Time and Events Schedule, will include the 
collection of adverse events, safety laboratory tests (including chemistry, fasting lipid profile, hematology, 
and urinalysis), vital signs (blood pressures and pulse rates), body weight, physical examinations, SMBG, 
and collection of potential hypoglycemic episodes (eg, from the subject diary provided to subjects).
EFFICACY EVALUATIONS
The primary measure of efficacy is change HbA1c(%) from baseline. Secondary measures of efficacy 
include changes from baseline in parameters like FPG, PPG, body weight, waist circumference and blood 
pressure.
STATISTICAL METHODS
Sample size: 276
Approximately 276 patients will be enrolled to obtain data of at least 251 patients, considering 10% dropout 
rate. Based on existing data available and considering treatment emergent adverse event rate to be 20.6% 
and margin of error 5%, a sample size of 251 will be required to yield a power of 80% and 5% level of 
significance. (Janssen Research & Development 2014)
Sample size is derived based on the formula: n = [(Z(1-alpha/2))^2 x p x (1- p)] / d^2
Where in, n is calculated sample size, Z is degree of confidence (ie, 95% which yields 1.96), d is maximum 
tolerated error or upper bound for the margin of error (0.05), p is proportion (0.206 considering rate of 
treatment emergent adverse events to be 20.6%).
Dropout rate of 10% is considered for sample size calculation.
Safety parameters to be evaluated at 24 weeks is: the percentage (%) of adverse events (AEs), serious 
adverse events (SAEs), unexpected adverse events or adverse drug reactions. The statistical evaluation will 
be performed using SAS®, version 9.4 or later. Data will be summarized using descriptive statistics 
(number of subjects [n], mean, standard deviation [SD], median, minimum, and maximum) for continuous 
variables, and using frequency and percentage (i.e., number and proportion of subjects – n, %) for 
discrete/categorical variables, unless specified otherwise.
Secondary parameters to be evaluated at week 12 and week 24 is: change from baseline in Glycosylated 
Haemoglobin (HbA1c) %. Other exploratory endpoints include change from baseline in parameters like 
FPG, PPG, body weight, waist circumference, blood pressure and proportion of patients achieving HbA1c 








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2.
INTRODUCTION
Canagliflozin is an orally active inhibitor of SGLT2. It lowers RTG and leads to increase in urinary 
glucose excretion (UGE), thereby lowering plasma glucose in patients with type 2 diabetes 
mellitus. Metformin decreases hepatic glucose production and improves insulin sensitivity by 
increasing peripheral glucose uptake and utilization. Fixed dose-combination of canagliflozin and 
metformin IR is approved by USFDA in August 2014. Bioequivalence of this FDC is shown in 
clinical trials. Efficacy and safety of canagliflozin + metformin IR is supported by multiple clinical 
trials. FDC is advantageous for patients in simplifying the treatment regimens. This can also 
improve treatment adherence (Fleming JW 2015).
The term “study intervention” throughout the protocol, refers to Canagliflozin + metformin 
hydrochloride IR FDC. 
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.
2.1.
Study Rationale
Marketing authorization in India is granted by DCGI (drug controller general of India) in form-45 
dated 27th March 2018 for six dosage strengths of FDC: canagliflozin + metformin hydrochloride 
IR (50 mg + 500 mg, 150 mg + 500 mg, 50 mg + 850 mg, 150 mg + 850 mg, 50 mg + 1000 mg, 
150 mg + 1000 mg). As a condition for approval, marketing authorization holder has been asked 
to conduct a phase 4 clinical trial. The protocol of phase 4 needs to be submitted for review by the 
subject expert committee of DCGI; before launching the product in the market. ((India) 2018)
(Central Drug Standard Control Organization)
This study will provide data on safety, and efficacy of this combination in Indian population and
fulfill the premarketing regulatory commitment in India. 
2.2.
Background
Efficacy/Safety Studies
Pivotal supporting data for the CANA/MET IR FDC efficacy include:

Phase 3 clinical studies of canagliflozin as add-on therapy in subjects on metformin (alone or 
in combination with other oral agents or insulin)

One Phase 2 clinical study (28431754DIA2003 [DIA2003]) evaluating canagliflozin bid as 
add on therapy to metformin, conducted specifically to support canagliflozin bid dosing

Four of the 7 Phase 1 studies that support the CANA/MET IR FDC evaluated the 
pharmacokinetic (PK) bioequivalence of the to-be-marketed formulation of the CANA/MET 
IR FDC tablets to the individual tablet components (DIA1039, DIA1052, DIA1051, and 
DIA1038)

One Phase 1 study evaluated the effect of food on the PK of the to-be-marketed formulation 
of the CANA/MET IR FDC (DIA1037)


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
One Phase 1 study evaluated the PK and Pharmacodynamics (PD) (including the RTG: the 
plasma glucose concentration above which tubular reabsorption of glucose cannot increase 
further, and glucose is excreted into the urine in direct proportion to the glucose concentration 
above this threshold) of canagliflozin once-daily dosing versus bid dosing (DIA1032)

One Phase 1 study evaluated the relative bioavailability of the CANA/MET IR FDC tablets 
(6 different dose strengths), serving as a pilot for the Phase 1 bioequivalence studies 
(DIA1036)
Safety results supporting CANA/MET IR FDC include:

A pooled dataset including 3 placebo-controlled Phase 3 studies (DIA3002, DIA3006, and 
DIA3012) in which canagliflozin was added to subjects on antihyperglycemic agent (AHA) 
regimens including metformin (alone or in combination with other oral AHAs) (DS1-M).

A pooled dataset including those subjects whose background diabetes therapy at baseline 
included metformin from 6 Phase 3 studies (DIA3002, DIA3006, DIA3008, DIA3009, 
DIA3010, and DIA3012), with a data cutoff date of 01 July 2012 (DS3M-LT2).

A Phase 2 study (DIA2003) that examined twice-daily dosing of canagliflozin (50 mg and 
150 mg bid).

Four Phase 1 studies that demonstrated the bioequivalence of the to-be-marketed CANA/MET 
IR FDC to the individual components (for the tablet strengths of 50/850 mg, 150/850 mg, 
50/1,000 mg, and 150/1,000 mg [studies DIA1039, DIA1052, DIA1051, and DIA1038, 
respectively]) (refer to Module 2.7.1 for detail).

Study DIA1037 evaluating the to-be-marketed CANA/MET IR FDC that showed that food 
did not affect canagliflozin bioavailability following single-dose administration of the 
150/1,000 mg CANA/MET IR FDC tablet (refer to Module 2.7.1 for detail).

A relative bioavailability study (DIA1036) that served as a pilot for the 4 Phase 1 
bioequivalence studies.
Table 1:
Subjects from India in Efficacy Analysis
(Modified Intent-to-Treat Analysis Set)
Summary of Efficacy Findings
Both the 300 mg and the 100 mg canagliflozin doses provided clinically relevant - reductions in
HbA1c, FPG, and body weight in subjects on the background of metformin alone or in combination 
with other oral AHA. The improvement in these efficacy parameters was similar in subjects from 
India relative to the overall population (Janssen Research & Development 2014).


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Table 2:
Subjects from India in Safety Analysis (ISS Phase 3 Broad Dataset 3)
Summary of Safety Findings
In summary, the overall safety profile, including the overall incidence of adverse events, specific 
adverse events, serious adverse events, death, and adverse events leading to discontinuation, are 
generally similar between the total population and the Indian subgroup in the DS3M-LT2 dataset. 
No notable differences in the pattern of adverse events were seen between the total population and 
the Indian subgroup (Janssen Research & Development 2014).
2.3.
Benefit/Risk Assessment
In support of the CANA/MET IR FDC, analyses of results from the canagliflozin Phase 3 program 
relevant to this FDC were evaluated. To assess efficacy in add-on use with metformin (alone or 
with another AHA), 6 Phase 3 studies were examined as the primary efficacy assessment, 
including add-on to metformin, to metformin and a SU agent, to metformin and pioglitazone, and 
to metformin and insulin. The results demonstrated efficacy with reductions in HbA1c, FPG, and 
body weight, comparable to that demonstrated in the broader canagliflozin program.
To assess safety in add-on use with metformin, a pooled dataset including 3 placebo-controlled 
Phase 3 studies (DIA3002, DIA3006, and DIA3012) in which canagliflozin was added to subjects 
on antihyperglycemic agent (AHA) regimens including metformin (alone or in combination with 
other oral AHAs) (DS1M) and a pooled dataset (DS3M-LT2) including those subjects whose 
background diabetes therapy at baseline included metformin from 6 Phase 3 studies (DIA3002, 
DIA3006, DIA3008, DIA3009, DIA3010, and DIA3012) were assessed. For subjects on 
metformin at baseline in the Phase 3 studies, a total of 4,202 had approximately a year or more 
exposure, and 2,284 had approximately 1.5 years or more exposure. The safety assessment in these 
subjects demonstrated a safety profile comparable to that identified for canagliflozin.
The efficacy data of subjects from India in selected individual studies showed that canagliflozin 
100 mg and 300 mg on the background of metformin alone or in combination with other oral AHA, 
provided clinically relevant reductions in HbA1c, FPG, and body weight. The improvement in 
these efficacy parameters was similar in subjects from India relative to the overall population.


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The overall safety profile of canagliflozin in subjects from India on metformin alone or metformin 
in combination with another AHA (including the overall incidence of adverse events, specific 
adverse events [including ADRs], serious adverse events, death, and adverse events leading to 
discontinuation] was generally similar between the total population and the Indian subgroup in the 
DS3M-LT2 dataset. No notable differences in the pattern of adverse events were seen between the 
total population and the Indian subgroup.
In conclusion, both doses of canagliflozin on the background of metformin provide glycemic 
improvement and body weight reduction, and were well tolerated in subjects from India. A 
favorable benefit and risk profile of canagliflozin 100 mg and 300 mg in combination with 
metformin was seen in the Indian population, consistent with the benefit and risk profile in the 
overall population in the global development program. (Janssen Research & Development 2014)
More detailed information about the known and expected benefits and risks of Canagliflozin + 
metformin hydrochloride IR FDC may be found in the document canagliflozin/metformin FDC 
SAR (subgroup analysis report) for India (Janssen Research & Development 2014).
3.
OBJECTIVES AND ENDPOINTS
OBJECTIVES
Primary Objective
In adult Indian patients with type 2 diabetes mellitus when treatment with both canagliflozin and 
metformin is appropriate:
The primary objective is to assess safety of canagliflozin + metformin hydrochloride IR fixed-dose 
combination
Secondary Objective
In adult Indian patients with type 2 diabetes mellitus when treatment with both canagliflozin and 
metformin is appropriate:
The secondary is to assess efficacy of canagliflozin + metformin hydrochloride IR fixed-dose 
combination
Tertiary/Exploratory Objectives
In adult Indian patients with type 2 diabetes mellitus when treatment with both canagliflozin and 
metformin is appropriate:
The tertiary/exploratory objectives are to assess other efficacy parameters like FPG, PPG, body 
weight, waist circumference, BP, and proportion of patients achieving HbA1c goal of below 7%


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ENDPOINTS
Primary Endpoint
The percentage (%) of adverse events (AEs), serious adverse events (SAEs), unexpected adverse 
events or adverse drug reactions [Time Frame: 24 weeks]
Secondary Endpoint
Change from baseline in Glycosylated Haemoglobin (HbA1c) % [Time Frame: 12 and 24 weeks]
Tertiary/Exploratory Endpoints
Change from baseline in fasting plasma glucose (FPG) in mg/dL [Time Frame: 12 and 24 weeks]
Change from baseline in 2-hr post-prandial plasma glucose (PPG) in mg/dL [Time Frame: 12 and 
24 weeks]
Proportion of patients achieving HbA1c goal of below 7% [Time Frame: 12 and 24 weeks]
Change from baseline in blood pressure (BP) in mmHg [Time Frame: 12 and 24 weeks]
Change from baseline in body weight in Kg [Time Frame: 12 and 24 weeks]
Change from baseline in waist circumference in cm [Time Frame: 12 and 24 weeks].
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The study will be descriptive in nature to assess safety and efficacy of canagliflozin + metformin 
hydrochloride IR fixed-dose in Indian patients with type 2 diabetes mellitus.
4.
STUDY DESIGN
4.1.
Overall Design
This is a prospective, multi-center, open-label, single-arm, phase 4 study in Indian adults with type 
2 diabetes mellitus to evaluate the safety and efficacy of canagliflozin + metformin hydrochloride 
IR fixed-dose combination as an adjunct to diet and exercise to improve glycemic control when 
treatment with both canagliflozin and metformin is appropriate.
The study will be conducted in 3 phases: a 7-day screening phase, a 24 weeks treatment phase 
extending from Day 1 (baseline) to completing at the Week 24 visit (or the end-of-treatment [EOT] 
visit for subjects discontinuing study treatment early), and a 28 days post-treatment phase-
Telephone follow-up contact (or optional study visit, at the discretion of the investigator) 
approximately 28 days after the last dose of study drug. The duration of individual participation 
will be approximately 29 weeks.


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Key safety assessments include adverse events (AEs), serious adverse events (SAEs), unexpected 
adverse events or adverse drug reactions. Key efficacy assessments include HbA1C, FPG, PPG, 
blood pressure, body weight, and waist circumference. 
A total of 276 participants will be enrolled in this study.
4.2.
Scientific Rationale for Study Design
Prospective, Multi-Center, Single Arm, Open Label
Single arm design will be used to assess safety and efficacy parameters. Because of single arm 
study there is no risk of potential bias during data collection and analysis, so blinding is not 
required. 
Safety & Tolerability Assessment, Secondary Efficacy Endpoints
As this FDC of canagliflozin + metformin HCL IR, per se, will be first time used in Indian patients, 
analysis of safety as a primary endpoint is chosen considering regulatory requirement of 
conducting phase 4 studies in India. Inclusion of secondary efficacy endpoints will provide more 
data on potential benefits of study intervention in Indian population.
Dosing Forms, Strengths, Schedule, Route of Administration 
Two dosage strengths of canagliflozin + metformin HCl IR (50 mg + 500 mg; 50 mg + 1000 mg) 
will be utilized. These are to be dispensed as per local prescribing information of the study 
intervention. For dispensing details please refer to Section 6.1.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits, 
and potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The primary ethical concern is NOT APPLICABLE
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of the
American red cross (Blood Needs & Blood Supply, Facts & Statistics, Red Cross 2018).
4.3.
Justification for Dose
Two dosage strengths of canagliflozin + metformin HCl IR (50 mg + 500 mg; 50 mg + 1000 mg) 
will be utilized. Dose of study intervention canagliflozin + metformin HCL IR FDC is selected as 
per approved local prescribing information of the product and available commercialized strengths 
in India.


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4.4.
End of Study Definition
A participant will be considered to have completed the study if he or she has completed post 
treatment telephonic assessments visit.
For subjects discontinuing study drug before, Wk 24 of the Treatment Phase, an early withdrawal 
evaluation visit / EOT Visit, should be performed as soon as possible after stopping the study drug.
A telephonic follow-up should also be done 28 days after study drug discontinuation.
5.
STUDY POPULATION
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed. 
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female
2.
18 to 65 years of age, inclusive.
3.
Subject willing to adhere to diet and exercise regimen as recommended by the 
investigator
4.
T2DM with inadequate glycemic control on diet and exercise, who in Investigator’s 
opinion are eligible to receive study drug as per prescribing information along with 
standard care for management of T2DM
5.
Subject/ LAR must have signed an informed consent form (ICF) indicating that they
understand the purpose of, and procedures required for, the study and are willing to 
participate in the study. 
6.
Women must be:
–
Postmenopausal, defined as
o
>45 years of age with amenorrhea for at least 18 months, or
o
>45 years of age with amenorrhea for at least 6 months and <18 months 
and a serum follicle stimulating hormone (FSH) level >40 IU/L, or
–
surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal 
occlusion), or otherwise be incapable of pregnancy, or
–
sexually active and practicing a highly effective method of birth control, 
including hormonal prescription oral contraceptives, contraceptive injections, 
contraceptive patch, tubal ligation, intrauterine device, double-barrier method 
(eg, condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), 
or male partner sterilization, and consistent with local regulations regarding use 


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of birth control methods for subjects participating in clinical studies, for the 
duration of their participation in the study, or
–
not sexually active.
Note: subjects who are not sexually active at screening must agree to utilize a highly 
effective method of birth control if they become heterosexually active during their 
participation in the study 
7.
Women of childbearing potential (ie, those subjects who do not meet the 
postmenopausal definition above in Inclusion Criterion 6, regardless of age must have 
a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening 
and negative UPT at baseline (predose, Day 1).
8.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
9.
Treatment naïve patients or patients on stable AHA therapy (for at least 12 weeks before 
screening) and have a screening visit HbA1c of ≥7.0% and ≤10.0%.
10. In the opinion of the Investigator, the subject is capable of understanding and complying 
with protocol requirements. 
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study: 
1.
history of liver or renal insufficiency (estimated creatinine clearance below 
45 mL/min); significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, 
neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances. 
2.
Contraindication or limitation for administration of study drug according to local 
Prescribing Information; Metabolic acidosis)
3.
Known allergies, hypersensitivity, or intolerance to Canagliflozin, Metformin or
Canagliflozin + metformin hydrochloride IR FDC or its excipients (refer to local 
prescribing information) 
4.
Use of any other SGLT2 inhibitor () within 12 weeks before the screening visit
5.
If female, the subject is pregnant or lactating or intending to become pregnant before, 
during, or within 30 days after last dose of study medication; or intending to donate ova 
during such time period
6.
Received an investigational intervention or used an invasive investigational medical 
device within 30 days before the planned first dose of study intervention
7.
History of hereditary glucose‐galactose malabsorption or primary renal glucosuria


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8.
History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta‐cell 
transplantation, or diabetes secondary to pancreatitis or pancreatectomy
9.
Any condition for which, in the opinion of the investigator, participation would not be 
in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. The required source documentation to support meeting the 
enrollment criteria are noted in Appendix 4, Regulatory, Ethical, and Study Oversight 
Considerations.
5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation:
1.
Refer to Section 6.5, Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
Dose of study drug is given with meals, twice a day.
Diet and exercise instructions are advised to participants as per standard of care.
5.4.
Screen Failures
At the Screening Visit, the results of the following laboratory tests performed at the laboratory 
must be within the limits specified below (or in the inclusion criteria).
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and date of birth (as allowed by local regulations). In cases where the participant is 
not enrolled into the study, the date seen and date of birth (as allowed by local regulations) will be 
used.


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Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.
6.
STUDY INTERVENTION
6.1.
Study Interventions Administered
The study intervention (canagliflozin + metformin hydrochloride IR fixed-dose combination), 
50 mg + 500 mg or 50 mg + 1000 mg, will be provided as tablets for oral administration. 
Participants will be instructed to take their assigned dose of the study intervention orally twice 
daily each day. The study intervention is to be taken with approximately 240 mL (8 ounces) of 
water. The tablets should be swallowed intact and participants should not attempt to dissolve them 
in water. Each dose should be taken with meal, at approximately the same time each day. Dosing 
can be adjusted based on effectiveness and tolerability while not exceeding the maximum 
recommended daily dose of metformin 2000 mg and canagliflozin 300 mg in patients with an 
eGFR of 60 mL/min/1.73 m2 or greater. Dose initiation and dose adjustment will be done as per 
local prescribing information of canagliflozin + metformin hydrochloride IR, as determined by the 
investigator.
Study intervention administration must be captured in the source documents and the CRF.
Canagliflozin + metformin hydrochloride IR FDC will be manufactured and provided under the 
responsibility of the sponsor.
6.2.
Preparation/Handling/Storage/Accountability
All study intervention must be stored as per label.
The dispensing of study intervention to the participant, and the return of study intervention from 
the participant (if applicable), must be documented on the intervention accountability form. 
Participants, or their legally acceptable representatives where applicable, must be instructed to 
return all original containers, whether empty or containing study intervention.
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The study intervention administered to the 
participant must be documented on the intervention accountability form. All study intervention 
will be stored and disposed of according to the sponsor's instructions. Study-site personnel must 
not combine contents of the study intervention containers.
Study intervention 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 intervention, and study intervention returned by the 
participant, must be available for verification by the sponsor's study site monitor during on-site 
monitoring visits. The return to the sponsor of unused study intervention, or used returned study 
intervention for destruction, will be documented on the intervention return form. When the study 
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this 
must also be documented on the intervention return form.


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Study intervention 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 intervention will be 
supplied only to participants participating in the study. Returned study intervention must not be 
dispensed again, even to the same participant except if mentioned in IP procedure manual. Study 
intervention may not be relabeled or reassigned for use by other participants. The investigator 
agrees neither to dispense the study intervention from, nor store it at, any site other than the study 
sites agreed upon with the sponsor.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Not applicable
6.4.
Study Intervention Compliance
The number of study intervention dispensed will be recorded and compared with the number 
returned. 
6.5.
Concomitant Therapy
Prestudy therapies administered up to 12 weeks before first dose of study intervention must be 
recorded at screening.
Concomitant therapies (all medications since the first dose of study drug on Day 1) must be 
recorded throughout the study beginning with start of the first dose of study intervention to 28 days 
after the last dose of study intervention. 
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study intervention must be recorded in the CRF.
Recorded information will include a description of the type of therapy, duration of use, dosing 
regimen, route of administration, and indication.
6.5.1.
Rescue Medication
The use of rescue medications is allowable at any time during the study. The date and time of 
rescue medication administration as well as the name and dosage regimen of the rescue medication 
must be recorded.
The sponsor will not supply insulin or other rescue medication that will be obtained locally
6.6.
Dose Modification
Any dose/dosage adjustment should be overseen by medically-qualified study-site personnel 
(principal or subinvestigator unless an immediate safety risk appears to be present).
The study intervention JNJ-28431754 (canagliflozin + metformin hydrochloride IR fixed-dose 
combination), will be provided as tablets for oral administration. Participants will be instructed to 
take their assigned dose of the study intervention orally twice daily each day. Dosing can be 
adjusted based on effectiveness and tolerability while not exceeding the maximum recommended 


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daily dose of metformin 2000 mg and canagliflozin 300 mg in patients with an eGFR of 
60 mL/min/1.73 m2 or greater. Dose initiation and dose adjustment will be done as per local 
prescribing information of canagliflozin + metformin hydrochloride IR, as determined by the 
investigator.
The decision to proceed to the next dose level of Canagliflozin + metformin hydrochloride IR FDC
(either an increase or a decrease) will be made by the investigator based on safety, tolerability, and 
as per local prescribing information of the study drug.
6.7.
Intervention After the End of the Study
Telephone contact (or optional study visit, at the discretion of the investigator) will be made to 
determine any serious adverse events 4 weeks after the last dose of study intervention, unless the 
participant has died, is lost to follow-up, or has withdrawn consent. If the information on any 
serious adverse events is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the participant has died, 
the date and cause of death will be collected and documented on the CRF.
Participants will be instructed that study intervention will not be made available to them after they 
have completed/discontinued study intervention and that they should return to their primary 
physician to determine standard of care.
7.
DISCONTINUATION
OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the participant to discontinue study intervention

The participant becomes pregnant 
If a participant discontinues study intervention for any reason before the end of the treatment phase, 
assessments should be obtained and follow-up telephonic call should be done 28 days after last 
dose of study drug. If the reason for withdrawal from the study is withdrawal of consent then no 
additional assessments are allowed.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be automatically withdrawn from the study if they have to discontinue study 
intervention before the end of the intervention regimen. 
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent


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
Death

Noncompliance defined as participant failed to take ≥80% of study intervention over 
24 weeks. 

Discontinuation of study intervention for any reason. A participant's study intervention will 
be automatically discontinued if:

The investigator or sponsor believes (eg, that for safety or tolerability reasons 
(eg, adverse event) it is in the best interest of the participant to discontinue study 
intervention

The participant becomes pregnant 
When a participant withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study intervention assigned to the withdrawn 
participant may not be assigned to another participant. Additional participants will be entered to 
ensure the protocol-specified number of participants complete the study. If a participant 
discontinues study intervention and withdraws from the study before the end of the treatment
phase, assessments should be obtained and follow-up telephonic call should be done 28 days after 
last dose of study drug. If the reason for withdrawal from the study is withdrawal on consent then 
no additional assessments are allowed.
7.3.
Lost to Follow-up
If a participant is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up must be documented. Refer to Section 7.2, Participant 
Discontinuation/Withdrawal From the Study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy and safety
measurements applicable to this study.
Additional urine pregnancy tests may be performed, as determined necessary by the investigator 
or required by local regulation, to establish the absence of pregnancy at any time during the 
participation in the study.
For each participant, the maximum amount of blood drawn from each participant in this study will 
not exceed 100 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. 


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Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Study-Specific Materials
The investigator will be provided with the following supplies:

Package Insert for Canagliflozin + Metformin HCl IR FDC
8.1.
Efficacy Assessments
The primary measure of efficacy is HbA1c. Secondary measures of efficacy include FPG, 2hr 
PPG, body weight, and blood pressure.
Efficacy endpoints (ie, criteria for evaluation of efficacy measures) include the following:
The secondary efficacy endpoint will be the change in HbA1c from baseline to Week 12 and 
week 24; only subjects who have both baseline and at least 1 post-baseline measurement will be 
included.
Key exploratory efficacy endpoints will include the change from baseline to Week 12 and week 24 
in FPG, 2 hr PPG, body weight, waist circumference, blood pressure.
The proportion of subjects with HbA1c <7.0% at Week 24 will also be a key exploratory endpoint.
8.2.
Safety Assessments
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events and Serious Adverse Events and Appendix 5, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities:
The primary safety endpoint is the percentage (%) of adverse events (AEs), serious adverse events 
(SAEs), unexpected adverse events or adverse drug reactions occurring over a study period of 
24 weeks from the first day of study intervention. 
Safety evaluations, according to the time points provided in the Time and Events Schedule, will
include the collection of adverse events, hypoglycemic episodes, safety laboratory tests (including 
chemistry, hematology, and urinalysis), vital signs, body weight, height, physical examinations. 


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8.2.1.
Vital Signs
Pulse/heart rate, blood pressure will be assessed.
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. 
blood pressure should preferably be measured by the same individual, using the same equipment, 
at each clinic visit to reduce variability.
Blood pressure and pulse/heart rate measurements should be assessed with a automated device. 
Manual techniques may be used only if an automated device is not available.
8.2.2.
Electrocardiogram (ECG)
Electrocardiograms will be conducted at the investigator site or affiliated facility
During the collection of ECGs, participants should be in a quiet setting without distractions 
(eg, television, cell phones). Participants should rest in a supine position for at least 5 minutes 
before ECG collection and should refrain from talking or moving arms or legs. If blood sampling 
or vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw.
8.2.3.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and first morning void urine for urinalysis
will be collected as noted in Appendix 3, Clinical Laboratory Tests. The investigator must review 
the laboratory results, document this review, and record any clinically relevant changes occurring 
during the study in the adverse event section of the CRF. The laboratory reports must be filed with 
the source documents.
8.2.4.
Hypoglycemia Episodes
Subjects will be asked for any symptoms like dizziness, sweating, etc. during the study period. 
Laboratory parameters would also be recorded during hypoglycemic episodes. Dosage of study 
drug may be adjusted, or rescue therapy may be provided as per assessment by investigator. 
8.3.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, 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.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally acceptable representative) for the duration of the study.


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Anticipated events will be recorded and reported as described in Appendix 2.
For further details on adverse events and serious adverse events (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints, refer to Appendix 5, Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
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 participant's last study-
related procedure, which may include contact for follow-up of safety. In this study, 28-day 
telephonic follow-up will be done after last dose of study drug to assess adverse events.
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.
Serious adverse events, including those spontaneously reported to the investigator within 28 days 
after the last dose of study intervention, must be reported using the Serious Adverse Event Form. 
The sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol.
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).
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire 
about adverse event occurrence. 
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the participant is 
specifically questioned.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the participant is not specifically 
questioned.


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8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Appendix 5, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
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). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the intervention caused a 
serious anticipated event, they will submit a safety report in narrative format to the investigators 
(and the head of the institute where required). The sponsor assumes responsibility for appropriate 
reporting of anticipated events to the regulatory authorities according to requirements of the 
countries in which the studies are conducted. The investigator (or sponsor where required) must 
report SUSARs to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the IEC/IRB.
8.3.5.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants 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, still birth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes 
pregnant during the study must be promptly withdrawn from the study and discontinue further 
study intervention.
Follow up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
8.3.6.
Disease-Related Events and Disease-Related Outcomes not Qualifying 
as Adverse Events or Serious Adverse Events
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.
8.4.
Treatment of Overdose
For this study, any dose of Canagliflozin + metformin hydrochloride IR FDC greater than 300 mg 
+ 2000 mg within a 24-hour time period will be considered an overdose. The sponsor does not 
recommend specific intervention for an overdose. 


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In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities until Canagliflozin 
+ metformin hydrochloride IR FDC can no longer be detected systemically (at least 7 days).

In the event of an overdose, it is reasonable to employ the usual supportive measures, 
eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, 
and institute supportive treatment as dictated by the patient’s clinical status. The most 
effective method to remove lactate and metformin is hemodialysis. Canagliflozin was 
negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be 
dialyzable by peritoneal dialysis.

Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
Not applicable.
8.6.
Pharmacodynamics
Not applicable.
8.7.
Genetics
Not applicable.
8.8.
Biomarkers
Not applicable.
8.9.
[Health Economics] [Medical Resource Utilization and Health Economics]
Not applicable.
9.
STATISTICAL CONSIDERATIONS
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.
9.1.
Statistical Hypotheses
No formal hypothesis testing will be conducted.
9.2.
Sample Size Determination
As described in synopsis.


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9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Safety
All randomized participants who take at least 1 dose of study intervention. Participants will be 
analyzed according to the intervention they actually received.
9.4.
Statistical Analyses
Data will be summarized using descriptive statistics. Continuous variables will be summarized 
using the number of observations, mean, SD, coefficient of variation, median, and range as 
appropriate. Categorical values will be summarized using the number of observations and 
percentages as appropriate.
9.4.1.
Safety Analyses
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Intervention-emergent adverse 
events are adverse events with onset during the intervention phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of participants who experience at 
least 1 occurrence of the given event will be summarized.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an adverse event, or who experience a 
severe or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and
at each scheduled time point. Changes from baseline results will be presented in pre- versus post-
intervention cross-tabulations (with classes for below, within, and above normal ranges). A listing 
of participants with any laboratory results outside the reference ranges will be provided. A listing 
of participants with any markedly abnormal laboratory results will also be provided.
Vital Signs
Descriptive statistics of pulse and blood pressure (systolic and diastolic) values and changes from 
baseline will be summarized at each scheduled time point. The percentage of participants with 
values beyond clinically important limits will be summarized.


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Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings (including body weight and waist circumference) will be 
summarized at each scheduled time point. Descriptive statistics will be calculated at baseline and 
for observed values and changes from baseline at each scheduled time point. Frequency tabulations 
of the abnormalities will be made.
9.5.
Interim Analysis
Not applicable.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS


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10.1.
Appendix 1: Abbreviations and Trademarks
ADR
adverse drug reaction
AE
adverse event
BP
Blood Pressure
CANA
Canagliflozin
CANA/MET IR FDC
canagliflozin + metformin HCL IR FDC
CRF
case report form(s) (paper or electronic)
ECG
Electrocardiogram
EGFR
estimated glomerular filtration rate
EOT
End of treatment
FDC  
Fixed Dose combination
FPG
fasting plasma glucose
HbA1C
glycosylated hemoglobin
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IR
Immediate release
IRB
Institutional Review Board
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PPG
post-prandial plasma glucose
RTG
Renal threshold of glucose
SAE
Serious adverse event
SGLT2I
sodium Glucose cotransporter 2 inhibitor
SoA
Schedule of Activities
T2DM
Type 2 Diabetes mellitus
UGE
Urinary glucose excretion
WOCBP
Woman of Childbearing Potential


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10.2.
Appendix 2: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
For the purposes of this study the following events will be considered anticipated events:

Urinary tract infection

Genital mycotic infection

Polyuria/Pollakiuria

Volume depletion adverse events
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated 
events and will be reported to the sponsor as described under All Adverse Events in Section 8.3.1, 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information. 
Any anticipated event that meets serious adverse event criteria will be reported to the sponsor as 
described under Serious Adverse Events in Section 8.3.1, Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information. 




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10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
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 participants, 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) involve only logistic or administrative aspects of the study, the IEC/IRB (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 
listed in the Contact Information page(s), which will be provided as a separate document. 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 CRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
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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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
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, ICF, any recruiting materials, and if 
applicable, participant 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

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 
participant:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and
test 
reliability 
(eg, accreditation/license), if applicable
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 participants)

Local Prescribing Information of the study drug


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
Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants 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 participants

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 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant 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.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
INFORMED CONSENT PROCESS 
Each participant (or a legally acceptable representative) must give written consent according to 
local requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the participant can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, 
and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants or 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. Participants will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 


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that choosing not to participate will not affect the care the participant will receive for the treatment 
of his or her disease]. [Participants 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 participant identification register for the purposes of long-
term follow up if needed and that their records may be accessed by health authorities and 
authorized sponsor personnel without violating the confidentiality of the participant, to the extent 
permitted by the applicable law(s) or regulations. By signing the ICF the participant or legally 
acceptable representative is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the participant agrees to allow his 
or her study physician to recontact the participant for the purpose of obtaining consent for 
additional safety evaluations. 
The participant 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 participant's or his or her legally 
acceptable representative's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the participant.
If the participant or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
participant or legally acceptable representative is obtained.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants 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 participants confidential.
The informed consent obtained from the participant (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.


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The participant 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.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding Canagliflozin + metformin 
hydrochloride IR FDC 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  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 + metformin 
hydrochloride IR FDC, 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 data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of analyses 
performed after the Clinical Study Report has been issued will be reported in a separate report and 
will not require a revision of the Clinical Study Report. 
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the 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. 


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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 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law.
DATA QUALITY ASSURANCE
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. Written 
instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRF for accuracy and completeness during on-site 
monitoring visits and after their return to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. The data will be entered into the study database and 
verified for accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in printed or 
electronic format. All data relating to the study must be recorded in CRF. All CRF entries, 
corrections, and alterations must be made by the investigator or authorized study-site personnel. 
The investigator must verify that all data entries in the CRF are accurate and correct.
For paper CRF use: All printed forms must be filled out legibly in black ballpoint pen or typed. 
The appropriate pages of the CRF must be signed and dated by the investigator.


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For electronic CRF use: The study data will be transcribed by study-site personnel from the source 
documents onto an electronic CRF, if applicable. Study-specific data will be transmitted in a secure 
manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
For paper CRF: Corrections to paper CRF must be made in such a way that the original entry is 
not obscured. Correction fluid or tape must NOT be used. The correct data must be inserted, dated, 
and initialed. If multi-part pressure-sensitive CRF are used, the separated parts of the CRF left at 
the study site must not be written on once the original has been sent to the sponsor. Completed 
CRF will be continuously submitted according to the sponsor's instructions and reviewed by the 
sponsor to determine their acceptability. If corrections to a CRF are needed after removal of the 
original CRF copy from the study site, Data Correction/Clarification Forms (DCF) will be 
generated and transmitted to the study site. The CRF must be adjusted (if applicable) and a 
response provided to the query (complete, sign, and date the DCF).
For electronic CRF use: If necessary, queries will be generated in the eDC tool. If corrections to a 
CRF are needed after the initial entry into the CRF, this can be done in either of the following 
ways:

Investigator and 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).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; 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; 
intervention receipt/dispensing/return records; study intervention administration information; and 
date of study completion and reason for early discontinuation of study intervention or withdrawal 
from the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).


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The following data will be recorded directly into the CRF and will be considered source data: 

Race

Age

Disease History

Medical History and medication history

Blood pressure and pulse/heart rate 

Height and weight 

Details of physical examination
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
CRF.
MONITORING
The sponsor will use a combination of monitoring techniques remote and/or on-site monitoring to 
monitor this study
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. At these visits, 
the monitor will compare data entered into the CRF with the source documents 
(eg, hospital/clinic/physician’s office medical records); 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 CRF 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 documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review 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 documents 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.
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. Participant privacy must, however, be 


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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.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, 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.
For paper CRF use: For CRF completed on pressure-sensitive paper, a copy is to be retained in the 
archives of the sponsor. A second copy must be archived by the investigator.
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.
STUDY AND SITE CLOSURE
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.


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The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development


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10.5.
Appendix 5: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a medicinal (investigational or noninvestigational-) product. An adverse event does not necessarily 
have a causal relationship with the intervention. 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 noninvestigational) product, whether or not related 
to that medicinal (investigational or -noninvestigational) 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 All Adverse 
Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last adverse event recording).
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 participant 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 participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.


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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 + metformin hydrochloride IR FDC, the 
expectedness of an adverse event will be determined by whether or not it is listed in the local 
prescribing information. 
Adverse Event Associated With the Use of the Intervention
An adverse event is considered associated with the use of the intervention if the attribution is 
possible, probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An adverse event that is not related to the use of the intervention.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant treatment(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the intervention. An alternative explanation, 
eg, concomitant treatment(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the intervention. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant treatment(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 treatment(s), concomitant disease(s). The 
relationship in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention


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
Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
intervention

Unexpected therapeutic or clinical benefit from use of a sponsor study intervention

Medication error involving a sponsor product (with or without participant/patient exposure to 
the sponsor study intervention, eg, name confusion)

Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
PROCEDURES
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
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 CRF 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.
For all studies with an outpatient phase, including open-label studies, the participant 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 participant 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

Participant number

Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the participant's participation in the study, must be followed until any of 
the following occurs:

The event resolves

The event stabilizes


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
The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant 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 participant'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 CRF).
The cause of death of a participant in a study within 28 days of the last dose of study intervention, 
whether or not the event is expected or associated with the study intervention, is considered a 
serious adverse event.
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 in the Contact Information 
page(s), which will be provided as a separate document.
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 participants, 
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.
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 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious Adverse 


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Event Information). A sample of the suspected product should be maintained for further 
investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.


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10.6.
Appendix 6: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and 
Appendix 5 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT 
Highly Effective Methods That Are User Independent Failure rate of ≤1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner


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(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. 
If not, additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulationb
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of >1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode 
of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)
a) 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 participants in clinical 
studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.7.
Appendix 7: Genetics
Not applicable.
10.8.
Appendix 8: Liver Safety: Suggested Actions and Follow-up Assessments
Not applicable.
10.9.
Appendix 9: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Not applicable.
10.10. Appendix 10:
Not applicable.
10.11. Appendix 11: Protocol Amendment History
This is protocol with amendment 1.


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11.
REFERENCES
(India), D. C. (2018, March 27). Form 45. Grant of Permission to import and market FDC of Canagliflozin + 
Metformin HCl. New Delhi, India.
Blood Needs & Blood Supply, Facts & Statistics, Red Cross. (2018). Retrieved from American Red Cross: 
https://www.redcrossblood.org/donate-blood/how-to-donate/how-blood-donations-help/blood-needs-blood-
supply html
Central Drug Standard Control Organization. (n.d.). 42nd Endocrinology recommendations_13_02_2018. Retrieved 
from Central Drug Standard Control Organization: 
http://cdsco nic.in/writereaddata/42nd%20Endocrinology%20recommendations_13_02_2018.pdf
Fleming JW, F. L. (2015). Fixed-dose combinations in type 2 diabetes - role of the canagliflozin metformin 
combination. Diabetes Metab Syndr Obes, 8, 287-94. doi:10.2147/DMSO.S69282
Janssen Research & Development. (2014, October 30). Information Package for India: Canagliflozin/Metformin for 
The Treatment of Type 2 Diabetes.




CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 31 May 2021
Johnson & Johnson Private Limited
Clinical Protocol
COVID-19 Appendix
A prospective, multi-centric, open-label, single-arm, phase 4 study to evaluate the safety
and efficacy of canagliflozin + metformin hydrochloride IR fixed-dose combination as an
adjunct to diet and exercise to improve glycemic control in Indian adult patients with type2 
diabetes mellitus when treatment with both canagliflozin and metformin is appropriate
A study to evaluate the safety and efficacy of canagliflozin + metformin hydrochloride IR
fixed-dose combination in Indian adults with type 2 diabetes
Protocol 28431754DIA4032; Phase [4]
JNJ-28431754)  Canagliflozin
Status:
Approved
Date:
31 May 2021
Prepared by:
Johnson & Johnson Private Limited
EDMS number:
EDMS-RIM-453560, 1.0
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.
NCT04288778


COVID-19 Appendix
JNJ-28431754) Canagliflozin
Clinical Protocol 28431754DIA4032
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 31 May 2021
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 
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 to the extent 
possible 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 via COVID-19 Appendix after consultation with the participant, investigator, and 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 case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID 19, 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
JNJ-28431754) Canagliflozin
Clinical Protocol 28431754DIA4032
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3
Status: Approved,  Date: 31 May 2021

MISSED ASSESSMENTS WILL BE CAPTURED IN THE CLINICAL TRIAL 
MANAGEMENT SYSTEM FOR PROTOCOL DEVIATIONS, WITH THE ACTUAL 
VISIT DATE DOCUMENTED OR REASON FOR WITHDRAWALS SPECIFIED; 
DISCONTINUATIONS OF STUDY INTERVENTIONS AND WITHDRAWAL FROM 
THE STUDY WILL BE CAPTURED WITH THE PREFIX “COVID-19-RELATED” IN 
THE CRF.

IF SITE VISITS ARE NOT POSSIBLE, TEMPORARY DIRECT-TO-PATIENT 
SHIPMENT OF STUDY DRUG FROM THE SITE MAY BE CONSIDERED FOR 
ONGOING PATIENTS. SITE STAFF NEED TO OBTAIN PERMISSION FROM THE 
SUBJECT 
AND 
RECORD
THIS 
IN 
THE 
SUBJECT 
SOURCE 
RECORD. 
DOCUMENTATION REQUIREMENTS WILL BE COMMUNICATED BY THE 
SPONSOR TO THE SITE.

ALTERNATIVES TO STUDY INTERVENTION DISPENSING, ADMINISTRATION, 
AND CLINICAL SAFETY LABORATORY ASSESSMENTS (INCLUDING HOME 
HEALTH NURSING) COULD BE CONSIDERED TO ALLOW CONTINUED STUDY 
PARTICIPATION FOR SUBJECTS PARTICIPATING IN THIS STUDY.
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR 
NONCOVID-19 CLINICAL TRIALS

RECORD COVID-19 VACCINE AS A CONCOMITANT THERAPY.



SAP_001.pdf: 
1 
Approved, Date: 10 March 2022 
Johnson & Johnson Private Limited 
Statistical Analysis Plan 
A prospective, multi-centric, open-label, single-arm, phase 4 study to evaluate the safety 
and efficacy of canagliflozin + metformin hydrochloride IR fixed-dose combination as an 
adjunct to diet and exercise to improve glycemic control in Indian adult patients with type 
2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate 
Protocol 28431754DIA4032; Phase 4 
 JNJ-28431754  (canagliflozin) 
Status: 
Approved 
Date: 
10 March 2022 
Prepared by: 
Janssen Research & Development, LLC 
Document No.: EDMS-RIM-641506, 1.0 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential. 
NCT04288778


JNJ-28431754  (canagliflozin)  
 
 
 
Statistical Analysis Plan 28431754DIA4032  
2 
Approved, Date: 10 March 2022  
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
AMENDMENT HISTORY .............................................................................................................................. 3 
ABBREVIATIONS ........................................................................................................................................ 4 
1. 
INTRODUCTION.................................................................................................................................. 5 
1.1. 
Trial Objectives ................................................................................................................................ 5 
1.2. 
Trial Design ...................................................................................................................................... 5 
1.3. 
Statistical Hypotheses for Trial Objectives ....................................................................................... 5 
1.4. 
Sample Size Justification ................................................................................................................. 6 
1.5. 
Randomization and Blinding ............................................................................................................ 6 
2. 
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 6 
2.1. 
Analysis Sets .................................................................................................................................... 6 
2.1.1. 
All Enrolled Analysis Set ............................................................................................................... 6 
2.1.2. 
Safety Analysis Set ....................................................................................................................... 6 
2.1.3. 
Efficacy Analysis Set .................................................................................................................... 6 
2.2. 
Study Day and Relative Day ............................................................................................................ 6 
2.3. 
Baseline ........................................................................................................................................... 7 
2.4. 
General Analysis Rules ................................................................................................................. 7 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW ......................................... 7 
4. 
PARTICIPANT INFORMATION .......................................................................................................... 8 
4.1. 
Demographics and Baseline Characteristics ................................................................................... 8 
4.2. 
Disposition Information..................................................................................................................... 8 
4.3. 
Treatment Compliance ..................................................................................................................... 9 
4.4. 
Extent of Exposure ......................................................................................................................... 10 
4.5. 
Protocol Deviations ........................................................................................................................ 10 
4.6. 
Prior and Concomitant Medications ............................................................................................... 10 
4.7. 
Medical History ............................................................................................................................... 11 
5. 
SAFETY ............................................................................................................................................. 11 
5.1. 
Adverse Events .............................................................................................................................. 11 
5.2. 
Clinical Laboratory Tests................................................................................................................ 12 
5.3. 
Vital Signs and Physical Examination Findings ............................................................................. 12 
5.4. 
Electrocardiogram .......................................................................................................................... 13 
5.5. 
Hypoglycemia episodes ................................................................................................................. 13 
6. 
EFFICACY ......................................................................................................................................... 13 
6.1. 
Efficacy Endpoint ........................................................................................................................... 13 
6.1.1. 
Definition ..................................................................................................................................... 13 
6.1.2. 
Analysis Methods ........................................................................................................................ 14 
6.2. 
Secondary Efficacy Endpoints ....................................................................................................... 14 
6.2.1. 
Definition ..................................................................................................................................... 14 
6.2.2. 
Analysis Methods ........................................................................................................................ 14 
7. 
APPENDIX ......................................................................................................................................... 15 
7.1. 
Anticipated Events ......................................................................................................................... 15 
8. 
REFERENCES................................................................................................................................... 16 
 
 
 


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AMENDMENT HISTORY 
Not applicable 
 
 


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ABBREVIATIONS 
AE 
Adverse event 
ATC 
Anatomic and therapeutic Class 
BMI 
Body mass index 
BP 
Blood Pressure 
CI 
Confidence Interval 
CM 
Concomitant Medication 
COVID-19 
Coronavirus-2019 
CRF 
Case report form 
DMC 
Data Monitoring Committee 
DPS 
Data Presentation Specifications 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated Glomerular Filtration Rate 
EOS  
End of Study 
EOT 
End of Treatment 
EW 
Early withdrawal 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
HbA1c 
Glycosylated Hemoglobin 
IR 
Immediate release 
MedDRA 
Medical Dictionary for Regulatory Activities 
PPG 
Post-prandial Plasma Glucose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
 
 
 
 
 


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1. 
INTRODUCTION 
This study is designed to evaluate safety and efficacy of canagliflozin + metformin hydrochloride 
IR fixed-dose combination as an adjunct to diet and exercise to improve glycemic control in Indian 
adult patients with type 2 diabetes mellitus when treatment with both canagliflozin and metformin 
is appropriate. 
This statistical analysis plan (SAP) for the 28431754DIA4032 describes the statistical analysis for 
participant information, safety, and efficacy data. 
1.1. 
Trial Objectives 
Primary Objective 
x 
The primary objective is to assess safety of canagliflozin + metformin hydrochloride IR fixed-
dose combination. 
Secondary Objective 
x 
The secondary objective is to assess efficacy of canagliflozin + metformin hydrochloride IR 
fixed-dose combination. 
Tertiary/Exploratory Objectives 
x 
The tertiary/exploratory objectives are to assess other efficacy parameters like FPG, PPG, 
bodyweight, waist circumference, BP and proportion of patients achieving HbA1c goal of 
below 7%. 
1.2. 
Trial Design 
This is a prospective, multi-center, open-label, single-arm, phase 4 study in Indian adults with type 
2 diabetes mellitus to evaluate the safety and efficacy of canagliflozin + metformin hydrochloride 
IR fixed-dose combination as an adjunct to diet and exercise to improve glycemic control when 
treatment with both canagliflozin and metformin is appropriate. 
A total of 276 participants consisting of male and female between 18 to 65 years of age will be 
enrolled in this study. Study participants will receive canagliflozin + metformin hydrochloride IR 
fixed-dose combination tablets at a dose determined by the investigator. Study participants will be 
asked to take one tablet orally twice daily with meals throughout the study period.  
The study will be conducted in 3 phases: a 7-day screening phase, a 24 weeks treatment phase 
extending from Day 1 (baseline) to completing at the Week 24 visit (or the end-of-treatment [EOT] 
visit for participants discontinuing study treatment early whichever occurs earlier), and a 28 days 
post-treatment phase- Telephone follow-up contact (or optional study visit, at the discretion of the 
investigator) approximately 28 days after the last dose of study treatment. The duration of 
individual participation will be approximately 29 weeks. 
1.3. 
Statistical Hypotheses for Trial Objectives 
The study will be descriptive in nature, no formal hypothesis testing will be conducted. 


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1.4. 
Sample Size Justification 
Approximately 276 patients will be enrolled to obtain data of at least 251 patients, considering 
10% dropout rate. Based on existing data available and considering treatment emergent adverse 
event rate to be 20.6% and margin of error 5%, a sample size of 251 will be required to yield a 
power of 80% and 5% level of significance. (Janssen Research & Development, 2014) 
Sample size is derived based on the formula:  
݊ൌ
ቂܼቀͳ െߙ
ʹቁቃ
ଶ
݌ሺͳ െ݌ሻ
݀ଶ
 
Where in, n is calculated sample size, Z is degree of confidence (i.e. 95% which yields 1.96), d is 
maximum tolerated error or upper bound for the margin of error (0.05), p is proportion (0.206 
considering rate of treatment emergent adverse events to be 20.6%). 
1.5. 
Randomization and Blinding 
This is an open label and single arm study, randomization and blinding procedures are not 
applicable. 
2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Analysis Sets 
2.1.1. 
All Enrolled Analysis Set 
All enrolled analysis set is defined as those participants who have signed the informed consent and 
are enrolled in the study.  
2.1.2. 
Safety Analysis Set 
All participants who had taken at least 1 dose of study treatment will be included in the safety 
analysis set. Participants will be analyzed according to the treatment they actually received. 
2.1.3. 
Efficacy Analysis Set 
The efficacy analysis set will include all participants who have taken at least 1 dose of study 
treatment and have both baseline and at least 1 post-baseline efficacy assessment.  
2.2. 
Study Day and Relative Day  
Study Day 1 or Day 1 refers to the start of the first study treatment administration. All efficacy and 
safety assessments at all visits will be assigned a day relative to this date. 
Study day or relative day for a visit is defined as: 
x 
Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1 
x 
Visit date - Date of Day 1, if visit date <date of Day 1 


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There is no 'Day 0'. 
End of treatment (EOT) will be defined as assessments done at Week 24 and in case of early 
withdrawal it will be the last available assessment present in the data. 
End of study (EOS) will be defined as Week 24 plus 28 days for participants who had completed 
the treatment period (24 Weeks) and post treatment visit (i.e. 28 days after the last dose of study 
treatment). In case of early withdrawal it will be withdrawal date plus 28 days. 
2.3. 
Baseline  
Baseline is defined as the last observation prior to the start of the first study treatment 
administration. 
2.4. 
General Analysis Rules 
The below mentioned general principles will be followed throughout the study. 
x 
Continuous data will be summarized by descriptive statistics, including number of non-
missing participants (N), mean, standard deviation (SD), 95% confidence interval (CI), 
median, and range (minimum; maximum) and for categorical variables the frequencies and 
percentages of participants will be presented. 
x 
The minimum and maximum will be presented to the same number of decimal places as the 
original data. The mean, median and 95% CI will be rounded to one additional decimal place 
than the original data, while SD will be approximated to two additional decimal places. 
x 
The percentages (%) in tables will be presented to 1 decimal place unless the sample sizes for 
the percentages are small enough to warrant presenting as integers. 
x 
If a count is 0, the percentage (0%) should not be displayed. The 0 count will be displayed, 
but the corresponding percentage should be omitted. 
x 
All study data will be included in study data listings. In general, all data will be listed by time 
point within participant. 
x 
The change from baseline is defined as the post-baseline value minus the baseline value.  
x 
The analysis visits will be labelled as “Screening”, “Baseline (Day 1)”, “Week 6”, “Week 12”, 
“Week 18”, “Week 24” and EOT/Early Withdrawal (EW) At each analysis visit, the number 
of participants with available data for a particular parameter will be displayed in the outputs.  
x 
SAS® version 9.4 will be used for all analyses. 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW 
There is neither interim analysis nor data monitoring committee (DMC) review planned for this 
study. 


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4. 
PARTICIPANT INFORMATION 
4.1. 
Demographics and Baseline Characteristics 
Table 1 presents a list of the demographic variables and baseline characteristics that will be 
summarized for all enrolled analysis set. 
Table 1: Demographic Variables and Baseline Characteristics 
Continuous Variables: 
Summary Type 
Age (years) 
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]). 
Weight (kg) 
Height (cm) 
Body Mass Index (BMI) (kg/m2) 
Waist circumference (cm) 
Glycosylated Hemoglobin (HbA1c) % 
Fasting Plasma Glucose (FPG) (mg/dL) 
Post-prandial Plasma Glucose (PPG) (mg/dL) 
Systolic Blood Pressure (mm/Hg) 
Diastolic Blood Pressure (mm/Hg) 
Estimated Glomerular Filtration Rate (eGFR) (mL/min/1.73m2) 
Categorical Variables 
 
Sex (male, female) 
Frequency distribution with the 
number and percentage of 
participants in each category. 
Racea (Indian, Non-Indian) 
eGFR categories (<60, 60 - <90, >=90) (mL/min/1.73m2) 
Age categories (<35, 35 - <65, >=65) (years) 
BMI categories (<30, 30-<35, >=35) (kg/m2) 
HbA1c (below 7%, above 7%) 
aIf multiple race categories are indicated, the Race is recorded as 'Multiple' 
 
The last non missing record before dosing will be considered as baseline for weight and height. 
Body mass index (BMI) will be calculated using baseline height and weight. 
The demographics and baseline characteristics will be listed for all participants. 
4.2. 
Disposition Information 
The summary of analysis datasets and study disposition will be summarized for using the following 
categories based on all screened subjects: 
x 
Number of participants screened 
x 
Number of participants screened but not enrolled 
x 
Number of participants enrolled (in the All Enrolled Analysis Set) 
x 
Number of participants enrolled but not receiving the study treatment 
x 
Number of participants in the Safety Analysis Set 
x 
Number of participants in the Efficacy Analysis Set 
Below disposition summaries will be presented based on Safety analysis set. 
A participant will be considered to have completed the study if he or she has completed post 
treatment telephonic assessments visit. 


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The summary for the treatment disposition will be as follows: 
x 
Number of participants receiving study treatment 
x 
Number of participants who completed the study treatment 
x 
Number of participants discontinued the study treatment 
x 
Reasons for discontinuation of study treatment 
The Summary for the study disposition will be as follows: 
x 
Number of participants enrolled 
x 
Number of participants receiving study treatment 
x 
Number of participants completed the study 
x 
Participants who terminated study prematurely 
x 
Reasons for termination of study 
The number of participants in the following disposition categories (discontinued) will be 
summarized throughout the study under the following categories: 
x 
Adverse Event 
x 
Death 
x 
Lost to Follow-Up 
x 
Non-Compliance with Study Drug 
x 
Withdrawal by Subject 
x 
Pregnancy 
x 
Other 
 Listings of participants will be provided for the following categories: 
x 
Participants who discontinued study treatment 
x 
Participants who terminated study prematurely 
4.3. 
Treatment Compliance 
Study treatment compliance is calculated as the actual total number of tablets taken divided by the 
expected total number of tablets during this study. Percentages of completed doses for categories 
(<80, 80-<100%, equal to 100%) will be summarized. 
Compliance rate (%) = 100 h the actual total number of tablets/ the expected total number of 
tablets, where the actual number of tablets = (number of intervention dispensed tablets – number 
of missing tablets) and the expected number of tablets = per protocol daily expected number of 


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tablets (e.g.  the total daily tablets = 2 given 1 tablet once but oral twice daily) h 24 (in a 24-week 
treatment phase) h7 (per week 7 days).   
4.4. 
Extent of Exposure 
Total treatment duration (in Weeks), number of participants with, without dose modification, 
number of participants who received Canagliflozin 50mg + Metformin hydrochloride 500mg and 
Canagliflozin 50mg + Metformin hydrochloride 1000mg will be summarized.  Participants who 
received study dose will be listed.  
The total treatment duration is defined as [{(last dose date - first dose date) + 1}/7] 
4.5. 
Protocol Deviations 
Major protocol deviations will be defined. Participants with major protocol deviations will be 
summarized based on all Enrolled analysis set. A listing of participants with a major protocol 
deviation will be provided.  
A listing of participants with a COVID-19 related major protocol deviation will be provided 
separately. 
4.6. 
Prior and Concomitant Medications 
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study treatment. Concomitant medications are defined as any therapy 
used on or after the same day as the first dose of study treatment, including those that started before 
and continue on after the first dose of study treatment. 
Prior and concomitant medications will be summarized by ATC code 2 and decoded CM term.  
The data on prior and concomitant medications will be provided in separate listings. Listings will 
be repeated for participants who had covid-19 infection. 
Considerations to be taken while mapping the Prior and Concomitant medications: 
x 
If both start date and end date are missing, then this medication will be considered as both 
prior and concomitant medications. 
x 
If a medication record misses components of its start and/or end dates (day and/or month 
and/or year) will be handled as: 
x 
In case of partial start or end dates, the medication records will be allocated using the 
available partial information, without imputations. If, for example, only month and year 
are available, these will be compared to the month and the year of the date/time of the 
study treatment intake. 
x 
In case of a completely missing start date, the medication will be considered as having started 
before the study (prior of the study treatment intake). 


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x 
In case of a completely missing end date, the medication will be considered as ‘ongoing’ at 
the end of the study. 
Rescue medication 
New Antidiabetic medication started after the study drug is initiated. Concomitant medications 
with rescue medications will be summarized and listed. 
4.7. 
Medical History 
Medical History will be summarized and listed for all participants on all enrolled analysis set. 
A listing for pre-planned surgery/procedure will be provided. 
5. 
SAFETY 
All safety analyses will be performed on the safety analysis set based on actual treatment received, 
unless otherwise specified.  
The primary safety endpoint is the percentage (%) of adverse events (AEs), serious adverse events 
(SAEs), unexpected adverse events or adverse drug reactions occurring over a study period of 24 
weeks from the first day of study treatment. Safety evaluations include the hypoglycemic episodes, 
safety laboratory tests (including chemistry, hematology, and urinalysis), vital signs, body weight, 
height, physical examinations. 
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, 95% CI, median, minimum, and maximum. Categorical variables will be summarized 
using frequency counts and percentages. 
5.1. 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the available version of the Medical Dictionary for Regulatory Activities (MedDRA version 24.1). 
Any AE occurring at or after the initial administration of study treatment through the day of last 
dose plus 28 days is considered to be treatment emergent. Treatment-emergent adverse events are 
adverse events with onset during the treatment phase or that are a consequence of a pre-existing 
condition that has worsened since baseline. If the event occurs on the day of the initial 
administration of study agent, and either event time or time of administration are missing, then the 
event will be assumed to be treatment emergent. If the event date is recorded as partial or 
completely missing, then the event will be considered to be treatment emergent unless it is known 
to be prior to the first administration of study treatment based on partial onset date or resolution 
date. All reported treatment-emergent adverse events will be included in the analysis. For each 
adverse event, the number and percentage of participants who experience at least 1 occurrence of 
the given event will be summarized. 
Summary tables will be provided for: 
x 
TEAEs 
x 
Serious TEAEs (SAEs) 


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x 
TEAEs leading to discontinuation of study treatment 
x 
TEAEs leading to termination of study participation 
x 
TEAEs by severity (Mild, Moderate, Severe) 
x 
TEAEs by relationship to study treatment (Not Related, Doubtful, Possible, Probable, Very 
Likely) 
x 
TEAEs by SOC and PT 
In addition listings will be provided for participants who had: 
x 
TEAEs 
x 
Serious TEAEs (SAEs) 
x 
TEAEs leading to discontinuation of study treatment  
x 
TEAEs Leading to Death 
Listings will be repeated for participants who had covid-19 infection. 
A list of anticipated AEs is attached in the Section 7 appendix. A listing of unexpected AEs will 
be provided if unexpected AEs are identified. 
5.2. 
Clinical Laboratory Tests 
All clinical laboratory tests will be displayed for the participants included in the safety analysis 
set. This includes assessment of Chemistry, Hematology and Urinalysis. 
Abnormality is defined as any lab value which is outside the normal range. The normal ranges will 
be based on standard units for the lab parameters. 
The following summary tables will be provided: 
x 
Descriptive statistics for all chemistry, hematology and urinalysis laboratory tests and change 
from baseline at each scheduled time point of measurement. 
x 
Number of participants with abnormal laboratory values will be summarized. 
In addition to the summary tables, the following listings will be provided: 
x 
Clinical laboratory test results and change from baseline. 
x 
Participants with abnormal laboratory values. 
x 
Normal reference ranges. 
5.3. 
Vital Signs and Physical Examination Findings 
Vital sign parameters including pulse rate, blood pressure (systolic and diastolic) will be 
summarized using mean, standard deviation, median, minimum and maximum at each assessment 
time point. 


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Body Mass Index will be calculated as weight (kg)/(height (m))2, at each time point that body 
weight is measured. The height measurement collected at screening will be used in the calculation. 
Three consecutive blood pressure reading will be taken and recorded at intervals of at least 1 
minute apart. The value with highest blood pressure will be considered the ‘Visit’ blood pressure 
result for each assessment time points. 
Abnormality is defined as any value which is outside the normal range specified in Table 2. 
Change from baseline will also be summarized at each time point. Descriptive statistics for change 
from baseline (mean, standard deviation, 95% CI, median, minimum and maximum) will be 
presented. 
Incidence of abnormalities in vital signs will be summarized for participants who had a baseline 
assessment and at least 1 postbaseline assessment for that vital sign. 
Listing of vital sign measurements and change from baseline will be presented for all participants. 
A listing of abnormal vital signs will be presented, including unscheduled visits. 
Table 2: Normal Ranges for Vital Signs 
Vital Signs Parameter 
Range 
Pulse 
50 Beats/min to 100 Beats/min 
SYSBP 
90 mmHg to 140 mmHg 
DIABP 
50 mmHg to 90 mmHg 
 
Abnormal physical examination results will be listed. 
5.4. 
Electrocardiogram 
All ECG parameters will be listed by participant. 
5.5. 
Hypoglycemia episodes 
Summary of participants with Hypoglycemic episodes (0,1,2 or > 3) prior to rescue medication 
will be provided. A separate listing will for Hypoglycemia episodes will also be provided. 
6. 
EFFICACY 
6.1. 
Efficacy Endpoint 
Analysis for efficacy endpoints will be based on efficacy analysis set.  
6.1.1. 
Definition 
The primary measure of efficacy is HbA1c (Glycosylated Hemoglobin). Change in HbA1c (%) 
from baseline to week 12 and week 24 will be evaluated.  


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6.1.2. 
Analysis Methods 
Change from baseline to week 12 and week 24 will be summarized descriptively for Glycosylated 
Hemoglobin (HbA1c) %.  
Summary tables will also be generated for below subgroups: 
x 
eGFR categories (<60, 60-<90, >=90) (mL/min/1.73m2) 
x 
Age categories (<35, 35-<65, >=65) (years) 
x 
BMI categories (<30, 30-<35, >=35) (kg/m2) 
6.2. 
Secondary Efficacy Endpoints 
Analysis for secondary efficacy endpoints will be based on efficacy analysis set.  
The tertiary/exploratory objectives are to assess other efficacy parameters like FPG, PPG, body 
weight, waist circumference, BP and proportion of patients achieving HbA1c goal of below 7%. 
6.2.1. 
Definition 
Secondary measures of efficacy include changes from baseline in parameters like FPG, PPG, body 
weight, waist circumference and blood pressure. Secondary parameters will be evaluated at week 
12 and week 24. The proportion of participants with HbA1c <7.0% at Week 24 will also be a key 
endpoint. 
6.2.2. 
Analysis Methods 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) for FPG, 
PPG, BP, Weight, waist circumference and their change from baseline to week 12 and week 24 
will be presented based on efficacy analysis set for each of the following parameters: 
x 
Fasting Plasma Glucose (FPG) in mg/dL 
x 
2-hr Post-prandial Plasma Glucose (PPG) in mg/dL 
x 
Blood Pressure (BP) in mmHg 
x 
Body Weight in Kg 
x 
Waist Circumference in cm 
The proportion of participants with HbA1c <7.0% will be summarized at baseline, Week 12 and 
Week 24.  
A separate listing for all the efficacy endpoints (HbA1c, FPG, PPG, BP, Weight, waist 
circumference) will be provided for all participants based on efficacy analysis set. 


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7. 
Appendix 
7.1. 
Anticipated Events 
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a    
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen. 
For the purposes of this study the following events will be considered anticipated events: 
x 
Urinary tract infection  
x 
Genital mycotic infection  
x 
Polyuria/Pollakiuria  
x 
Volume depletion adverse events 


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8. 
REFERENCES 
Not applicable.