Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 64
Healthy volunteers: no

Brief summary:
The main purpose of this study is to assess the effects of 4 weeks each of daily treatment with canagliflozin 300 milligram (mg) versus sitagliptin 100 mg as treatment adjuncts to metformin (at stable dosages) on intrapatient glycemic coefficient of variation (CV), expressed as a ratio percentage of standard deviation (SD) to mean glucose levels.

Detailed description:

Arms:
arm 1: Participants will receive metformin monotherapy at stable doses (greater than or equal to \[\>=\] 1500 milligram per day \[mg/day\]) orally once daily with canagliflozin 300 milligram (mg) tablet orally once daily (Treatment A) from Day 0 to 27 (treatment period 1), followed by sitagliptin 100 mg tablet orally once daily with metformin \>=1500 mg/day (Treatment B) from Day 44 to 71 (treatment period 2), under fasted condition. A washout period of at least 16 days (from Days 28 to 43) of metformin monotherapy will be maintained between each treatment period. arm 2: Participants will receive treatment B from Day 0 to 27 (treatment Period 1), followed by treatment A from Day 44 to 71 (treatment period 2), under fasted condition. A washout period of at least 16 days (from days 28 to 43) of metformin monotherapy will be maintained between each treatment period.

Interventions: intervention 1: Canagliflozin 300 mg intervention 2: Sitagliptin 100 mg intervention 3: Metformin
Intervention descriptions: intervention 1: Participants will receive canagliflozin 300 mg oral tablet once-daily for 28 days. intervention 2: Participants will receive sitagliptin 100 mg oral tablet once-daily for 28 days. intervention 3: Participants will receive metformin at a stable dose of \>= 1500 mg/day throughout the study including the washout period between each intervention.

Protocol document:
Prot_000.pdf: 
1 
Status: Approved, Date: 31 July 2017  
AMENDMENT #1 ENGLISH 
Janssen Research & Development/Janssen Latin America  
 
Clinical Study Protocol 
 
CANA CGM Trial COMETA: Overview  
 
 Canagliflozin Continuous Glucose Monitoring (CANA CGM) Trial: A Pilot Randomized, Double-Blind, 
Controlled, Crossover Study on the Effects of the SGLT-2 Inhibitor (vs. the DPP-4 Inhibitor Sitagliptin) on 
Glucose Variability in Mexican Patients With Type 2 Diabetes Mellitus Inadequately Controlled on 
Metformin  
 
Protocol: 28431754DIA4026; Phase: Post-market  
 
 JNJ-2843175  Canagliflozin  
 
Janssen Research & Development is a global organization that operates through different legal entities in various 
countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, 
such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag 
International NV; Janssen, Inc.; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The term 
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is identified on the 
Contact Information page that accompanies the protocol. 
This compound is approved for marketing in the following indication: 
Canagliflozin (Invokana®) is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor indicated as an adjunct to diet and 
exercise to improve glycemic control in adults with type 2 diabetes mellitus. 
 
Status:  
Approved   
Date: 
31 July 2017 
Prepared by: 
Janssen Research & Development/Janssen Latin America 
 
 
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. 
 
 
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1. 
SYNOPSIS.......................................................................................................................................................... 6 
2. 
INTRODUCTION ........................................................................................................................................... 11 
3. 
OBJECTIVES .................................................................................................................................................. 12 
4. 
METHODS ....................................................................................................................................................... 12 
4.1. 
Study Design ................................................................................................................................................. 12 
4.1.1 
Concise Summary of Procedures According to Visit and Subject (or Potential Subject), 
Investigator, and Study Site Personnel Responsibility .............................................................................. 13 
4.1.1.1 Optional Prescreening (Visit 1; Day −16 to −11 [with a ±3-day scheduling window]) ................................ 13 
4.1.1.2 Screening (Visit 2; Day −10 to −8 [with a ±3-day scheduling window]) ...................................................... 14 
4.1.1.3 Selection (Visit 3; Day −7 to −1 [with a ±3-day scheduling window] and visit 4; day -2) ........................... 15 
4.1.1.4 Randomization (Visit 5; Day 0 [with a ±3-day scheduling window]) ........................................................... 18 
4.1.1.5   Study Treatment (Visit 6; Begin treatment period A; Day 0 [with a ±3-day scheduling window]) ............ 18 
4.1.1.6      Study Treatment ("CGM In"; Visit 7; Day 22 [with a ±3-day scheduling window]) ............................... 19 
4.1.1.7       Study Treatment ("CGM out"; Visit 8; Day 27 [with a ±3-day scheduling window]) ............................ 20 
4.1.1.8     Washout (Visit 9; Day 28 [with a ±3-day scheduling window]) ............................................................... 21 
4.1.1.9   Study Treatment (Visit 10; Begin treatment period B; Day 44 [with a ±3-day scheduling           
window]) ....................................................................................................................................................... 22 
4.1.1.10      Study Treatment ("CGM In"; Visit 11; Day 66 [with a ±3-day scheduling window]) ............................. 23 
4.1.1.11  Study Treatment ("CGM out"; Visit 12; Day 71 [with a ±3-day scheduling window]) ............................... 24 
4.1.1.12     End-of-treatment follow-up (Visit 13; Day 72 [with a ±3-day scheduling window]) ............................... 25 
4.1.2 CANA CGM Trial: Overview ............................................................................................................................ 25 
4.2 
Endpoints and Hypotheses ............................................................................................................................ 25 
4.2.1. 
Efficacy Endpoints .................................................................................................................................... 25 
4.2.1.1. 
Primary Efficacy Outcome Measure ...................................................................................................... 26 
4.2.1.2. 
Secondary Efficacy Outcome Measures ................................................................................................. 26 
4.2.1.3. 
Exploratory Efficacy Outcome Measures .............................................................................................. 26 
4.2.1.4. 
Safety and Tolerability Outcome Measures ........................................................................................... 26 
4.2.1.4.1. 
Safety .................................................................................................................................................. 26 
4.2.1.4.2. 
Tolerability ......................................................................................................................................... 26 
4.2.2. 
Outcome Measures .................................................................................................................................... 27 
4.3. 
Interim Analysis and End of Study ............................................................................................................... 27 
4.4. 
Hypotheses .................................................................................................................................................... 27 
4.5. 
Treatments, Dosages, and Administration ..................................................................................................... 27 
4.5.1. 
Treatment of Interest: Canagliflozin .......................................................................................................... 27 
4.5.1.1. 
CANA 300 mg will be administered once daily, before the first meal of the day.................................. 28 
4.5.2. 
Reference Treatment: Sitagliptin (Active Comparator) ............................................................................. 30 
4.6 
Study Rationale ............................................................................................................................................. 31 
4.6.1 
Background: Clinical Studies Involving Canagliflozin or Sitagliptin ....................................................... 31 
4.6.2. 
CANA CGM Trial Rationale ..................................................................................................................... 35 
4.6.2.1. 
Potential Measures of Glycemic Variability .......................................................................................... 35 
5. 
STUDY PROCEDURES ................................................................................................................................. 36 
ABBREVIATIONS .................................................................................................................................................... 39 
5.1. 
Overview of Blinding, Control, Study Phases/Periods, and Treatment Groups ............................................ 40 
5.2. 
Study Population ........................................................................................................................................... 40 
5.2.1. 
Inclusion Criteria ....................................................................................................................................... 40 
5.2.2. 
Exclusion Criteria ...................................................................................................................................... 40 
5.3. 
Treatment ...................................................................................................................................................... 42 
5.3.1. 
Procedures for Randomization, Stratification, Allocation, and Blinding .................................................. 42 
5.3.1.1. 
Randomization ....................................................................................................................................... 42 
5.3.1.2. 
Stratification and Allocation .................................................................................................................. 42 
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5.3.1.3. 
Blinding .................................................................................................................................................. 42 
5.3.1.4. 
Dosage and Administration .................................................................................................................... 43 
5.3.1.5. 
Treatment Compliance ........................................................................................................................... 43 
5.3.1.6. 
Prestudy and Concomitant Therapy ....................................................................................................... 43 
5.4. 
Study Procedures ........................................................................................................................................... 44 
5.4.1. 
Evaluations ................................................................................................................................................ 44 
5.4.1.1. 
Overview ................................................................................................................................................ 44 
5.4.1.2. 
Study Procedures by Visit ...................................................................................................................... 44 
5.4.1.2.1. 
Prerandomization Phase ..................................................................................................................... 44 
5.4.1.2.2. 
Randomization Phase ......................................................................................................................... 45 
5.4.1.2.3. 
Double-Blind Active Treatment Phase 1 ............................................................................................ 45 
5.4.1.2.4. 
Metformin Washout Phase ................................................................................................................. 46 
5.4.1.2.5. 
Double-Blind Active Treatment Phase 2 ............................................................................................ 46 
5.4.1.2.6. 
End-of-Study Phase/Early Withdrawal/Completion ........................................................................... 46 
5.4.1.2.6.1. 
Withdrawal from the Study ............................................................................................................. 46 
5.4.1.2.7. 
Post-treatment Phase (Follow-Up) ..................................................................................................... 47 
5.5. 
Efficacy Evaluations ..................................................................................................................................... 47 
5.6. 
Safety/Tolerability Evaluations ..................................................................................................................... 48 
5.6.1. 
Safety ......................................................................................................................................................... 48 
5.6.1.1. 
Physical Examination ............................................................................................................................. 48 
5.6.1.2. 
Vital Signs .............................................................................................................................................. 49 
5.6.1.3. 
Electrocardiogram (ECG) ...................................................................................................................... 49 
5.6.1.4. 
Clinical Laboratory Assessments ........................................................................................................... 49 
5.6.2. 
Tolerability: Adverse Events ..................................................................................................................... 50 
5.6.3. 
Other Evaluations ...................................................................................................................................... 50 
6. 
STATISTICAL ANALYSIS PLAN ............................................................................................................... 50 
6.1. 
Sample Size Determination ........................................................................................................................... 50 
6.2. 
Overall Statistical Methods ........................................................................................................................... 51 
6.2.1. 
Efficacy Outcome Measures and Hypothesis Testing ............................................................................... 52 
Descriptive statistics will be presented as mean (SD) for normally distributed continuous variables, median 
[interquartile range (IQR)] for non-normally distributed continuous variables, and numbers (%) for 
categorical variables. Baseline sociodemographic and other characteristics will be compared using 
Fisher’s Exact test for categorical variables and Student’s t-test for normally distributed continuous 
variables. ....................................................................................................................................................... 52 
6.2.2. 
Safety/Tolerability Measures ..................................................................................................................... 53 
7. 
ADVERSE EVENT REPORTING ................................................................................................................ 53 
7.1    Definitions .......................................................................................................................................................... 53 
7.1.1    Adverse Event Definitions and Classifications ................................................................................................ 53 
7.1.1.1. 
Adverse Events....................................................................................................................................... 53 
7.1.1.2. 
Serious Adverse Events .......................................................................................................................... 53 
7.1.1.3. 
Unlisted (Unexpected) Adverse Events/Reference Safety Information ................................................. 54 
7.1.1.4. 
Adverse Events Associated With the Use of the Drug ........................................................................... 54 
7.1.1.5. 
Attribution Definitions ........................................................................................................................... 54 
7.1.1.5.1. 
Not Related ......................................................................................................................................... 54 
7.1.1.5.2. 
Doubtful ............................................................................................................................................. 54 
7.1.1.5.3. 
Possible ............................................................................................................................................... 54 
7.1.1.5.4. 
Probable .............................................................................................................................................. 54 
7.1.1.5.5. 
Very Likely......................................................................................................................................... 55 
7.2. 
Severity Criteria ............................................................................................................................................ 55 
7.3    Special Reporting Situations ............................................................................................................................... 55 
7.3.1. 
Procedures ................................................................................................................................................. 55 
7.3.1.1. 
All Adverse Events ................................................................................................................................ 55 
7.3.1.2. 
Serious Adverse Events .......................................................................................................................... 56 
7.3.1.3. 
Pregnancy ............................................................................................................................................... 57 
7.4. 
Contacting Sponsor Regarding Safety ........................................................................................................... 57 
7.5. 
Product Quality Complaint Handling ............................................................................................................ 57 
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7.5.1. 
PQC Procedures ......................................................................................................................................... 58 
7.5.1.1. 
Contacting Sponsor Regarding Product Quality .................................................................................... 58 
8. 
STUDY DRUG INFORMATION .................................................................................................................. 58 
8.1. 
Physical Description of Study Drugs ............................................................................................................ 58 
8.2. 
Packaging ...................................................................................................................................................... 58 
8.3. 
Labelling ....................................................................................................................................................... 58 
8.4. 
Preparation, Handling, and Storage ............................................................................................................... 58 
8.5. 
Drug Accountability ...................................................................................................................................... 58 
9. 
STUDY-SPECIFIC MATERIALS ................................................................................................................. 59 
10. 
ETHICAL ASPECTS ...................................................................................................................................... 59 
10.1. 
Study-Specific Design Considerations .......................................................................................................... 59 
10.2. 
Regulatory Ethics Compliance ...................................................................................................................... 59 
10.2.1. 
Investigator Responsibilities ...................................................................................................................... 59 
10.2.2. 
Independent Ethics Committee or Institutional Review Board.................................................................. 59 
10.2.3. 
Informed Consent ...................................................................................................................................... 60 
10.2.4. 
Privacy of Personal Data ........................................................................................................................... 61 
11. 
ADMINISTRATIVE REQUIREMENTS ...................................................................................................... 61 
11.1. 
Protocol Amendments ................................................................................................................................... 61 
11.2. 
Regulatory Documentation ............................................................................................................................ 62 
11.2.1. 
Regulatory Approval/Notification ............................................................................................................. 62 
11.2.2. 
Required Prestudy Documentation ............................................................................................................ 62 
11.2.3. 
Subject Identification, Enrollment, and Screening Logs ........................................................................... 62 
11.2.4. 
Source Documentation .............................................................................................................................. 63 
11.2.5. 
Case Report Form Completion .................................................................................................................. 64 
11.2.6. 
Data Quality Assurance/Quality Control ................................................................................................... 64 
11.2.7. 
Record Retention ....................................................................................................................................... 65 
11.2.8. 
Monitoring ................................................................................................................................................. 65 
11.2.9. 
Study Completion/Termination ................................................................................................................. 65 
11.2.9.1. 
Study Completion/End of Study ............................................................................................................ 65 
11.2.9.2. 
Study Termination .................................................................................................................................. 66 
11.2.9.3. 
On-Site Audits ........................................................................................................................................ 66 
11.3. 
Use of Information and Publication .............................................................................................................. 66 
11.4. 
Registration of Clinical Studies and Disclosure of Results ........................................................................... 67 
12. 
REFERENCES ................................................................................................................................................ 68 
APPENDIX 1. 
SAMPLE SIZE CALCULATION BASED ON MEAN (SD) DIFFERENCE IN 
GLYCEMIC SD (SD OF 24-HOUR GLUCOSE PROFILE) IN PATIENTS RECEIVING 
CANAGLIFLOZIN 300 MG/SITAGLIPTIN 100 MG, EACH AS RELATED TO PLACEBO, 
ON CGM 
…………………………………………………………………………………………72 
APPENDIX 2. 
SAMPLE SIZE CALCULATION BASED ON MEAN (SD) DIFFERENCE IN 
ESTIMATED 
AVERAGE 
GLUCOSE 
BETWEEN 
CANAGLIFLOZIN 
300 
MG/SITAGLIPTIN 100 MG IN MEAN (SD) ESTIMATED AVERAGE GLUCOSE (EAG) IN 
DIRECT COMPARATIVE TRIALS WITHOUT CGM (CANTATA-D TRIAL, LATIN 
AMERICAN POPULATION) ........................................................................................................................ 73 
APPENDIX 3.  
SAMPLE SIZE CALCULATION BASED ON MEAN (SD) DIFFERENCE IN 
ESTIMATED AVERAGE GLUCOSE BETWEEN CANAGLIFLIZIN 300 MG AND 
SITAGLIPTIN 100 MG IN MEAN (SD) ESTIMATED AVERAGE GLUCOSE (EAG) IN 
DIRECT COMPARATIVE TRIALS WTIHOUT CGM CANTATA-D TRIAL, TOTAL 
POPULATION) ............................................................................................................................................... 74 
APPENDIX 4. 
 GRIZZLE'S TWO-STAGE MODEL TEST OF CARRYOVER: FORMULAS 
(SHEN, 2006) .................................................................................................................................................... 75 
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APPENDIX 5.  METHOD OF BLOOD PRESSURE MEASUREMENT ............................................................ 77 
APPENDIX 6.  ONE-TOUCH ULTRA MINI USER GUIDE ............................................................................... 78 
APPENDIX 7.A.  I PRO 2 USER GUIDE ............................................................................................................... 79 
APPENDIX 7.B.   CLINIC (SITE) CHECKLIST .................................................................................................. 80 
APPENDIX 7.C.  PATIENT INSTRUCTIONS: .................................................................................................... 82 
APPENDIX 8.   PATIENT LOG SHEET ................................................................................................................ 83 
APPENDIX 9.  INVESTIGATOR AGREEMENT ................................................................................................. 84 
APPENDIX 10: CLINICAL LABORATORY TESTS........................................................................................... 85 
 
 
 
 
 
 
 
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1. 
SYNOPSIS 
Name of Sponsor/Company 
Janssen Research & Development*/Janssen Latin America 
Name of Product  
 
Canagliflozin (JNJ-28431754) 
 
 
*Janssen Research & Development is a global organization that operates through different legal  
 
 
entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research  
 
 
& Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen  
 
 
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen  
 
 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used  
 
 
throughout the protocol to represent these various legal entities; the sponsor is identified on the  
 
 
Contact Information page that accompanies the protocol. 
 
Status:  
Approved 
Date:  
 
31 July 2017 
Prepared by:  
Janssen Research & Development/Janssen Latin America 
Protocol No: 
28431754DIA4026 
Title of Study: 
Canagliflozin Continuous Glucose Monitoring (CANA CGM) Trial: A Pilot Randomized, Double-
Blind, Controlled, Crossover Study on the Effects of the SGLT-2 Inhibitor (vs. the DPP-4 Inhibitor Sitagliptin) on 
Glucose Variability in Mexican Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Metformin 
 
NCT No.: TBD 
Clinical Registry No.: TBD 
Coordinating Investigator: Fernando Javier Lavalle-González, MD, Facultad de Medicina de la Universidad 
Autónoma de Nuevo León, Madero y Dr. Aguirre Pequeño, Col. Mitras Centro sin número 
 Mexico 
 Tel: 
  
 
Study Centers: A total of five study centers in Mexico 
 
Publication (Reference): None 
 
Study Period (See Figure 1 and Table 4.)  
 
Total =  97 days  
Prestudy: 16 days:  including prescreening period (6 days), screening period (3 days) and selection period (7 days) 
Two active treatments: each 28 days (56 days) 
Washout (with ongoing metformin): 16 days 
Post-study follow-up: 9 days  
Each visit day is surrounded by a ± 3-day scheduling window.  
Visit 1 = Optional prescreening: Day −16. 
Visit 2 = Screening: Day −10. 
Visit 3 = Selection/CGM qualification: Days −7 to −1, including 6 days of CGM monitoring, from Day −7 to −2 
 
study subject to perform calibration of CGM device by using glucometer. 
Visit 4 = Selection/qualification: On Day −1, if CGM data from Days −7 to −2 meet eligibility criteria, study 
 
participation is offered to patient. 
Visit 5 = Randomization: Day 0. 
Visit 6 = Initiate treatment period 1: Day 0. Dispense study medication (treatment A or B) and instructions.  
Visit 7 = CGM in: Insert CGM device for 6-day measurement (Day 22); study subject to perform calibration using 
 
glucometer during the 6 days of CGM measurement. 
Visit 8 = CGM out: Remove CGM device after 6 days and download data from CGM device, Glucometer and enter 
manually patient log information into the system (Day 27). 
Visit 9 = Treatment washout; Day 28, between treatment periods 1 and 2. Collect unused medications from 
 
treatment period 1 and perform pill count/compliance assessment (see below). Maintain ongoing 
 
metformin at stable dose. 
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Visit 10 = Treatment crossover visit: Day 44. Initiate treatment period 2. Dispense study medication (treatment B  
  
or A) and instructions (Day 44).  
Visit 11 = CGM in: Insert CGM device for 6-day measurement (Day 66); study subject to perform calibration using    
glucometer during the 6 days of CGM measurement. 
Visit 12 = CGM out: Remove CGM device after 6 days and download data from CGM device, Glucometer and enter 
manually patient log information into the system (Day 71). 
Visit 13 = End-treatment follow-up visit: Day 72. Collect unused medications from treatment period 2 and  
 
perform pill count/compliance assessment (see below). Allow for up to 9 days (to final Day, 80) to 
 
follow and resolve any safety or tolerability issues. Maintain ongoing metformin at stable dose. 
 
Phase of Development: Post-market 
 
Objectives: This trial is designed to compare the effects on glycemic variability (GV) of the sodium-glucose co-
transporter-2 (SGLT-2) inhibitor canagliflozin and the dipeptidyl dipeptidase-4 inhibitor sitagliptin when administered 
to Mexican subjects with type 2 diabetes mellitus (T2DM) who had inadequate glucose control on stable dosages of 
the biguanide metformin. The primary objective is to assess the effects of 4 weeks each of daily treatment with 
canagliflozin 300 mg versus sitagliptin 100 mg as treatment adjuncts to metformin (at stable dosages) on intrapatient 
glycemic coefficient of variation (CV), expressed as a ratio (%) of standard deviation (SD) to mean glucose levels. 
 
Secondary efficacy objectives are to assess the effects of 4 weeks each of daily treatment with canagliflozin 300 mg 
versus sitagliptin 100 mg as add-ons to metformin (at stable dosages) on mean (SD) changes from baseline in: 
 
• 
Glycemic SD for 24-hour glucose (mg/dL) 
• 
Mean 24-hour glucose profile ( mg/dL) 
• 
Preprandial glucose (fasting PG; mg/dL) 
• 
2-hour postprandial glucose (PPG; mg/dL)  
• 
Time (minutes), percent of 24 hours, or area under the PG time curve for 24 hours (AUC24h) with glucose = 
70−139 mg/dL (time spent in target range)  
• 
Time (minutes), percent of 24 hours, or AUC24h (mg/dL/hr) with glucose > 140 mg/dL (time above target 
range) 
• 
Time (minutes), percent of 24 hours, or AUC24h (mg/dL/hr) with glucose > 180 mg/dL (time spent markedly 
above target range)  
• 
Time (minutes), percent of 24 hours, or area over the PG time curve for 24 hours (AOC24h ; mg/dL/hr) with 
glucose < 70 mg/dL (time spent below target range)  
• 
Frequency (%) of 2+ consecutive glucose readings < 70 mg/dL (and/or of hypoglycemic symptoms requiring 
personal support) 
 
Exploratory efficacy objectives are to probe the effects of 4 weeks each of daily treatment with canagliflozin 300 mg 
versus sitagliptin 100 mg as add-ons to metformin (at stable dosages) on mean (SD) changes from baseline in: 
 
• 
AUC for glycemic variability (mg/dL/hr) throughout the day (0−24 hours), after breakfast (0−5 hours), after 
lunch (5−11 hours), after dinner (11−15 hours), and during sleep (15−24 hours). 
• 
Peak glucose (mg/dL) throughout the day (0−24 hours), after breakfast (0−5 hours), after lunch (5−11 hours), 
after dinner (11−15 hours), and during sleep (15−24 hours). 
• 
Overall hyperglycemia: AUCtotal (mg/dL/hr). 
• 
Nadir glucose (mg/dL): lowest glucose level over 72 hours. 
• 
Continuous overlapping net glycemic action (CONGA): the SD of summed differences between observations 
separated by n hours. 
• 
Mean of daily differences in PG (MODD). 
 
Further objectives are to assess the tolerability profile of each active treatment according to incidences (subjects and 
number of events) of treatment-emergent adverse events and the safety profile according to incidences of abnormal 
vital signs, 12-lead electrocardiograms (ECG), and clinical laboratory panels.  
Methodology: This is a randomized, double-blind, actively controlled, crossover, post-market, multicenter (all 4 study 
sites within Mexico) study to evaluate the efficacy, safety, and tolerability of the addition of canagliflozin 300 mg or 
sitagliptin 100 mg (each once-daily by mouth), for 4 weeks each, to metformin at stable dosages in Mexican subjects 
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with T2DM who have inadequate glycemic control (i.e. hemoglobin A1c 7.5%−10.5%) while receiving metformin 
monotherapy at the prescreening (Visit 1 – optional) or screenining visit (Visit 2). 
It is planned that approximately 60 subjects (≥18 years of age) with T2DM and inadequate glycemic control on 
metformin at screening will be randomly allocated in a 1:1 ratio (for treatment, period, and sequence) to two 4-week 
double-blind, actively controlled treatment phases with once-daily canagliflozin 300 mg or sitagliptin 100 mg added 
to ongoing metformin. Subjects are randomized to a sequence of either A/B (e.g. canagliflozin followed by sitagliptin) 
or B/A (vice versa). Metformin treatment at stable dosages will be administered during not only each active-treatment 
period but also a 16-day canagliflozin-sitagliptin washout interval between them. Randomization is stratified by 
gender-specific baseline body mass index tertile. The maximum total study duration for subjects who do not withdraw 
consent or otherwise discontinue is 97 days, including 1) a prestudy screening phase of 16 days (including an optional 
pre-screening   phase of  6 days,  a screening phase of 3 days, a selection phase of 7 days  and a randomization phase) 
; 2) 28 days for each active treatment phase; 3) 16 days for the washout phase (with ongoing metformin monotherapy); 
and 4) 9 days for follow-up after the final day of the second active treatment.  A ±3-day window around each study 
date is permitted to enable individual-subject scheduling of visits.  
During the screening period, potential subjects will wear the CGM device continuously for 6 days, an assessment of 
eligibility, as determined by a trained external monitor, will be made based on adherence to CGM requirements and 
successful CGM readings for ≥3 consecutive days (each day counted from hour 0 to hour 24) within the 6 days of  the 
selection phase. A successful CGM reading is defined as a value that does not have (within 1 day) a continuous 
interruption of >120 minutes in any postprandial interval or a continuous interruption of >180 minutes during a 
nocturnal/sleep interval. 
Diagnosis and Main Criteria for Inclusion: Men and women at least 18 years of age with a documented medical 
history of T2DM who meet the following (minimum) criteria at screening: 
• 
Inadequate glucose control while using MET monotherapy for at least 8 weeks at stable daily doses of at 
least 1,500 mg   
• 
Hemoglobin A1c of 7.5% through 10.5% 
• 
Estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2  
• 
Body mass index of 22 through 45 kg/m2  
 
Excluded from participation were patients with a history of any of the following at screening: 
• 
Diabetic ketoacidosis (DKA) 
• 
Type 1 diabetes mellitus (T1DM) 
• 
Pancreatic (e.g. β-islet cell) transplantation 
• 
Diabetes secondary to pancreatitis or pancreatectomy  
• 
Individual history of (or present) pancreatitis 
• 
One or more episodes of severe hypoglycemia (requiring assistance from others), as documented in the 
history obtained at Visit 1 
• 
Hereditary glucose-galactose malabsorption or primary renal glucosuria. 
• 
Repeated FPG or fasting self-monitored blood glucose (SMBG) > 270 mg/dL during the pretreatment phase 
• 
Treatment with parenteral antidiabetic medications (e.g. insulins). 
• 
Current use of “Natural medicines” or natural medicinal products for diabetes (e.g. cactus-derived nutrients, 
celery). 
• 
Unsuccessful initial CGM reading as indicated by a continuous interruption of >120 minutes in any 
postprandial interval, or a continuous interruption of >180 minutes in a nocturnal/sleep interval, over 3 
consecutive days (each day counted from hour 0 to hour 24 ) within the 6 days of  the selection phase 
 
Test Product, Dose and Mode of Administration: Canagliflozin tablets containing 300 mg for oral administration. 
[Batch No. TBD] 
Reference Therapy, Dose and Mode of Administration: Matching (blinded) sitagliptin phosphate tablets containing 
100 mg for oral administration. [Batch No. TBD] 
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Duration of Treatment: As shown in Figure 1 and as summarized above (page 7), the total duration of each subject's 
study participation is approximately 14 weeks  and will not exceed 97 days, including a 17-day prestudy period. 
Around each visit day was a ±3-day visit scheduling window. The study consisted of an optional 6-day prescreening 
phase, a 3-day screening phase, and a 7-day selection period (all on metformin alone). This prestudy phase was 
followed by randomization on Day 0; two 4-week (28-day) active-treatment phases separated from each other by a 
16-day washout of active treatments (with continued metformin monotherapy); and a 9-day end-treatment follow-up 
phase. 
Evaluations: Efficacy evaluations will include continuous-glucose-monitoring (CGM) parameters, which are 
measured over 6-day periods, in order to obtain a continuous 72-hour reading (valid hours of measurement is hour 0 
12:00 am to hour 72 which is 12:00 am after 3 days of continuous reading), at the end of the selection phase (Days −7 
to −1) and each active treatment (Days 22−27 at the end of treatment period 1 and Days 66−71 at the end of treatment 
period 2). These parameters include intrapatient glucose CV %, glycemic SD, 24-hour glycemia, 2-hour PPG, and 
percent of time (or area-under-the time concentration curve) spent within, above, or below the reference range for 
glucose, including frequencies of hypoglycemia. During each CGM interval, subjects will maintain diaries (log sheets) 
of nutrition, physical activity, and clinical symptoms, medication, and capillary blood glucose readings.   
Safety evaluations include physical examinations, vital signs, 12-lead electrocardiograms, and clinical laboratory tests 
at screening and the end-of-study visits. Heart rate, blood pressure, and body weight will be measured at each visit. 
Statistical Methods: 
Sample Size Determination: The effects of canagliflozin and sitagliptin on glycemic variability have never been 
assessed in a head-to-head study involving continuous glucose monitoring. However, effects on overall glycemia were 
compared in the Canagliflozin Treatment and Trial Analysis−DPP-4 Inhibitor Comparator Trial (CANTATA-D) trial. 
The mean (SD) difference in estimated average glucose between groups was 11.11 (26.28) mg/dL. According to a 
two-sided α = 0.05 and a power of 80%, a total of 46 subjects with paired data are needed to detect a mean (SD) 
difference of 11.11 (16.28) mg/dL between canagliflozin 300 mg and sitagliptin 100 mg as assessed by paired Student 
t-tests. Using a conservative subject attrition rate of 30% for an approximately 12-week study, the required sample 
size for this crossover trial is 46 + 13.8 = 60 subjects, each randomly allocated in a double-blind manner to two 
treatments, two periods, and two sequences involving canagliflozin 300 mg compared to sitagliptin 100 mg as add-
ons to metformin in T2DM subjects with glucose inadequately controlled on the biguanide as monotherapy who meet 
all eligibility criteria. 
 
Subjects will be randomized 1:1 to each treatment sequence. The CANTATA-D study found that treatment with 
canagliflozin 300 mg was associated with a 2.1% to 2.9% reduction in body weight compared to sitagliptin 100 mg 
when each was added to ongoing metformin over 52 weeks (Lavalle-Gonzalez et al., 2013a; Lavalle-Gonzalez et al., 
2016). The net reduction with canagliflozin 300 mg at 4 to 6 weeks was approximately 1.0% to 1.5%.  Nevertheless, 
it is possible that, once subjects lose weight while randomized to canagliflozin 300 mg, they will become more 
physically active. To minimize the effects of this potentially important covariate with relation to GV, randomization 
will be stratified according to gender-specific tertiles of body mass index (BMI) (Kriska et al., 2003). For men, tertile 
1 ranges from 17 to <28; 2, from 28 to <33; and 3 from 33 to <66, kg/m2. For women, tertile 1 ranges from 16 to <30; 
2, from 30 to <36; and 3, from 36 to <69 kg/m2. Because the eligibility criteria in this trial require a range of BMI = 
22 to 45 kg/m2 for study entry, the tertiles are redefined as follows. For men, tertile 1 ranges from 22 to <28; 2, from 
28 to <33; and 3 from 33 to <45, kg/m2. For women, tertile 1 ranges from 22 to <30; 2, from 30 to <36; and 3, from 
36 to <45 kg/m2. This stratified randomization method will control for any influence of the covariate of baseline BMI 
(surrogate for body weight).  
 
Efficacy: Three null hypotheses (NH) will be tested. 
H0A: There is no statistically significant difference between CANA 300 mg and SITA 100 mg in terms of 
their effects on mean intrapatient glucose CV % as measured by CGM over a 3-day period at baseline and 
after each active treatment. 
H1A [Alternative hypothesis (AH)]: There is a statistically significant difference between CANA 300 mg and 
SITA 100 mg in terms of their effects on mean intrapatientglucose CV % as measured by CGM over a 3-day 
period at baseline and after each active treatment. 
H0B: There is no statistically significant difference between CANA 300 mg and SITA 100 mg in terms of 
their effects on mean intrapatient glycemic SD for 24-hour glucose profiles from baseline as measured by 
CGM over a 3-day period at baseline and after each active treatment. 
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H1B: There is a statistically significant difference between CANA 300 mg and SITA 100 mg in terms of their 
effects on mean intrapatient glycemic SD for 24-hour glucose profiles from baseline as measured by CGM 
over a 3-day period at baseline and after each active treatment. 
H0C: There is no statistically significant difference between CANA 300 mg and SITA 100 mg in terms of 
their effects on mean 24-hour glucose profiles from baseline as measured by CGM over a 3-day period at 
baseline and after each active treatment. 
H1C: There is a statistically significant difference between CANA 300 mg and SITA 100 mg in terms of their 
effects on mean 24-hour glucose profiles from baseline as measured by CGM over a 3-day period at baseline 
and after each active treatment. 
 
 
Descriptive statistics will be presented as mean (SD) for normally distributed continuous variables, median 
[interquartile range (IQR)] for non-normally distributed continuous variables, and numbers (%) for categorical 
variables. Baseline sociodemographic and other characteristics will be compared using Fisher’s Exact test for 
categorical variables and Student’s t-test for normally distributed continuous variables. 
  
The primary efficacy analyses will be conducted in the intent-to-treat (ITT) population: subjects who received at least 
one dose of medication and had CGM recordings at baseline and after each active treatment (i.e. >70% of tracings 
available). A secondary analysis will be conducted in the per-protocol population: members of the ITT population 
who completed the study without major protocol violations. Although a previous randomized controlled trial 
compared effects of another SGLT-2 inhibitor (and also open-label sitagliptin 100 mg) using a modified last 
observation carried forward approach (with linear interpolation) to missing data(Rosenstock et al., 2013), data will 
not be imputed in the present study, which has a limited number of visits (six) and duration (80 days). 
 
As in a previous CGM study, the distribution of each glycemic indicator (except for SD; see below), as well as body 
weight, will be assessed for normality via the Shapiro-Wilk test (Nomura et al., 2011). For normally distributed data, 
the mean (SD) value will be presented and, for non-normally distributed data, the median and IQR. Most between-
treatment differences will be assessed using a paired Fisher’s Exact test for baseline categorical variables and paired 
t-tests or Wilcoxon signed rank sum tests for normally and non-normally distributed continuous efficacy endpoints 
(respectively), according to the Shapiro-Wilk test results. 
 
Also paralleling a previous CGM study involving sitagliptin 100 mg, data for analyses of the CANA CGM Trial's 
secondary endpoints related to AUC24hr (and AOC24hr for hypoglycemia) will be included per subject only if >70% of 
his or her CGM readings are available during each assessment period (3-day CGM at the end of the baseline and each 
of two treatment intervals); and AUC values will be adjusted for preprandial (FPB) readings (Ellis et al., 2011). Some 
of these variables (e.g. percentage of time with PG in different ranges) are known to be non-normally distributed and, 
as in previous CGM studies, will be evaluated using paired Wilcoxon rank sum tests on median and IQR values 
(Nomura et al., 2011; Nishimura et al., 2015).  
 
Body weight will be measured at each visit. In the event of a significant mean (SD) [or median (IQR)] difference in 
change from baseline in body weight or physical activity between canagliflozin 300 mg and sitagliptin 100 mg 
(according to a statistical assessment informed by the Shapiro-Wilk test), a statistical approach similar to that of a 
prior SGLT-2 (vs. SITA) trial will be taken (Rosenstock et al., 2013); namely, a sensitivity analysis using either: 1) a 
repeated-measures mixed-effect model with baseline CGM values as fixed effects and on-treatment body weight and 
subject as random effects; or 2) an analysis of covariance with visit-wise body weights and physical activity as 
covariates.  
 
To evaluate carry-over effects, Grizzle’s two-stage model will be employed to statistically test for treatment x period 
interactions (Shen, 2006). In the event of a significant carryover effect, the methodology enables comparison of the 
effects of CANA 300 mg versus SITA 100 mg on parameters of GV in one of the two treatment periods. 
All tests will be conducted at a two-sided α = 0.05 (i.e. a priori significance level of p < 0.05). 
 
Safety: Subjects receiving at least one dose of active treatment will comprise the safety population. Safety will be 
assessed according to mean values for vital signs (pulse rate, blood pressure, respiration rate, body temperature),  
12-lead ECGs, and clinical laboratory assessments at the screening and end-of-study visits in this population: baseline 
safety assessments may occur at Visit 1 (Day −16 to −11; prescreening [optional]) or Visit 2 (Day −10 to −8; screening) 
and the end-of-study visit occurs at Visit 13 (Day 72 to 80 after randomization).  Heart rate and blood pressure will 
be measured at each visit, as detailed in Appendix 5. Incidences of abnormal safety evaluations will be based on 
predefined, local reference ranges and each Investigator's customary clinical practice. Adverse events will be elicited 
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by open-ended questioning at each visit post ICF signature and also coded as to system organ class, and preferred term 
using Medical Dictionary of Regulatory Activities (MedDRA) version 14 (or higher). Safety will be further assessed 
according to incidences of SAEs, AEs leading to treatment discontinuation, and serious drug-related AEs.   
2. 
INTRODUCTION 
Diabetes is a major, burgeoning public-health challenge for Latin American societies. Numbers of patients with 
diabetes in this region are projected to increase from about 13 million in 2000 to 33 million in 2030 (Wild et al., 2004). 
The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study reported that the 
prevalence of type 2 diabetes mellitus (T2DM) was 7.0% (Escobedo et al., 2009). Mexico has among the highest 
prevalences of diabetes around the world (14.4%). Annual direct and indirect costs associated with this chronic 
disorder in Mexico have been estimated at US$15 billion (Guzman et al., 2010; Villalpando et al., 2010). 
 
Evidence from the Diabetes En America Latina (DEAL) study suggests that management of T2DM is less than optimal 
among primary-care practitioners in Latin America (Stewart et al., 2007).  Across nine countries, poor glucose control, 
as evidenced by a fasting plasma glucose (FPG) ≥ 110 mg/dL was reported in 78%, and HbA1c < 7.0% in 43.2%, of 
Latin American adults. In Mexico, only about 30% of adults had HbA1c below the 7.0% HbA1c cut point often 
identified as a treatment target (Stewart et al., 2007).   
 
Regional consensus guidelines for T2DM management in Latin America were formulated before SGLT-2 inhibitors 
became widely available (Guzman et al., 2010). Consensus practice guidelines issued by other health authorities, such 
as the US American Diabetes Association (ADA), do not clearly specify which second-line medication to add in the 
event of inadequate T2DM management after lifestyle counseling and treatment with the biguanide metformin (MET) 
(American Diabetes Association, 2016). 
 
According to the most recent guidelines from ADA, practitioners should consider combining one of six potential 
treatments with MET if the HbA1c target is not met within about 3 months: a sulfonylurea, thiazolidinedione, SLGT2 
inhibitor, DPP-4 inhibitor, glucagon-like peptide-1 receptor agonist (GLP-1RA), or basal insulin. However, there is a 
paucity of evidence from active-comparator trials to inform the selection of one therapy over another. According to 
the ADA guidance, "there are numerous trials comparing dual therapy with [MET] alone, [but] few directly compare 
drugs as add-on therapy [to MET]." As potential criteria to determine which of the six therapies to add in the event of 
inadequate glucose control on behavioral modification and MET, the ADA lists patient preferences, disease and drug 
characteristics, as well as psychosocial, health-economic, and clinical factors (American Diabetes Association, 2016).  
 
One such clinical factor is glycemic variability (GV), which is not captured by HbA1c; the latter variable indicates 
average glucose over a 1- to 2-month interval (Koenig et al., 1976). HbA1c only partially captures acute glycemic 
fluctuations from nadir (interprandial) to peak (postprandial) (Monnier and Colette, 2008; Di Flaviani A. et al., 2011). 
On a clinical level, the Diabetes Control and Complications Trial (DCCT) demonstrated that increases in HbA1c 
accounted for only 11% of the variance in diabetic retinopathy (Lachin et al., 2008). 
 
In recent years, the biological consequences of within-day and day-to-day fluctuations in glucose profiles have come 
into increasingly greater focus (Kilpatrick, 2009; Nalysnyk et al., 2010; Hu et al., 2010; Di Flaviani A. et al., 2011; 
Tylee and Trence 2012; Lin et al., 2014; Xixiang et al., 2014).  In short, oscillations in daily glucose profiles may play 
a pathogenic role in the development of diabetic complications beyond mean elevations in average plasma glucose 
(PG) or HbA1c (The Diabetes Control and Complications Trial Research Group, 1997; Hirsch and Brownlee, 2005; 
Brownlee and Hirsch, 2006; Di Flaviani A. et al., 2011). 
 
Such variability may adversely affect endothelial function and oxidative stress, potentially raising both macrovascular 
(cardiovascular) and microvascular (including peripheral neuropathy) disease risk (Hirsch and Brownlee, 2005; 
Ceriello, 2005; Monnier et al., 2006; Ceriello et al., 2008; Bragd et al., 2008; Monnier et al., 2008; Buscemi et al., 
2010; Kohnert et al., 2012; Ogawa et al., 2012; Saisho, 2014). Intermittently elevated glucose may contribute to 
worsening dysregulation of adipokine (adiponectin, resistin) production, also potentially via oxidative mechanisms 
(Sun et al., 2010). One surrogate marker of evolving cerebral atherosclerosis is the change in carotid-artery intima-
media thickness (IMT). In a clinical trial involving DPP-4 inhibition, reductions in daily glucose excursions, but not 
in chronic hyperglycemia, were associated with declines in carotid IMT (Barbieri et al., 2013). 
  
There are other potential clinical ramifications of instability in daily glucose profiles among patients with T2DM 
(Praet et al., 2006). Clinical trials have demonstrated associations between GV and reduced postprandial β-cell 
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function, increased incidences of hypoglycemia (in patients with T1DM and T2DM) diabetic complications, and 
clinical endpoints such as all-cause mortality, mortality during intensive care (even in patients without diabetes), 
diabetes-specific mortality (and morbidity), cardiovascular-specific mortality, and ischemic stroke (Muggeo et al., 
1995;Muggeo et al., 2000; Kohnert et al., 2009; Nalysnyk et al., 2010; Takao et al., 2010; Krinsley, 2010; Hermanides 
et al., 2010; Lin et al., 2012; Devries, 2013; Lin et al., 2014). 
 
In addition to these findings, increased GV has been independently associated with diminished health-related quality 
of life and sense of well-being (Penckofer et al., 2012).  In patients with T1DM, hyperglycemia has been related to 
increased levels of tension and anger (Hermanns et al., 2007).  In addition, fear of hypoglycemia among both patients 
and physicians comprises a treatment barrier that can erode patient adherence and discourage physicians from 
intensifying regimens (i.e. "clinical inertia"), further compromising the effectiveness of care (Cryer, 2008; Avignon 
et al., 2012; Lovshin and Zinman, 2013; Strain et al., 2014). 
 
 
The use of self-measured blood glucose (or CGM) can reduce GV and, conversely, enhance glucose control (reducing 
the risk of hyperglycemia and hypoglycemia) as well as potentially reducing patient and physician concerns about 
experiencing (or causing) hypoglycemia and/or intensifying regimens (DeBlock C. et al., 2008; Reach, 2008; Rodbard 
et al., 2009; Kohnert et al., 2012). Clinical trials have demonstrated that the use of CGM was associated with 
significant reductions in markers of systemic inflammation and oxidative stress (Rizzo et al., 2012). 
 
3. 
OBJECTIVES 
The chief aim of this trial is to compare the effects of 4 weeks each of CANA 300 mg versus SITA 100 mg  as add-
on to metformin at stable dose on glycemic variability (GV; as measured using CGM), when each agent is added to 
MET at stable dosages in Mexican patients with T2DM and inadequate glucose control on MET monotherapy. The 
primary efficacy outcome measure is the intrapatient coefficient of variation of mean intrapatient CV (SD/mean FPG). 
Other central study purposes include comparisons between the effects of these adjunctive treatments on changes from 
baseline in: 
 
1. Mean (SD) 24-hour glucose levels  
2. Mean (SD) preprandial glucose [fasting plasma glucose (FPG)] 
3. Mean (SD) 2-hour postprandial glucose (PPG) 
4. Time, percent of time, or AUC24hr (or AOC24hr for hypoglycemia) with glucose in euglycemic, 
hyperglycemic, and hypoglycemic ranges. 
    A further objective is to evaluate the safety and tolerability profile of active treatments. 
 
4. 
METHODS  
4.1. 
Study Design 
This multi-center (4-center), 2 x 2 randomized, double-blind, actively controlled crossover study randomly allocates 
patients with T2DM and inadequate glucose control on metformin (MET) monotherapy at stable doses (≥1500 
mg/day) to oral once-daily treatment with canagliflozin 300 mg (CANA) or the dipeptidyl peptidase 4 (DPP-4) 
inhibitor sitagliptin phosphate 100 mg (SITA) once daily added to metformin (MET) at stable doses for 28 days, with 
a 16-day MET monotherapy washout. The interval between the first and last dose of randomized adjunctive treatment 
is hence 72 days. Given a 16-day prestudy interval (6-day optional prescreening; 3-day screening; 7-day selection) 
and a post-treatment follow-up period of up to 9 days, the maximum study duration for each subject who tolerates 
medications and does not withdraw consent or otherwise discontinue is thus 97 days. Each of these visits is surrounded 
by a ±3-day window to enable individual-subject scheduling. Patients are randomized in a double-blind manner to 
treatment, period, and sequence. 
Figure 1 depicts the design of this multi-center (4-center), 2 x 2 x 2 (2 sequences, periods, and treatments) double-
blind, actively controlled crossover study. 
 
 
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Figure 1. 
Study design schema and timeline for the CANA CGM trial.  Because the prescreening visit is optional, 
Visit 1 can be the same as Visit 2. Study medications and instructions are dispensed at Visits 6 (Day 1; 
treatment period 1) and 10 (Day 44; treatment period 2); the CGM device is inserted at Visits 7 (Day 
22; treatment period 1) and 11 (Day 66; treatment period 2) and removed (with downloading of data) 
at Visits 8 (Day 27; treatment period 1) and 12 (Day 71; treatment period 2), after 6 days of CGM 
measurements. Visit 9 is the washout visit and occurs on Day 28 (between the two treatment periods).  
Visit 13 is the end-treatment follow-up visit and occurs on Days 72 to 80.  
______________________________________________________________________________ 
4.1.1 
Concise Summary of Procedures According to Visit and Subject (or Potential Subject), 
Investigator, and Study Site Personnel Responsibility 
Following are key instructions for the investigator or other appropriately trained and authorized study site personnel. 
The guidance is expressed in greater detail in Section 5.4 of this document.  
4.1.1.1 Optional Prescreening (Visit 1; Day −16 to −11 [with a ±3-day scheduling window]) 
 Potential subject's responsibilities: 
o 
Sign an Informed Consent Form (ICF) with 2 witnesses before participating in any protocol procedure 
(including assessment) after having the risks and benefits of protocol participating explained to you. If 
you do not understand these risks and benefits, ask the investigator or study site personnel to clarify them 
before signing the ICF.  
 
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o 
Meet with the investigator and answer his or her questions, including items about your current health 
status, medical history, and current medications. To participate in the study, you must be taking metformin 
at a stable dose for at least 8 weeks.  
 
 Investigator's responsibilities: 
o 
Before any protocol procedure, including any assessment, discuss with the subject the potential benefits 
and risks of participation in the study. Obtain his or her written informed consent by distributing the study 
ICF and document this process within the medical charts.  If needed, potential subjects have the right to 
an interpreter or to have the study explained orally and provide oral assent. 
 
o 
Baseline safety assessments can occur at this visit or the Screening Visit (Day −10; see below) 
 
o 
Measure vital signs: pulse rate, blood pressure (according to blood pressure measurement instructions in 
Appendix 5); pulse rate (Pulse rate will be measured once at each clinic visit) and blood pressure 
measurements and will be obtained after the subject has been in the sitting position for 5 minutes.  Three 
consecutive blood pressure readings will be taken and recorded, at intervals of at least 1 minute apart. 
Respiration rate and body temperature. Perform12-lead ECG. Measure blood pressure according to 
instructions in Appendix 5.  Document the data in the CRF and within the medical chart. 
 
o 
Perform (submit to central laboratory) fasting laboratory panels, including serum chemistries and 
hematology. If the baseline laboratory and other requirements meet qualifications, proceed to the selection 
(qualifying-CGM) phase. Document the data in the CRF and within the medical chart (appendix 10). 
 
o 
If the entire safety profile is not obtained (as above) measure pulse rate and blood pressure and record 
those in the CRF (measure blood pressure according to instructions in Appendix 5).  
 
o 
Measure body weight (in part because randomization is stratified by body mass index [BMI]). Body 
weight will be measured (at every visit) using the same calibrated and certified scale at each visit. Subjects 
will be weighed at approximately the same time of day on the same scale (with the subject wearing 
underwear and gown but no shoes). Subjects will be instructed to empty their bladder before being 
weighed. Document the data in the CRF and within the medical chart. 
 
o 
Through dialogue with the patient (interview), review the eligibility criteria. (See above, "Diagnosis and 
Main Criteria for Inclusion" [pp 7-8].) And document it within the medical charts.  
 
o 
Urine pregnancy testing will be performed for all women according to local procedures unless they are 
surgically sterile or unless there is a documented history of their postmenopausal status. Additional serum 
or urine pregnancy tests may be conducted throughout the study in sufficient number, as determined by 
the investigator or required by local regulations, to establish the absence of pregnancy during the study. 
Pregnancy test must be performed in Central laboratory and the result reviewed prior to randomization 
(appendix 10). 
 
o If the subject meets all eligibility criteria (aside from the CGM and laboratory requirements below), 
proceed to the screening period. 
 
 Study site personnel's responsibilities: 
o 
Make sure that the potential subject has signed the ICF and that it is properly filed.  
 
o 
If the subject meets all eligibility criteria (aside from the CGM requirement), request the potential 
subject's contact information, in order to arrange future study site visits. 
 
In the case that the site opts not to have the optional pre-screening visit, the site and patient will conduct this 
phase activities during Visit 2 (screening visit). 
 
4.1.1.2 Screening (Visit 2; Day −10 to −8 [with a ±3-day scheduling window]) 
 Potential subject's responsibilities: 
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o 
Attend the study site for assessments. 
 Investigator's responsibilities: 
o 
Perform a physical examination if not conducted at Visit 1 (optional prescreening) Physical examinations 
will include a full review of body systems (head and neck, eyes, chest and lungs, breast, cardiovascular 
(CV), extremities and back, abdomen, and neurologic examination). A pelvic/genitourinary system 
examination (ie, prostate, rectal, and gynecologic examinations) should be performed if considered 
clinically appropriate by the investigator. Whenever possible, the assessments should be made at the same 
time of day by the same investigator for each subject.  Measure vital signs: pulse rate, blood pressure 
(according to blood pressure measurement instructions in Appendix 5); pulse rate (Pulse rate will be 
measured once at each clinic visit ) and blood pressure measurements and will be obtained after the subject 
has been in the sitting position for 5 minutes and before taking blood samples.  Three consecutive blood 
pressure readings will be taken and recorded, at intervals of at least 1 minute apart. Respiration rate and 
body temperature. Perform12-lead ECG. Measure blood pressure according to instructions in Appendix 
5.  Document the data in the CRF and within the medical chart. 
 
o 
If not conducted at Visit 1 (optional prescreening) perform (submit to central laboratory) fasting 
laboratory panels, including serum chemistries and hematology (Subjects must fast for at least 8 hours 
before blood sample collection). If the baseline laboratory and other requirements meet qualifications, 
proceed to the selection (qualifying-CGM) phase (appendix 10).  
 
o 
If the entire safety profile was obtained (as above) during the optional prescreening visit, measure only 
pulse rate and blood pressure and record them in the CRF and within the medical chart.  
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document the data in the CRF and within the medical chart. 
 
o 
If not conducted at Visit 1 (optional prescreening) urine pregnancy testing will be performed for all 
women according to local procedures unless they are surgically sterile or unless there is a documented 
history of their postmenopausal status. Additional serum or urine pregnancy tests may be conducted 
throughout the study in sufficient number, as determined by the investigator or required by local 
regulations, to establish the absence of pregnancy during the study. Pregnancy test must be performed in 
Central laboratory and the result reviewed prior to randomization (appendix 10). 
 
 Study site personnel's responsibilities: 
o 
Take blood sample(s) for fasting laboratory panels, label and process samples, and inform the central 
laboratory to arrange for sample pick up. 
 
o 
Ensure that safety data have been recorded in the medical chart. 
 
o 
Ensure that the potential subject's laboratory samples have been collected by the local laboratory for 
analysis. 
 
o 
Advise the potential subject that study site personnel will contact him or her if the baseline laboratory 
results qualify for the next phase (selection). 
 
o 
Contact the potential subject on Day −8 if the baseline laboratory results qualify him or her for the next 
phase (selection).  
 
4.1.1.3 Selection (Visit 3; Day −7 to −1 [with a ±3-day scheduling window] and visit 4; day -2) 
This will be the potential subject's first experience using the CGM device. Following are the key steps, according to 
the responsibilities of the potential subject, investigator, and other appropriately qualified and trained study site 
personnel.   
 
 Potential subject's responsibilities: 
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o 
Wear the CGM iPro2 continuously for 6 days while following normal daily activities (see Appendix 7C). 
 
o 
On Day 1, calibrate the device using the One Touch UltraMini™ (See instructions in Appendix 6.) by 
doing the following:  After the CGM iPro2 has been inserted (on the same day of insertion), measure your 
plasma glucose 3 times with the glucometer One Touch Ultra Mini ™: 1 hour after insertion, 2 hours after 
insertion, and once before bedtime, on the day of insertion (Appendix 6) and write down the results of 
these measurements in the Patient Log Sheet (Appendix 8).  
 
o 
Use the same glucose meter and lot of strips for the entire study. Do not allow anyone else to use the 
glucose meter during the study. 
 
o 
On each of the other 5 days of the selection phase (day 2, 3, 4, 5 and 6 of measurement), measure your 
plasma glucose with the glucometer One Touch Ultra Mini ™ 4 times a day: after you awake from sleep 
and after each of your 3 daily meals.  Write down the results of each of these measurements in the Patient 
Log Sheet (Appendix 8) 
 
o 
Receive the pedometer and learn how to use it. 
 
o 
Receive the Glucometer and strips, making sure you understand how to use the glucometer appropriately 
(Appendix 6) during the different days of CGM readings (Appendix 7C). 
 
o 
Receive instructions from the investigator and study site personnel regarding the use of the Patient Log 
Sheet (Appendix 8) and make sure that you understand it before leaving the clinic during your visit to the 
study investigator/personnel. 
 
o 
Use the Patient Log Sheet (Appendix 8) to record what you eat at each meal; any exercise or strenuous 
activities and the times when these occur; times when you take your study medications (should be soon 
after awakening from sleep), numbers of daily steps as per pedometer readings,  glucometer  capillary 
blood glucose readings and any unusual signs or symptoms that you may experience (Appendix 7A, 7C). 
These may include side effects of the medication and/or signs or symptoms of hypoglycemia. The 
symptoms of hypoglycemia include: 
 
- 
Excessive hunger, fatigue, sweating, unsteady feeling, or fainting 
 
- 
Confusion or other mental effects  
▪ 
Irritability 
▪ 
Blurred vision 
▪ 
Sense of "pins and needles" 
▪ 
Anxiety 
▪ 
Slurred speech 
▪ 
Tremor 
 
- 
Shakiness or light-headedness 
 
- 
Nausea or vomiting 
 
- 
Dry or tingling lips 
 
- 
Sense of abnormal heart beat 
 
Patient will be instructed that in the case of signs and symptoms of hypoglycemia, he or she will 
immediately consult to the nearest Emergency service or ambulance service. The information regarding 
which service will be reviewed with the site personnel. 
 
o 
Keep the Patient Log Sheet accessible at all times (Appendix 8), so that you can immediately write 
down the needed information. Write down the time and date within 5 minutes of each blood glucose 
reading. 
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o 
Bring Patient Log Sheet to visit 4 to the site and make it available for the study personnel. 
 
o 
Maintain ongoing treatment with Metformin at stable dose. 
 
 Investigator's responsibilities: 
 
o 
On visit 3, insert the CGM device (iPro2) subcutaneously in the patient's abdomen, according to 
manufacturer instructions (Day −7; Appendix 7A, 7B).  
 
o 
On visit 3, distribute and thoroughly review the Patient Log Sheet (Appendix 8) with the potential 
subject. Ensure that the individual understands the key dietary, physical-activity, number of steps by 
pedometer readings, medication and clinical-symptom information that needs to be recorded, as well as 
capillary blood glucose readings. 
 
o 
On visit 4, remove the sensor, within 24 hours of finishing the CGM reading period of 6 days, according 
to manufacturer's instructions (Day −1; Appendix 7A, 7B). 
 
o 
Manually enter all data from the Patient Log Sheet into the system on the same day that the sensor is 
removed from the patient. 
 
o 
Download data from the CGM iPro2 as well as calibration data from the One Touch Ultra Mini™ 
glucometer on the same day that the sensor is removed from the patient. Glucose measurement data for 
calibration will be recorded in the Patient Log Sheet. Therefore, in case of problems downloading 
calibration data from the One Touch Ultra Mini ™ glucometer device, the data can be entered manually 
as well (Appendix 6). 
  
o 
Send results of CGM baseline reading/CGM test to the External Monitor. The External Monitor will 
respond to each site within 24 hours of receiving the data (to confirm data acceptability and suitability 
for patient selection to participate and be enrolled/randomized). 
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated and 
certified scale at each visit. Subjects will be weighed at approximately the same time of day on the same 
scale (with the subject wearing underwear and gown but no shoes). Subjects will be instructed to empty 
their bladder before being weighed. Document the data in the CRF and within the medical chart. 
 
 Study site personnel's responsibilities: 
o 
Receive training in the use of the CGM iPro2 ( Appendix 7A), as well as the web-based program for 
data collection (CareLink iPro2) and the One Touch Ultra Mini™ glucose meter for CGM device 
calibration (Appendix 6).  
 
o 
Set the glucose meter (one Touch Ultra Mini ™) to time and date according to instructions (Appendix 
6). 
 
o 
Review the following items with the potential subject, and make sure that he/she understands each; 
answer any questions or confirm that he/she has  no questions about: 
 
- 
Using the CGM iPro2 (Appendix 7A, 7C) and the One Touch UltraMini™ to calibrate the device 
(according to manufacturer's instructions; Appendix 6).  
 
- 
Telephone numbers to call in case of questions about: 1) the study overall; 2) adverse events in 
particular (including signs and symptoms of hypoglycemia); 3) the CGM iPro2 and One Touch 
UltraMini™  (Appendix 6); and 4), including malfunctions and other mechanical issues of the 
devices 
 
- 
Complying with the Patient Log Sheet and understanding how to use it (Appendix 8). 
- 
Potential problems related to detachment of the CGM device. 
 
NCT03267576


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Approved   Date: 31 July 2017  
- 
Taking all study medications as instructed. 
 
- 
Returning to the study site, after 6 days of blood-glucose monitoring during the selection phase, 
so that the study personnel can: 1) download the CGM data and 2) review the Patient Log Sheet 
with the potential subject. 
 
o 
Advise the potential subject that study site personnel will contact him or her if the CGM results qualify 
him or her for the next phase (Randomization). 
 
o 
Contact the potential subject at least once during the 6-day CGM reading period to remind about 
Capillary blood glucose readings with the glucometer. 
 
o 
Contact the potential subject on Day −1 if the CGM results qualify him or her for the next phase 
(Randomization) and schedule next visit within the next 3 days. 
4.1.1.4 Randomization (Visit 5; Day 0 [with a ±3-day scheduling window]) 
Patients who meet overall eligibility criteria and have qualifying laboratory and CGM results will  be 
offered 
an 
opportunity to participate in the study. 
 
 Subject's responsibilities: 
o 
Report to the study site to receive: 
- 
Study medications 
- 
Assessments and instructions from the investigator and study site personnel 
 
 Investigator's responsibilities: 
o 
Review the overall purposes of the study and remind subjects to: 
 
- 
Take their study medications as instructed. 
- 
Measure their fasting plasma glucose with the glucometer One Touch Ultra Mini ™ every morning 
during the study, additional to the additional measurements during the time they will be wearing 
the CGM as instructed. 
- 
Report any AEs (that occur between clinic visits) to the central study telephone number. 
- 
Return to the study site 6 days before the end of the treatment period (Day 22; approximately 3 
weeks from the randomization visit) to receive CGM device and associated materials.  
- 
Measure pulse rate and blood pressure (according to blood pressure measurement instructions in 
Appendix 6). 
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document the data in the CRF and within the medical chart. 
 
 Study site personnel's responsibilities: 
o 
Reinforce the overall purposes of the study and remind subjects to: 
- 
Take their study medications as instructed 
- 
Report any AEs to the study telephone number 
- 
Return to the study site 6 days before the end of the treatment period to receive CGM and 
associated materials 
 
o 
Provide the central study telephone number so that the subject can report any AEs. 
4.1.1.5 Study Treatment (Visit 6; Begin treatment period A; Day 0 [with a ±3-day scheduling 
window]) 
 Subject's responsibilities: 
o 
Receive blinded treatment period A study medication and instructions.  
 
NCT03267576


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Approved   Date: 31 July 2017  
o 
Take medications (including metformin) as specified and be prepared to return to the study site for CGM 
monitoring and to return any unused medications. 
 
o 
Measure your plasma glucose with the glucometer One Touch Ultra Mini ™ every morning after you 
awake from sleep before the first meal of the day.  Write down the results of each of these measurements 
in in the log provided by the sponsor. 
 
o 
Report to the site any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl. 
 
o 
Report any AEs to the central study telephone number provided. 
 
o 
Return to the study site to receive and have inserted the CGM iPro2 and receive the glucometer One 
Touch UltraMini™ and pedometer 6 days before the end of the treatment period (Visit 7; Day 22; 
Figure 1).  
 
 Investigator's responsibilities: 
o 
Dispense study medications and instructions. 
 
o 
Measure pulse rate and blood pressure (Appendix 5).  
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document the data in the CRF or within the medical chart. 
 
o 
Address any questions or concerns from the subject or study personnel that are of a clinical nature and 
relate to the subject's continued safe and effective participation in the study. 
 
o 
If subject reports any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl, perform 
confirmatory FPG in Laboratory. 
 
 Study site personnel's responsibilities: 
o 
Instruct the patient that in the case of signs and symptoms of hypoglycemia and/or Diabetic ketoacidosis 
(DKA), he or she will immediately consult to the nearest Emergency service or ambulance service. The 
information regarding which service will be reviewed with the site personnel. 
 
o 
Contact the subject by telephone, in order to remind the subject to return to the study site at the 
appropriate time (Day 22) for the CGM visit. 
4.1.1.6      Study Treatment ("CGM In"; Visit 7; Day 22 [with a ±3-day scheduling window]) 
 Subject's responsibilities: 
o 
Return to the study site to receive the CGM iPro2 device, which will be inserted in your abdomen by 
the investigator.  
 
o 
Wear the CGM iPro2 continuously for 6 days while following normal daily activities (including taking 
your study medications) (Appendix 7C). 
 
o 
On Day 1 with the CGM (Day 22 overall), calibrate the device using the glucometer One Touch 
UltraMini™ (See instructions in Appendix 6.) (Appendix 7C):  After the CGM iPro2 has been inserted, 
measure plasma glucose 3 times with the glucometer One Touch Ultra Mini ™ : 1 hour after insertion, 
2 hours after insertion, and once before bedtime, on the day of insertion (Appendix 7A and 7C).   Write 
the result of these measurements in the Patient Log sheet (Appendix 8) 
 
o 
On each of the other 5 days of the CGM reading (day 2, 3, 4, 5 and 6 of measurement), measure your 
plasma glucose with the glucometer One Touch Ultra Mini ™ 4 times a day: after you awake from sleep 
and after each of your 3 daily meals. Record the results of each of these measurements in the Patient 
Log Sheet (Appendix8). 
NCT03267576


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Approved   Date: 31 July 2017  
 
o 
Use the same glucose meter and lot of strips for the entire study. Do not allow anyone else to use the 
glucose meter during the study. 
 
o 
Receive instructions from the investigator and study site personnel regarding the use of the Patient Log 
Sheet (Appendix 8) and make sure that you understand how to use it before leaving the clinic during 
your visit to the study investigator/personnel. 
 
o 
Receive instructions from the investigator and study site personnel regarding the use of pedometer and 
Glucometer and make sure that you understand how to use it before leaving the clinic during your visit 
to the study investigator/personnel. 
 
o 
Use the Patient Log Sheet (Appendix 8) to record: what you eat at each meal; any exercise or strenuous 
activities and the times when these occur; times when you take your study medications (should be soon 
after awakening from sleep); and any unusual signs or symptoms that you may experience, number of 
daily steps as measured by the pedometer. These may include side effects of the medication and/or signs 
or symptoms of hypoglycemia (as explained above).  
 
o 
Keep the Patient Log Sheet (Appendix 8) accessible at all times, so that you can immediately write 
down the needed information. Write down the results of the plasma glucose measurements from the 
glucometer including time and date within 5 minutes of each blood glucose reading. 
 
 Investigator's responsibilities: 
o 
On visit 7, insert the CGM (iPro2) sensor subcutaneously in the patient's abdomen, according to 
manufacturer instructions (Day −7; Appendix 7A, 7B).  
 
o 
Distribute and thoroughly review the Patient Log Sheet (Appendix 8) with the subject. Ensure that the 
individual understands the key dietary, physical-activity (including daily number of steps by pedometer 
measurements), medication, and clinical-symptom information that need to be recorded. 
 
o 
Distribute pedometer and teach the patient how to use it. 
 
o 
Distribute the Glucometer and strips, making sure the individual understand how to use it (Appendix 6) 
during the different days of CGM readings (Appendix 7C). 
 
o 
On each visit, measure pulse rate and blood pressure (according to blood pressure measurement 
instructions in Appendix 5). Record data in the CRF. 
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document data in the CRF. 
 
 Study site personnel's responsibilities: 
 
o 
Contact the subject at least once during the 6-day CGM reading period to remind about  Capillary blood 
glucose readings with the glucometer and Remind the patient of  schedule visit #8 
4.1.1.7       Study Treatment ("CGM out"; Visit 8; Day 27 [with a ±3-day scheduling window]) 
 Subject's responsibilities: 
o 
Return to the study site to have the CGM iPro2 sensor removed from your abdomen by the investigator.  
 
o 
Return with your completed Patient Log Sheets. 
 
 Investigator's responsibilities: 
o 
On visit 8, remove the CGM (iPro2) sensor from the patient's abdomen, within 24 hours of finishing the 
CGM reading period of 6 days, according to manufacturer's instructions (Appendix 7A, 7B). 
NCT03267576


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Approved   Date: 31 July 2017  
 
o 
Download data from the CGM iPro2 as well as calibration data from the One Touch Ultra Mini™ 
glucometer on the same day that the sensor is removed from the patient. Glucose measurement data for 
calibration will be recorded in the Patient Log Sheet. Therefore, in case of problems downloading 
calibration data from the One Touch Ultra Mini™ glucometer device, the data can be entered manually 
as well (Appendix 6).  
 
o 
Review data from the Patient Log Sheets with the subject.  
 
o 
Manually enter all data from the Patient Log Sheet into the CareLink iPro2 system on the same day that 
the sensor is removed from the patient. 
 
o 
Measure pulse rate and blood pressure (according to blood pressure measurement instructions in 
Appendix 5). Document data in the CRF and patient chart. 
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document data in the CRF and patient chart. 
 
 Study site personnel's responsibilities: 
o 
Remind the subject to return to the study site the next day (Day 28) to begin the washout period. 
4.1.1.8     Washout (Visit 9; Day 28 [with a ±3-day scheduling window])  
 Subject's responsibilities: 
o 
If not returned in Visit 8, return to the study site with vial containing unused study medications. 
 
o 
Return all unused medications to study site personnel (to enable compliance check). 
 
o 
Take medication as directed during washout period 
 
o 
Measure your plasma glucose with the glucometer One Touch Ultra Mini ™ every morning after you 
awake from sleep before the first meal of the day.  Write down the results of each of these measurements 
in the log provided by the sponsor. 
 
o 
Report to the site any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl. 
 
 
 Investigator's responsibilities: 
o 
Elicit any AEs from the subject via open-ended questioning. In a nonthreatening dialogue, ask the 
subject if he/she has any other ongoing questions or concerns about the study.  
 
o 
Address any questions or concerns from the subject or study personnel that are of a clinical nature and 
relate to the subject's continued safe and effective participation in the study. 
 
o 
Instruct the subject to take only metformin and no other study medications during the following 16 days.  
 
o 
Measure pulse rate and blood pressure (according to blood pressure measurement instructions in 
Appendix 5). Record data in the CRF. 
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document data in the CRF and patient chart. 
 
o 
If subject reports any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl, perform 
confirmatory FPG in Laboratory. 
NCT03267576


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Approved   Date: 31 July 2017  
 
 Study site personnel's responsibilities: 
o 
Collect all unused study medications. If no unused study medications are returned, ask the subject if he 
or she has taken all medication during the treatment period or has forgotten to return with unused 
medications.  
 
o 
Perform pill count and compliance check. Compute pill count as the number of pills taken (# of pills 
dispensed – # of pills counted). The number of pills expected to have been taken is calculated by 
multiplying the daily dose (1 tablet) by the number of days since the date dispensed (Lee JK et al. Ther 
Clin Risk Manag 2007; 3:685-90). An a-priori criterion of 80% to 120% will be applied to designate 
acceptable compliance.  
 
o 
If the subject has forgotten to return to the study site with unused study medications, schedule a follow-
up return appointment as soon as possible to collect them. 
 
o 
Instruct subject to return to the study site 16 days after the Washout visit to begin the next treatment 
period (treatment period B). 
4.1.1.9   Study Treatment (Visit 10; Begin treatment period B; Day 44 [with a ±3-day scheduling           
window]) 
 
 Subject's responsibilities: 
o 
Receive blinded treatment period B study medication and instructions.  
 
o 
Take medications (including metformin) as instructed. 
 
o 
Report any AEs to the central study telephone number provided. 
 
o 
Return to the study site  
 
o 
Measure your plasma glucose with the glucometer One Touch Ultra Mini ™ every morning after you 
awake from sleep before the first meal of the day.  Write down the results of each of these 
measurements in the log provided by the sponsor. 
 
o 
Report to the site any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl. 
 
 
 Investigator's responsibilities: 
o 
Dispense study medications and instructions. 
 
o 
Remind subjects to: 
- 
Take their study medications as instructed. 
- 
Measure their fasting plasma glucose with the glucometer One Touch Ultra Mini ™ every 
morning.  Write down their results of each of these measurements in  the log provided by the 
sponsor and report to the site any repeated fasting plasma Glucose (FPG) measurements >280 
mg/dl. 
- 
Report any AEs (that occur between clinic visits) to the central study telephone number. 
- 
Return to the study site to receive the CGM iPro2 and the One Touch UltraMini™ 6 days before 
the end of the treatment period (Visit 11; Day 66; Figure 1).  
 
o 
Measure pulse rate and blood pressure (Appendix 5).  
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated and 
certified scale at each visit. Subjects will be weighed at approximately the same time of day on the same 
scale (with the subject wearing underwear and gown but no shoes). Subjects will be instructed to empty 
their bladder before being weighed. Document the data in the CRF or within the medical chart. 
 
NCT03267576


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Approved   Date: 31 July 2017  
o 
If subject reports any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl, perform 
confirmatory FPG in Laboratory. 
 
o 
Address any questions or concerns from the subject or study personnel that are of a clinical nature and 
relate to the subject's continued safe and effective participation in the study. 
 
 Study site personnel's responsibilities: 
o 
Contact the subject by telephone 1 time each during Weeks 2 and 3, in order to remind the subject to 
return to the study site at the appropriate time (Day 66) for the CGM visit. 
4.1.1.10     Study Treatment ("CGM In"; Visit 11; Day 66 [with a ±3-day scheduling window]) 
 Subject's responsibilities: 
o 
Return to the study site to receive the CGM iPro2 device, which will be inserted in your abdomen by 
the investigator.  
 
o 
Wear the CGM iPro2 continuously for 6 days while following normal daily activities (including taking 
your study medications) (Appendix 7C). 
 
o 
On Day 1 with the CGM (Day 22 overall), calibrate the device using the One Touch UltraMini™ (See 
instructions in Appendix 6.) (Appendix 7C):  After the CGM iPro2 has been inserted, measure plasma 
glucose 3 times with the glucometer One Touch Ultra Mini ™ : 1 hour after insertion, 2 hours after 
insertion, and once before bedtime, on the day of insertion (Appendix 7A and 7C).   Write the result of 
these measurements in the Patient Log sheet (Appendix 8) 
 
o 
On each of the other 5 days of the CGM reading (day 2, 3, 4, 5 and 6 of measurement), measure your 
plasma glucose  with the glucometer One Touch Ultra Mini ™ 4 times a day: after you awake from 
sleep and after each of your 3 daily meals. Record the results of each of these measurements in the 
Patient Log Sheet (Appendix8). 
 
o 
Use the same glucose meter and lot of strips for the entire study. Do not allow anyone else to use the 
glucose meter during the study. 
 
o 
Receive instructions from the investigator and study site personnel regarding the use of the Patient Log 
Sheet (Appendix 8) and make sure that you understand how to use it before leaving the clinic during 
your visit to the study investigator/personnel. 
 
o 
Receive instructions from the investigator and study site personnel regarding the use of the pedometer 
and glucometer and make sure that you understand how to use it before leaving the clinic during your 
visit to the study investigator/personnel. 
 
o 
Use the Patient Log Sheet (Appendix 8) to record: what you eat at each meal; any exercise or strenuous 
activities and the times when these occur; times when you take your study medications (should be soon 
after awakening from sleep); number of daily steps as measured by the pedometer and any unusual signs 
or symptoms that you may experience. These may include side effects of the medication and/or signs 
or symptoms of hypoglycemia (as explained above).  
 
o 
Keep the Patient Log Sheet (Appendix 8) accessible at all times, so that you can immediately write 
down the needed information. Write down the results of the plasma glucose measurements from the 
glucometer including time and date within 5 minutes of each blood glucose reading. 
 
o 
Report to the site any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl. 
 
 Investigator's responsibilities: 
o 
Insert the CGM (iPro2) sensor subcutaneously in the patient's abdomen, according to manufacturer 
instructions (Appendix 7A, 7C).  
 
o 
Distribute pedometer and teach the patient how to use it. 
NCT03267576


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Approved   Date: 31 July 2017  
 
o 
Distribute the Glucometer and strips, making sure the patient understand how to use it (Appendix 6) 
during the different days of CGM readings (Appendix 7C). 
 
o 
Distribute and thoroughly review the Patient Log Sheets (Appendix 8) with the subject. Ensure that the 
individual understands the key dietary, physical-activity, medication, and clinical-symptom information 
that need to be recorded. 
 
o 
Measure pulse rate and blood pressure (according to blood pressure measurement instructions in 
Appendix 5). Record data in the CRF. 
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Record data in the CRF and medical chart. 
 
o 
If subject reports any repeated fasting plasma Glucose (FPG) measurements >280 mg/dl, perform 
confirmatory FPG in Laboratory. 
 
 Study site personnel's responsibilities: 
 
o 
Contact the subject at least once during the 6-day CGM reading period to remind about Capillary blood 
glucose readings with the glucometer and Remind the patient of and schedule visit #12 
4.1.1.11 Study Treatment ("CGM out"; Visit 12; Day 71 [with a ±3-day scheduling window]) 
 Subject's responsibilities: 
o 
Return to the study site to have the CGM iPro2 sensor removed from your abdomen by the investigator.  
 
o 
Return with your completed Patient Log Sheets. 
 
 Investigator's responsibilities: 
o 
On visit 12, remove the CGM (iPro2) sensor from the patient's abdomen, within 24 hours of finishing 
the CGM reading period of 6 days, according to manufacturer's instructions (Appendix 7A, 7B). 
 
o 
Download data from the CGM iPro2 as well as calibration data from the One Touch Ultra Mini™ 
glucometer on the same day that the sensor is removed from the patient. Glucose measurement data for 
calibration will be recorded in the Patient Log Sheet. Therefore, in case of problems downloading 
calibration data from the One Touch Ultra Mini™ glucometer device, the data can be entered manually 
as well (Appendix 6).  
 
o 
Review data from the Patient Log Sheets with the subject.  
 
o 
Manually enter all data from the Patient Log Sheet into the CareLink iPro2 system on the same day that 
the sensor is removed from the patient. 
 
o 
Measure pulse rate and blood pressure (according to blood pressure measurement instructions in 
Appendix 5). Document data in the CRF and patient chart. 
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document data in the CRF and patient chart. 
 
 Study site personnel's responsibilities: 
o 
Remind the subject to return to the study site (Day 72) for the end-of-treatment follow-up visit. 
NCT03267576


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Approved   Date: 31 July 2017  
4.1.1.12    End-of-treatment follow-up (Visit 13; Day 72 [with a ±3-day scheduling window]) 
 Subject's responsibilities: 
o 
Return to the study site. 
 
o 
Return all unused medications to study site personnel. 
 
o 
Undergo vital-signs and other end-of-treatment measures and receive further instructions. 
 
 Investigator's responsibilities: 
o 
Measure pulse rate, blood pressure, and body weight. Perform other end-of-study assessments, including 
12-lead ECG and fasting laboratory panels, to match the baseline safety screening. 
 
o 
Elicit any AEs from the subject via open-ended questioning.  
 
o 
Follow up any AE or abnormality in each of the 4 vital signs, ECG, or laboratory abnormalities, which 
are present on Day 72, over the remaining 9 days of the study (through Day 80). Record relevant data 
in the CRF.  
 
o 
Measure body weight. Body weight will be measured (at every visit) using the same calibrated scale at 
each visit. Subjects will be weighed at approximately the same time of day on the same scale (with the 
subject wearing underwear and gown but no shoes). Subjects will be instructed to empty their bladder 
before being weighed. Document the data in the CRF and within the medical chart. 
 
o 
Perform (submit to central laboratory) fasting laboratory panels, including serum chemistries and 
hematology (Subjects must fast for at least 8 hours before blood sample collection). 
 
o 
Remind the subject to continue taking his/her metformin at the same dose as at baseline and throughout 
the study.  
 
 
 Study site personnel's responsibilities: 
o 
Collect all unused study medications. If no unused study medications are returned, ask the subject if he 
or she has taken all medication during the treatment period or has forgotten to return with unused 
medications.  
 
o 
If the subject has forgotten to return to the study site with unused study medications, schedule a follow-
up return appointment as soon as possible to collect them. 
 
o 
The end-of-study visit will occur 1 day after the final CGM assessments. Refer to the instructions above 
for responsibilities related to CGM. 
 
o 
Ensure that all forms and other documents (e.g. CRFs, Patient Log Sheets), and any other study material 
(e.g. unused study medications, pedometers) have been returned. 
 
o 
Schedule a follow-up visit with the investigator within 9 days after the end-of-treatment visit if there 
are any ongoing or unresolved adverse events or abnormalities in vital signs, ECG, or laboratory panels.    
4.1.2 CANA CGM Trial COMETA: Overview  
The main agent being evaluated is CANA, which has a target indication of improving glycemic control in adults with 
T2DM, as an adjunct to diet and exercise. The active comparator is the DPP-4 inhibitor SITA, which shares CANA's 
target indication. 
4.2 
Endpoints and Hypotheses 
4.2.1. 
Efficacy Endpoints 
Efficacy endpoints will be measured in the intent-to-treat (ITT) population, which comprises all subjects who received 
at least one dose of medication and in whom CGM recordings at baseline and after each active treatment were 
NCT03267576


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Approved   Date: 31 July 2017  
successful (>70% of tracings available). Efficacy will also be analyzed in the per-protocol (PP) population: members 
of the ITT population who complete the study without major protocol violations. 
4.2.1.1. Primary Efficacy Outcome Measure 
The primary efficacy endpoint is the mean (SD) intrapatient coefficient of variation (glucose CV %; SD/mean 
glucose), as assessed using CGM over a 3-day period at baseline and after each active treatment.   
4.2.1.2. Secondary Efficacy Outcome Measures 
Secondary efficacy endpoints include the mean (SD) change from baseline in each of the following as measured using 
CGM over a 3-day period at baseline and after each active treatment: 
1. Glycemic SD for 24-hour glucose profile (mg/dL). 
2. Mean 24-hour glucose profile (mg/dL). 
3. Preprandial glucose (FPG; mg/dL). 
4. 2-hour PPG (mg/dL).  
5. Time (minutes), percent of 24 hours, or area under the glucose-time curve for 24 hours (AUC24h) with glucose 
= 70−139 mg/dL (i.e. time spent with glucose in target range).   
6. Time (minutes), percent of 24 hours, or AUC24h (mg/dL/hr) with glucose > 140 mg/dL (i.e. time spent with 
glucose above target range). 
7. Time (minutes), percent of 24 hours, or AUC24h (mg/dL/hr) with glucose > 180 mg/dL (time spent with 
glucose markedly above target range).  
8. Time (minutes), percent of 24 hours, or area over the glucose-time curve for 24 hours (AOC24h ; mg/dL/hr) 
with glucose < 70 mg/dL (time spent with glucose below target range).  
9. Frequency (%) of 2+ consecutive glucose readings < 70 mg/dL (and/or of hypoglycemic symptoms requiring 
personal support). 
4.2.1.3. Exploratory Efficacy Outcome Measures 
Exploratory endpoints in this pilot study will include mean (SD) changes from baseline in: 
1. AUC for glycemic variability (mg/dL/hr) throughout the day (0−24 hours), after breakfast (0−5 hours), after 
lunch (5−11 hours), after dinner (11−15 hours), and during sleep (15−24 hours). 
2. Peak glucose (mg/dL) throughout the day (0−24 hours), after breakfast (0−5 hours), after lunch (5−11 hours), 
after dinner (11−15 hours), and during sleep (15−24 hours). 
3. Overall hyperglycemia: AUCtotal (mg/dL/hr). 
4. Nadir glucose (mg/dL): lowest glucose level over 72 hours. 
5. Continuous overlapping net glycemic action (CONGA): the SD of summed differences between observations 
separated by n hours. 
6. Mean of daily differences in PG (MODD). 
 
Body weight and levels of physical activity (assessed by wearable pedometers) will also be evaluated at the screening 
visit, each active-treatment 3-day CGM visit, and the washout visit. 
4.2.1.4. Safety and Tolerability Outcome Measures 
Incidences of AEs related to safety and tolerability will be predicated on the safety population, which comprises 
subjects receiving at least one dose of active treatment. 
4.2.1.4.1. 
Safety 
Medical history, physical examination, vital signs (body temperature, pulse rate, blood pressure, and respiration rate), 
12-lead electrocardiograms, serum chemistries, haematology, and urinalysis will be assessed at the screening and end-
of-study visits.  Pulse rate and blood pressure will be measured at every visit during the study.  
4.2.1.4.2. 
Tolerability 
Adverse events (AEs) will be elicited via open-ended questioning at each study visit. Treatment-emergent adverse 
events (TEAEs) will be defined as events that first occur, or are present at screening and worsen, after initial 
randomization and the randomized crossover.  
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4.2.2.   Outcome Measures 
Safety will be assessed according to mean values for vital signs, 12-lead ECGs, and clinical laboratory assessments at 
the screening and end-of-study visits in this population (Visits 1 and 6). Incidences of abnormal safety test results will 
be based on predefined, local reference ranges and each Investigator's customary clinical practice. Adverse events will 
be elicited by open-ended questioning at each visit and coded as to system organ class and preferred term using 
Medical Dictionary of Regulatory Activities (MedDRA) version 14 (or higher). Tolerability will be determined as the 
incidence of subjects with one or more TEAEs (by treatment group). Safety will be further evaluated according to 
incidences (number of patients and events) of SAEs, AEs leading to treatment discontinuation, and serious drug-
related AEs.   
4.3. Interim Analysis and End of Study 
Consistent with the short-term (two 28-day active treatment phases), cross-over design of this study, there will be no 
pre specified interim analysis. In addition, the relatively small targeted enrollment (see below) largely precludes 
subgroup analyses. 
4.4. Hypotheses 
The primary hypothesis is that mean changes from baseline in mean intrapatient glucose CV % are statistically 
significantly lower after 28 days of treatment with CANA 300 mg (vs. SITA 100 mg) when each is combined with 
MET in patients with T2DM inadequately managed while using this biguanide as monotherapy. Specific null 
hypotheses and alternative hypotheses are stated in the Statistical Analysis Plan. 
4.5. Treatments, Dosages, and Administration 
4.5.1. Treatment of Interest: Canagliflozin  
 
Figure 2. Molecular structure of canagliflozin (CANA). 
_________________________________________________________________________ 
 
 
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4.5.1.1. CANA 300 mg will be administered once daily, before the first meal of the day.  
CANA is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor. SGLT-2 is expressed in the proximal renal tubules, 
mediating reabsorption of filtered glucose from the lumen of the tubule.  By inhibiting the activity of this transporter, 
CANA elevates urinary glucose excretion, reducing reabsorption of filtered glucose. The dissociation constant for 
CANA's competitive inhibition of SGLT-2 is Ki = 0.84 ± 0.06 nM.  In cultured SGLT-2−expressing cells, CANA 
decreases α-methyl-D-glucopyranoside (AMG) uptake with an IC50 value of 4.2 ± 1.5 nM. The IC50 value for 
inhibition of AMG by SGLT1−expressing cells is 555 ± 31 nM. Hence, CANA inhibits SGLT-2 with 109 times greater 
selectivity compared to SGLT1 (Kuriyama et al., 2014).   
CANA significantly reduced fasting plasma glucose (FPG), by approximately 35−45 mg/dL, and PPG by 45−60 
mg/dL, in clinical trials (Figure 3) (Inagaki et al., 2013; Stenlof et al., 2013; Janssen, 2013). One reason that CANA 
does not increase the risk of hypoglycemia is that the renal threshold for glucose (RTG) typically remains above the 
hypoglycemia threshold (Sha et al., 2014). High-dose CANA may reduce PPG by nonrenal mechanisms (i.e. beyond 
urinary glucose excretion; potential enteral SGLT-1 mechanism) (Stein et al., 2014). CANA may be able to delay and 
attenuate PPG excursions (Sha et al., 2015).  However, no clinical trial to date has specifically evaluated the effects of 
CANA + metformin (MET) vs. MET + a dipeptidyl peptidase 4 (DPP4) inhibitor on GV in patients with inadequate 
glucose control while using MET monotherapy.  
 
Figure 3.  
Effects of canagliflozin 300 mg (vs. baseline and placebo) on fasting plasma glucose (FPG; preprandial 
glucose) and 2-hour postprandial glucose (PPG) (Janssen, 2013). 
_____________________________________________________________________________________________ 
 
Potential safety issues with CANA (when administered without insulin or insulin secretagogues) include hypotension 
(secondary to reductions in intravascular volume), hyperkalemia, hypersensitivity reactions, and genital mycotic 
infection. Because of its renal mechanism of action, CANA is contraindicated in patients who have severe renal 
impairment or end-stage renal disease and/or are undergoing dialysis. In randomized controlled trials, adverse drug 
reactions observed with CANA that had incidences of ≥5% included increased urination and genitourinary infections 
(Janssen, 2013). 
    
During a routine review of unblinded interim data from an ongoing Phase 3 study, the Independent Data Monitoring 
Committee observed a non-dose-dependent increase in the incidence of non-traumatic, lower-extremity amputations 
(mostly of the toes) in the canagliflozin 100 mg and 300 mg groups compared to placebo. With a mean duration of 
follow-up in CANVAS of approximately 4.5 years, the annualized incidence of lower-extremity amputation was 0.73, 
0.54, and 0.30 events per 100 patient-years in the canagliflozin 100 mg, canagliflozin 300 mg, and placebo groups, 
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respectively. Overall, treatment with canagliflozin was associated with an approximately 2-fold increase in amputation 
event rates (relative risk [RR] 2.15; 95% CI: 1.3 - 3.5). The Phase 3 study IDMC, which has access to unblinded CV 
outcomes data, notified the sponsor that “after consideration of all outcomes, the IDMC feels the study should 
continue.” Infections were the events most commonly associated with amputations, and most amputations were of the 
toe. The factors associated with the greatest risk for amputation included prior amputation, peripheral vascular disease, 
and neuropathy. 
 
 Final results from two clinical trials – the CANVAS (Canagliflozin Cardiovascular Assessment Study) and 
CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes 
Mellitus) – showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin 
compared to patients treated with placebo, which is an inactive treatment. The CANVAS trial showed that over a 
year’s time, the risk of amputation for patients in the trial were equivalent to:  
• 5.9 out of every 1,000 patients treated with canagliflozin  
• 2.8 out of every 1,000 patients treated with placebo  
 
The CANVAS-R trial showed that over a year’s time, the risk of amputation for patients in the trial were equivalent 
to:  
• 7.5 out of every 1,000 patients treated with canagliflozin  
• 4.2 out of every 1,000 patients treated with placebo  
 
Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, below 
and above the knee, also occurred. Some patients had more than one amputation, some involving both limbs. 
 
For subjects who develop conditions that are associated with amputation such as a lower extremity infection, skin 
ulcer, osteomyelitis, gangrene, or critical limb ischemia, study drug should be interrupted until the condition has 
resolved in the opinion of the investigator. In the event of an amputation, restarting of dosing with canagliflozin should 
only be done after careful consideration of the individual risk:benefit and following discussion with the sponsor. 
 
As of 11 May 2015, in the T2DM clinical development program, incidence rates of unblended serious adverse events 
of diabetic ketoacidosis (DKA), ketoacidosis, metabolic acidosis, and acidosis were 0.0522 (0.07%, 4/5337), 0.0763 
(0.11%, 6/5350), and 0.0238 (0.03%, 2/6909) per 100 subject-years with canagliflozin 100 mg, canagliflozin 300 mg, 
and comparator, respectively. Of the 12 subjects with serious adverse events of DKA, ketoacidosis, metabolic acidosis, 
or acidosis (all of whom were hospitalized), 6 subjects on canagliflozin (3 on canagliflozin 100 mg and 3 on 
canagliflozin 300 mg), and none on comparator were reported to have autoimmune diabetes (latent autoimmune 
diabetes of adulthood [LADA] or type 1 diabetes) or tested positive for GAD65 antibodies after being diagnosed with 
a serious DKA-related event. Eight of the 10 subjects on canagliflozin were receiving insulin therapy. The blood 
glucose values around the time of admission in 9 of 10 subjects on canagliflozin ranged from 347 to 571 mg/dL (9.3 
to 31.7 mmol/L). The remaining subject had blood glucose values ranging from 148 to 320 mg/dL (8.2 to 17.8 
mmol/L). Diabetic ketoacidosis has also been reported during post-marketing surveillance and has occurred in patients 
with blood glucose values less than 250 mg/dL (13.9 mmol/L). As a result, DKA is considered a rare adverse drug 
reaction. 
 
In preclinical studies in rats, hyperostosis (increased trabecular bone) was observed; mechanistic toxicology studies 
demonstrated that hyperostosis, like the tumors discussed above, related to carbohydrate malabsorption in rats treated 
with canagliflozin, with consequent marked hypercalciuria (which is not seen in human).  A detailed analysis of bone 
safety was conducted in the Phase 3 program, including an assessment using DXA in a dedicated Phase 3 study (a 
study conducted in older subjects [ages >55 and <80 years] with T2DM) and a cross-program assessment of fracture 
incidence. Bone mineral density (BMD) was examined at 4 sites: at the lumbar spine, total hip, distal radius, and 
femoral neck. Minimal changes in BMD from baseline to Week 104 were seen in the lumbar spine (a cancellous bone 
region), femoral neck (a mixed cancellous and cortical bone region), and distal forearm. A decrease in BMD from 
baseline to Week 104 in the total hip, a site comprised of mixed cortical and cancellous bone (like the femoral neck), 
was observed for both canagliflozin treatment groups (-0.9% and -1.2% in the canagliflozin 100 mg and 300 mg 
groups, respectively, placebo adjusted). In a cardiovascular study of 4,327 subjects with known or at high risk for 
cardiovascular disease (Study DIA3008), the incidence rates of bone fracture were 1.6, 1.6, and 1.1 per 100 subject 
years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, with the fracture 
imbalance initially occurring within the first 26 weeks of therapy.  The final results of  this same study (CANVAS 
program) reported an HR of  1.23 (95% CI, 0.99–1.52) for Low-trauma fracture for Canagliflozin vs placebo. In other 
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T2DM studies with canagliflozin, which enrolled a general diabetes population of approximately 5,800 subjects, no 
difference in fracture risk was observed relative to control. 
 
4.5.2. Reference Treatment: Sitagliptin (Active Comparator)  
 
 
Figure 4.  
Molecular structure of sitagliptin. 
SITA 100 mg will be administered once daily at the same time as CANA 300 mg (within each period, not concurrently 
with CANA 300 mg). 
SITA is a dipeptidyl peptidase 4 (DPP-4) inhibitor with a molecular structure depicted in Figure 4. By inhibiting DPP-
4, which catalyzes N-terminal amino-acid (alanine/proline) enzymatic degradation of the endogenous incretins 
glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide, DPP-4 inhibitors such as SITA 
promote glucose-dependent insulin release via the endocrine action of the hormone glucagon in enterocytes and other 
target cells; the activities of both GLP-1 and GIP cease when PG falls below 55 mg/dL (Richter et al., 2008). DPP-4 
is expressed widely in the body, not only in the intestine; other sites of DPP-4 include the capillary endothelium, 
kidney, liver, and a variety of immune effector cells, including B and T lymphocytes and natural-killer cells. The 
aminopeptidase DPP-4 spans cell surfaces and transduces intracellular signals via both circulating and intracellular 
molecules (Richter et al., 2008). 
DPP-4 is a member of a family of enzymes that also includes DPP-4β, DPP-6, DPP-8, DPP-9, quiescent cell proline 
dipeptidase, and fibroblast activation protein. Sitagliptin metabolites M1, M2, and M5 are (respectively) about 300-, 
1,000-, and 1,000-fold less active as DPP-4 inhibitors compared to SITA; the IC50 values for these metabolites are 
about 5, >20, and >20 µM (respectively) compared to 18 nM for SITA. Sitagliptin is highly selective as a substrate 
for DPP-4 compared to DPP-8/9; binding to the latter molecules can result in severe toxicity (European Medicines 
Agency, 2007).   
In randomized controlled trials, SITA 100 mg reduced FPG by approximately 23 mg/dL and 2-hour PPG by 52 mg/dL 
compared to placebo (Figure 5)(Merck, 2010). 
 
Figure 5.  
Effects of SITA 100 mg (vs. baseline and vs. placebo) on FPG (preprandial glucose) and 2-hour PPG 
(Merck, 2010). 
_____________________________________________________________________________________________ 
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Potential safety issues with SITA (when administered without insulin or insulin secretagogues) include potentially 
fatal necrotizing or hemorrhagic acute pancreatitis; acute renal failure; allergic and hypersensitivity reactions; and 
severe and disabling arthralgia. In randomized controlled trials, adverse drug reactions observed that had incidences 
of ≥5% with SITA included nasopharyngitis, upper-respiratory-tract infection, and headache (Merck, 2010).   
4.6 
Study Rationale 
4.6.1 
Background: Clinical Studies Involving Canagliflozin or Sitagliptin 
The CANA CGM trial is unprecedented in comparing the effects of CANA (vs. SITA) on GV using CGM. One non-
CGM study (with more than one report) compared the effects of CANA and SITA on glucose control (Schernthaner 
et al., 2013; Lavalle-Gonzalez et al., 2013; Lavalle-Gonzalez et al 2016). Previous CGM studies have mainly assessed 
the effects of these agents on glucose profiles at study conclusion (vs. baseline) or against other comparators (e.g. 
placebo).  Some of these studies did not include CGM (Table 1)(Rosenstock et al., 2012; Schernthaner et al., 2013; 
Cefalu et al., 2013; Lavalle-Gonzalez et al., 2013b) and others did include this technology (Table 2)(Ellis et al., 2011; 
Guerci et al., 2012; Argento and Nakamura, 2016) (Janssen Protocol 28431754DIA2004). 
In these clinical trials, subjects receiving CANA 300 mg had more marked reductions in parameters of glucose control 
when directly compared to SITA 100 mg in non-CGM studies (Table 1 and Figure 6) and also greater reductions in 
mean (SD) glycemic SD when CANA 300 mg or SITA 100 mg was compared to placebo in CGM studies. Data in 
Tables 1 and 2 inform sample size calculations in the Statistical Analysis Plan (see below).   
 
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Table 1. Effects of CANA vs. SITA in Non-CGM Studies  
Trial/duration/ 
Population 
Treatment 1 mg/day  
(n = ) 
Treatment 2 mg/day (n = ) 
Mean (SD) difference in eAG*, 
mg/dL 
(CANA – SITA) 
Other endpoints 
Mean (CANA – SITA) 
CANTATA-D (Latin American 
subgroup)(Lavalle-Gonzalez et al., 
2016) (52-wk): adults with T2DM and 
HbA1c ≥ 7.0% to ≤10.5% on stable 
MET 
SITA 100 (80) 
CANA 300 (76) 
−41.00 (−38.55) 
Mean (SD) difference (CANA vs. 
SITA) in: 
• 
Body weight = −3.7% (−8.0%) 
• 
Systolic blood pressure = −4.0 
(−22.3) mm Hg 
 
Schernthaner et al(Schernthaner et al., 
2013)  
(52-wk): adults with T2DM and 
HbA1c ≥ 7.0% to ≤10.5% on stable 
MET+SU 
SITA 100 (378) 
CANA 300 
(377) 
∆ = −11.11  
(−26.28) 
 
2-hr PPG, mg/dL (no SD provided)  
• 
−39.9 (SITA) 
• 
−58.5 (CANA) 
Mean change in body weight: 
• 
+0.3% (SITA) 
• 
−2.5% (CANA; p < 0.001) 
 
Rosenstock et al  
(12 wk)(Rosenstock et al., 2012)¶ : 
adults with T2DM and HbA1c ≥ 7.0% 
to ≤10.5% on stable MET 
SITA 100 (65) 
CANA 300 (64) 
Δ = −5.4 [No SD provided] 
— 
 
*Estimated average glucose (eAG; mg/dL) was computed from hemoglobin A1c (%) using Nathan et al’s formula eAG = (28.7 X HbA1c) − 46.7 (Nathan et al., 2008). 95% confidence intervals were converted 
to SD using the following formula:  SD = CI/3.96 X √N
2
.  
 
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Table 2. Effects of CANA/SITA vs. PBO in CGM Studies   
 
 
 
 
 
 
 
 
 
Differences in measures of GV 
Trial/design/ 
duration/ 
population 
Treatment 1 
mg/day  
(n = ) 
Treatment 2 mg/day  
(n = ) 
SD 
SD 
CV (SD/mean glucose) 
CV 
(SD/MG) 
Mean 24-hr glucose 
Mean 24-hr glucose 
CANA trials 
 
 
mg/dL 
mg/dL 
% 
% 
mg/dL 
mg/dL 
Argento 2016(Argento and 
Nakamura, 2016):  
retrospective case-control 
study of patients with T1DM 
≥5 years with intensive 
insulin doses taking CANA x 
mean = 3.7 mo. 
CANA 100 (27) 
Controls: (27): 
candidates for CANA 
but received only 
insulin adjustment (at 
most) 
CANA:  
BL =  
67.6 (13.1)  
Follow-up = 56.3 
(10.7) 
Δ = −11.30 
Controls: 
BL = 63.7 (13.0) 
Follow-up = 63.4 
(11.8) 
Δ = −0.3 
 
CANA:  
BL =  
0.400 (0.044)  
Follow-up = 0.382 
(0.053) 
Δ = −0.018 
Control: 
BL = 0.381 (0.074)  
Follow-up = 0.382 
(0.070) 
Δ = −0.001 
 
CANA:  
BL =  
168.3 (21.1)  
Follow-up = 146.9 
(15.3) 
Δ = −21.4 
Control: 
BL = 169.2 (24.1)  
Follow-up = 167.6 
(22.4) 
Δ = −1.6 
 
Phase 2 study*: parallel-
group, treat-to-target, 18-wk 
study of patients with T1DM 
with inadequate control on 
basal-bolus insulin 
CANA 300 
(117)  
Placebo (118) 
CANA: 
BL = 69.3 (12.74) 
18 wk = 57.06 (12.60) 
Δ = −12.24 (−13.90) 
Placebo: 
BL = 68.04 (12.85) 
18 wk = 
69.66 (15.82)   
Δ = +1.62 (+14.04) 
Not available 
Not available 
CANA: 
BL = 164.70 (24.37)  
18 wk = 152.46 
(20.95) 
Δ = −12.24 (−21.62) 
Placebo: 
BL = 162.00 (31.05) 
18 wk = 
172.26 (21.89)   
Δ = +10.08 (+35.13) 
SITA trials 
 
 
 
 
 
 
 
 
Sakamoto 2012 
(J-VICTORIA)(Sakamoto et al., 
2012): actively controlled 
crossover study 4 wk of each 
treatment in T2DM patients 
with HbA1c = 6.5−9.5% w/o 
MET 
Vildagliptin 
(VILDA) 100 
(20) 
SITA 50 (20) 
VILDA: 
35.5 (12.6) 
SITA: 
37.0 (13.9) 
VILDA: 
Not reported  
SITA: 
Not reported 
VILDA: 
142.1 (14.0) 
SITA: 
153.2 (29.7) 
Guerci 2012 (Guerci et al., 
2012): open-label actively 
controlled study of 2 DPP-4Is 
x 8 wk in T2DM patients with 
HbA1c = 6.5−8.0% on stable 
MET    
VILDA 100 (14) 
SITA 100 (16) 
VILDA: 
BL =  
29.3 (8.0)  
Follow-up = 24.2 (6.0) 
Δ = −5.1  
(p = 0.20) 
SITA: 
BL =  
29.1 (5.6)  
Follow-up = 23.1 (5.5) 
Δ = −6.0 
VILDA:  
Not reported 
SITA: 
Not reported 
VILDA: 
BL =  
29.3 (8.0)  
Follow-up = 24.2 (6.0) 
Δ = −5.1  
(p = 0.20) 
SITA: 
BL =  
29.1 (5.6)  
Follow-up = 23.1 (5.5) 
Δ = −6.0 
Ellis 2011 (Ellis et al., 2011): 
Controlled crossover 8-wk 
study of adults with T1DM 
and HbA1c = 8.5%−12.0% on 
stable insulin doses 
SITA 100 (20) x 
4 wk 
Placebo (20) 
X 4 wk 
Between-group 
difference: 
Δ = −2.52 (−2.34; p = 
0.29) 
 
Between-group 
difference: 
Mean (SD) Δ = 1.1 
(0.9; p = 0.27) 
 
Between-group 
difference: 
Δ = −10.8 (−3.6) 
 
*Janssen Protocol 28431754DIA2004. 
 
 
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Figure 6. CANA vs. SITA (CANTATA-D). In this active-comparator study, including all (left panels) and Latin American (right panel) subjects, CANA 300 mg reduced 
hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) compared to SITA 100 mg (Schernthaner et al., 2013; Lavalle-Gonzalez 
et al., 2016).    
 
 
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4.6.2. CANA CGM Trial Rationale 
The impetus for the CANA CGM Trial in Mexican patients with T2DM derives in part from the recently reported 
Canagliflozin Treatment and Trial Analysis−DPP-4 Inhibitor Comparator Trial (CANTATA-D; Clinicaltrials.gov ID 
NCT01106677; Study DIA3015) in a Latin American subpopulation. This study, by Lavalle-González and co-workers 
in Brazil, Colombia, Costa Rica, and Mexico, showed that CANA 300 mg + MET (at stable doses) reduced HbA1c 
(net = −0.21%) and other clinical endpoints, including body weight (net = −3.7%) and systolic blood pressure (net = 
−4.0 mmHg), to a greater degree than SITA 100 mg + MET (Lavalle-Gonzalez et al., 2016). 
Interpreting these differences, the authors pointed to the finding that Hispanic/Latino T2DM subpopulations 
experience reduced insulin sensitivity as their pivotal metabolic defect, and that CANA may hence be advantageous 
in these patients because it reduces PG through an insulin-independent mechanism (i.e. increased glucose excretion) 
(Cusi and Ocampo, 2011). On the other hand, SITA has minimal effects on measures of insulin sensitivity and 
resistance [assessed using the quantitative insulin sensitivity check index (QUICKI) and homeostasis model 
assessment insulin resistance (HOMA-IR)], consistent with the overall modest effects of the class of incretin mimetics 
on these parameters (Hansen and Corbett, 2005; Aschner et al., 2006).  
A recent study evaluated model-based measures of β-cell function and insulin sensitivity using frequently sampled 
mixed-meal tolerance tests. Via this method, Polidori and European co-workers evaluated the effects of CANA 300 
mg (vs. SITA 100 mg) when each was added to MET + SU in adults with T2DM and HbA1c 7.0%−10.5%, FPG < 
300 mg/dL, and eGFR ≥ 55 mL/min (1.73 m2)-1 in the CANTATA-D trial (Clinicaltrials.gov NCT01137812) 
(Schernthaner et al., 2013; Polidori et al., 2014). Treatment with CANA 300 mg resulted in least-squares mean 
increases of 30 to 50 mL min-1 m-2 on the oral glucose insulin sensitivity (OGIS) index as compared to a smaller 
increase of 12 mL min-1 m-2 with SITA 100 mg (each comparison p ≤ 0.02). The range of values reflects raw data for 
OGIS and after adjustment for urinary glucose excretion. 
Consequently, the CANA CGM Trial will, for the first time, compare the effects of CANA and SITA—which have 
divergent effects on insulin sensitivity—on glycemic variability using CGM in a Latin American population, which 
may serve as a parallel for other diabetic populations with reduced insulin sensitivity as their chief metabolic defect. 
4.6.2.1. Potential Measures of Glycemic Variability 
A number of measures have been proposed as indices of GV. Table 3 summarizes their potential advantages and 
pitfalls in terms of methodology, associations with pathobiological and clinical outcomes, and other considerations. 
 
Table 3. Measures of GV and Dispersion     
Measure 
Potential Advantages 
Potential Pitfalls 
Glucose CV % 
Contributes the most to hypoglycemia (40%), vs. 10% 
for MAG and <5% for SD and MAGE (Qu et al., 2012). 
Not reported in most CGM trials of SGLT-2 and DPP-4 
inhibitors 
SD 
• 
Linear relationship with mean PG and other key 
indices of GV: GA/A1c ratio and FCPR index. 
• 
Linear relationship with PG interquartile range if 
not normally distributed 
• 
Associated with mortality in some 
studies(Meynaar et al., 2012) 
SD is a measure of dispersion rather than variability. A 
patient can (in theory) have a high glycemic SD without 
oscillating PG pattern. 
MAG 
• 
Associated with ICU mortality in some 
studies(Hermanides et al., 2010) 
 
Sometimes difficult to separate signal from noise given 
method = simple summation of all absolute changes in PG 
divided by the time over which measurements were taken. 
MAGE 
Captures mealtime-related glucose excursions. 
• 
Postprandial glucose excursions can be more 
effective measured using CGM AUC. 
• 
Calculation is operator dependent/not standardized. 
• 
Outcome differs if computing is based on a 
postprandial increase or decrease (ascending or 
descending limb) 
• 
May not take into account relatively small, but still 
clinically meaningful changes. 
A1c, hemoglobin A1c; CV, coefficient of variation; FCPR index, fasting C-peptide immunoreactivity to fasting plasma glucose (FPG) ratio; GA, 
glycated albumin; MAG, mean absolute glucose; MAGE, mean amplitude of glycemic excursions; PG, plasma glucose; Data from DeVries and 
Ogawa et al (Ogawa et al., 2012; DeVries, 2013). 
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5. 
STUDY PROCEDURES 
Table 4 summarizes the time and events schedule for the study. 
Table 4. Time and Events Schedule   
 
 
 
 
 
 
 
 
Phases (Visits), Timing (days), and Events 
Study assessment/ 
Procedure 
Prescreening 
(Optional) 
 
Screening  
(Prescreening 
assessments can 
be performed 
here) 
Selection   
Randomization  
 
Active 
treatment 1 
(period 1) 
 
CGM in  
CGM out 
Washout 
Active 
treatment 
2 (period 2) 
CGM in 
 
CGM out 
End study  
 
Visit  
V1 
V2  
V3−V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V132 
Days  
 Day −16 to 
−11 
Day −10 to −8 
Day −7 to −1 (see 
page below) 
Day 0 
Day 0 
Day 22 
Day 27 
Day 28 
Day 44 
Day 66 
Day 71 
Days 72 to 
80 
Screening/administrativ
e 
X 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent Form  
(ICF)a 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
Review medical history 
requirements 
X 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteriab 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Non-study therapy 
(establish metformin at 
stable dose and 
continue it on trial) 
X 
X 
 
X  
(Ensure that 
subject 
continues 
metformin) 
X  
(Ensure that 
subject 
continues 
metformin) 
 
 
X  
(Ensure 
that 
subject 
continues 
metformin) 
X  
(Ensure 
that 
subject 
continues 
metformin) 
 
 
X  
(Ensure 
that 
subject 
continues 
metformin)  
Study drug 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense/ administer 
drug  
 
 
 
 
X 
 
 
 
X 
 
 
 
Drug accountability (pill 
count) 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
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Phases (Visits), Timing (Days), and Events 
Study assessment/ 
Procedure 
Prescreeni
ng 
(Optional) 
 
Screening  
(Prescreening 
assessments can be 
performed here) 
Selection   
Randomization  
 
Active 
treatment 
1 (period 1) 
 
CGM in  
CGM out 
Washout 
Active 
treatment 2  
(period 2) 
CGM in 
 
CGM out 
End study  
 
Visit  
V1 
V2  
V3−V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
Days  
 Day −16 to 
−11 
Day −10 to −8 
Day −7 to −1 
Day 0 
Day 0 
Day 22 
Day 27 
Day 28 
Day 44 
Day 66 
Day 71 
Days 72 to 80 
CGM device inserted for 
6-day CGM glucose 
measurements (patient 
calibrates device using 
glucometerd) 
 
 
X (Day −7) 
 
 
X 
 
 
 
X 
 
 
CGM device removed 
and data downloaded 
from CGM device and 
Glucometer 
 
 
X (Day −1) 
 
 
 
X 
 
 
 
X 
 
Patient Log Sheets 
distributed 
 
 
X (Day -7) 
 
 
X 
 
 
 
X 
 
 
Data from patient log 
sheets entered manually 
into the system 
 
 
X (Day -1) 
 
 
 
X 
 
 
 
X 
 
Glucometer  (One Touch 
Ultra) and strips  
distributed 
 
 
X (Day -7) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Data from Glucometer 
readings  downloaded to 
system or entered 
manually 
 
 
X (Day -1) 
 
 
 
X 
 
 
 
X 
 
Pedometer distribution  
 
 
X 
 
 
X 
X 
 
 
X 
X 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
Lower limb examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (pulse rate, 
blood pressure, 
respiration rate, body 
temperature) 
 
X 
 
 
 
 
 
 
 
 
 
X 
Pulse rate and blood 
pressure (alone) 
X 
(Measured as part 
of vital signs above) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Measured as 
part of vital 
signs above) 
12-lead ECG 
 
X 
 
 
 
 
 
 
 
 
 
X 
Clinical laboratory 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting serumc 
chemistries 
 
X 
 
 
 
 
 
 
 
 
 
X 
Hematology 
 
X 
 
 
 
 
 
 
 
 
 
X 
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Approved   Date: 31 July 2017  
Study assessment/ 
Procedure 
Prescreeni
ng 
(Optional) 
 
Screening  
(Prescreening 
assessments can be 
performed here) 
Selection   
Randomization  
 
Active 
treatment 
1 (period 1) 
 
CGM in  
CGM out 
Washout 
Active 
treatment 2  
(period 2) 
CGM in 
 
CGM out 
End study  
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
HbA1C /C peptide 
 
X 
 
 
 
 
 
 
 
 
 
X 
Fasting serum lipid 
profile 
 
X 
 
 
 
 
 
 
 
 
 
X 
Fasting plasma glucose 
 
X 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy testing 
in Central laboratory e 
 
X 
 
 
 
 
 
 
 
 
 
 
Other assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
aMust be signed before first study-related activity.  
 
bMinimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 10.2.4, Source Documentation. Check clinical status again before first dose of study medication. 
cFor fasting laboratory assessments, if the subject has not fasted before the visit, the visit may proceed, but the subject must return within 24 hours in a fasted state to provide the necessary sample(s) for the 
assessments.  
 
dCGM device calibration to be performed by the study subject using the One Touch UltraMini™ glucometer (Appendix 6).  
 
e Urine pregnancy testing, unless a serum pregnancy test is preferred at the discretion of the investigator or if required by local regulations, for all women unless they are surgically sterile or unless there is a 
documented history of their postmenopausal status 
 
 
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Approved   Date: 31 July 2017  
ABBREVIATIONS 
   AE 
 
  Adverse event 
   AOC 
 
  Area over the curve 
AUC 
Area under the curve 
BMI 
CANA 
CANA CGM 
CANTATA-D 
CGM 
CONGA 
COA 
Body mass index 
Canagliflozin 
Canagliflozin Continuous Glucose Monitoring trial (present study's name) 
Canagliflozin Treatment and Trial Analysis−DPP-4 Inhibitor Comparator Trial 
Continuous glucose monitoring 
Continuous overlapping net glycemic action 
Clinical outcome assessment 
CRF 
Case report form 
CV 
DCF 
Coefficient of variation (glycemic SD/mean; %) 
Data clarification form 
DKA 
DM 
DMC 
Diabetic ketoacidosis 
Diabetes mellitus 
Data Monitoring Committee 
DPP-4 
Dipeptidyl peptidase-4 
eAG 
ECG 
Estimated average glucose 
Electrocardiogram 
eCRF 
eDC 
Electronic case report form 
Electronic data capture 
eGFR 
EMA 
FPG 
GCP 
GLP-1                       
Estimated glomerular filtration rate 
European Medicines Agency 
Fasting plasma glucose 
Good Clinical Practice 
Glucagon-like peptide-1 
GLP-1RA 
GV 
HbA1c 
ICF 
GLP-1 receptor agonist 
Glycemic variability 
Hemoglobin A1c 
Informed-consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IQR 
IRB 
Interquartile range 
Institutional Review Board 
ITT 
IVRS 
Intent-to-treat (population) 
Interactive voice response system 
MAGE 
MDRD 
MedDRA 
Mean amplitude of glucose excursions 
Modification of Diet in Renal Disease 
Medical Dictionary for Regulatory Activities 
MET 
MODD 
OGIS 
PG 
PI 
PP 
PPG 
PQC 
Metformin 
Mean of daily differences (in PG) 
Oral glucose insulin sensitivity 
Plasma glucose 
Prescribing information 
Per-protocol (population) 
Postprandial glucose  
Product Quality Complaint 
QUICKI 
SAP 
SGLT1 
SGLT-2 
SAE 
SD 
SITA 
SUSAR 
Quantitative insulin sensitivity check index 
Statistical Analysis Plan 
Sodium-glucose co-transporter 1  
Sodium-glucose co-transporter 2 
Serious AE 
Standard deviation 
Sitagliptin 
Suspected unexpected serious adverse reaction 
SMBG 
Self-Monitored Blood Glucose 
TEAE 
T1DM 
T2DM 
USP 
Treatment-emergent adverse event  
Type 1 diabetes mellitus 
Type 2 diabetes mellitus 
United States Pharmacopeia 
 
 
 
 
NCT03267576


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Approved   Date: 31 July 2017  
5.1. 
Overview of Blinding, Control, Study Phases/Periods, and Treatment Groups 
In this actively controlled crossover study, subjects will be randomized to treatment (e.g.  A or B), period, and sequence 
(i.e. A/B or B/A), separated by a MET-only washout interval. Randomization will be used to minimize bias in the 
assignment of subjects to treatment and sequence groups, to increase the likelihood that known and unknown subject 
attributes (e.g. sociodemographic and other baseline characteristics) are evenly balanced and to enhance the validity 
of statistical comparisons. Double-blinded treatment will be used to reduce potential bias during data collection and 
evaluations of clinical (including surrogate CGM) endpoints.  
5.2. 
Study Population 
Screening for eligibility will be performed within 16 days before administration of study drugs. The inclusion and 
exclusion criteria for enrolling subjects in this study are described in the following two subsections. If there is a 
question about the inclusion or exclusion criteria below, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a subject in the study. Waivers are not allowed. 
For a discussion of the statistical considerations of subject selection, refer to the Statistical Analysis Plan.  
5.2.1. Inclusion Criteria 
Each potential subject must satisfy all of the following Inclusion Criteria to be enrolled in the study. If any of the 
Exclusion Criteria are met, the patient is not eligible to be enrolled. 
1. 
Male or female. 
2. 
Age >18 (or other legal age of consent in Mexico) and <55 years. 
3. 
Type 2 diabetes mellitus. 
4. 
Inadequate glucose control while using MET monotherapy for at least 8 weeks at stable daily doses of at 
least 1,500 mg before screening visit (Visit 1).   
 
a. 
Hemoglobin A1c (HbA1c) = 7.5% to 10.5% at Visit 1. 
5. 
Adequate qualifying CGM reading during the prerandomization (selection) phase  
6. 
Estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2 at Visit 1. 
7. 
Body mass index of 22 through 45 kg/m2 at Visit 1. 
8. 
Women of childbearing potential must agree to use a highly effective means of contraception (as defined 
according to local regulations) during the study (from Visits 1 through 6) and at least 4 weeks after the 
end-of-study visit. 
9. 
Agree to sign an inform consent form (ICF) indicating that he/she understands the purpose of, and 
procedures required for, the study and is willing to participate in the study. 
10. 
Willing and able to adhere to the prohibitions and restrictions specified in this protocol. 
5.2.2.  Exclusion Criteria 
1.   History of any of the following (at Visit 1): 
a. 
Diabetic ketoacidosis (DKA) 
b. Type 1 diabetes mellitus (T1DM) 
c. 
Pancreatic (e.g. β-islet cell) transplantation 
d. Diabetes secondary to pancreatitis or pancreatectomy  
e. 
Personal history of, or ongoing, pancreatitis 
f. 
One or more episodes of severe hypoglycemia (requiring assistance from others), as documented in the 
history obtained at Visit 1 
g. Hereditary glucose-galactose malabsorption or primary renal glucosuria. 
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Approved   Date: 31 July 2017  
2. Repeated FPG or fasting self-monitored blood glucose (SMBG) > 270 mg/dL during the pretreatment phase 
3. Treatment with any other oral or parenteral antidiabetic medications different from metformin monotherapy, 
including but not limited to DPP-4 inhibitors, Sulphonylureas, thiazolidinediones, insulins and GLP-1RAs; 
SGLT-2 inhibitors and investigational agents. 
4. Safety parameters out of range (according to local reference ranges).  
a. 
If, on the basis of the medical history, physical examination, vital signs, and 12-lead ECG performed at 
the prescreening visit (Visit 1), there are abnormalities, they must be consistent with the underlying 
illness in the study population (T2DM). This determination must be recorded in the subject's source 
documents and initialed by the investigator. 
b. If, on the basis of the serum chemistry panel (including liver enzymes) and other specific tests such as 
hematology or urinalysis) are outside of normal reference ranges, the subject may be included only if 
the investigator judges the abnormalities or deviations from normal to be not clinically significant or to 
be appropriate and reasonable for5 the population under study. This determination must be recorded in 
the subject's source documents and initialed by the investigator. 
c. 
History of significant cardiac, vascular, pulmonary, gastrointestinal, neurologic, hematologic, 
rheumatologic, and psychiatric disturbances documented during the medical history obtained at 
screening (Visit 1) 
d. History of malignancy except for squamous- and basal-cell carcinoma of the skin, cervical carcinoma, 
or malignancy considered cured and with minimal risk of recurrence 
e. 
Known allergies, hypersensitivity, or intolerance to CANA or SITA (or excipients).  
f. 
Contraindications to use of CANA or SITA according to local prescribing information. 
g. Using disallowed therapies (see 3 above)  
5. Pregnancy: Urine pregnancy testing will be performed for all women according to local procedures unless 
they are surgically sterile or unless there is a documented history of their postmenopausal status. Additional 
serum or urine pregnancy tests may be conducted throughout the study in sufficient number, as determined 
by the investigator or required by local regulations, to establish the absence of pregnancy during the study. 
Pregnancy test must be performed in Central Laboratory and the result reviewed prior to randomization. 
6. Women of childbearing potential (or of uncertain potential or who becomes able to bear children during the 
study) must use a highly effective mode of contraception during the study and for 4 weeks after the end-of-
study visit (Visit 13). The definition of "highly effective contraception" must be consistent with the criteria 
of local regulations.   
7. Any condition for which any condition for which, in the opinion of the investigator, participation would not 
be in the best interest of the subject (e.g. compromise the well-being) or that could prevent, limit, or confound 
the protocol-specified assessments. 
8. Potential subjects who have had major surgery (requiring general anesthesia) within 12 weeks before the 
screening visit or will not have fully recovered from surgery, or has surgery planned during the time the 
subject is expected to participate in the study or within 12 weeks after the last dose of study administration. 
(Subjects with planned surgical procedures to be conducted under local anesthesia may participate.) 
9. Employee of the investigator or study site, with direct involvement in the proposed study or studies under the 
direction of that investigator or study site, as well as family members of the employees or the investigator. 
10. Received an investigational drug or vaccine or used an invasive investigational medical device within 30 
days before the planned first dose of study drug.  
11. Current use of “Natural medicines” or natural medicinal products for diabetes (e.g. cactus-derived nutrients, 
celery).  
12. History of atraumatic amputation within past 12 months of screening, or an active skin ulcer, osteomyelitis, 
gangrene, or critical ischemia of the lower extremity within 6 months of screening. 
13.  Any proposed changes to the above eligibility criteria must be documented via an amendment. 
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Approved   Date: 31 July 2017  
5.3. 
Treatment  
5.3.1. Procedures for Randomization, Stratification, Allocation, and Blinding 
5.3.1.1. Randomization 
Central randomization will be implemented in this study. Subjects will be randomly assigned to one of two treatments 
and one of two sequence groups based on a computer-generated randomization schedule prepared before the study by 
or under the supervision of the sponsor. 
5.3.1.2. Stratification and Allocation   
Randomized allocation of subjects will be balanced by using randomly permuted blocks and stratified by subject BMI 
tertiles at the screening visit (Visit 1), as follows: 
For men, tertile 1 ranges from 22 to <28; 2, from 28 to <33; and 3 from 33 to <45, kg/m2. For women, tertile 1 ranges 
from 22 to <30; 2, from 30 to <36; and 3, from 36 to <45 kg/m2. 
 
Stratified randomization will be performed by generating a separate block and assigning each subject to the appropriate 
block. A dynamic, permuted block randomization will be carried out to stratify subject allocation according to BMI 
tertile. For each block, a permutation (according to gender, gender-specific BMI tertile, and treatment sequence A/B 
or B/A) is chosen at random and subjects are allocated to treatment as they are enrolled according to that permutation. 
When the block is full, another permutation is chosen for the next group of patients. Block sizes will also be varied 
during the randomization. This procedure prevents potential selection bias, which can otherwise result because 
allocation of the last subject in a block is not random; it is completely determined by assignment of the prior subjects 
within the same block (Pond, 2011). This overall randomization procedure is compatible with the small projected 
sample population of the CANA CGM Trial (Suresh, 2011). 
 
An interactive voice response system (IVRS) will assign a unique treatment code, which will dictate the treatment 
assignment and matching study drug kit for the subject. Based on this randomization code, the study drug will be 
packaged and labeled for each subject. Study drug code numbers will be preprinted on the study drug labels and 
assigned as subjects qualify for the study and are assigned to treatment. The requestor must use his or her own user 
identification and personal identification number when contacting the IVRS, and will then give the relevant subject 
details to uniquely identify the subject.  
5.3.1.3.  Blinding 
 
The investigator will not be provided with randomization codes. The codes will be maintained within the IVRS, which 
has the functionality to allow the investigator to break the blind for an individual subject.  
Data that may potentially unblind the treatment assignment (e.g. treatment allocation) will be handled with special 
care to ensure that the integrity of the blind is maintained and the potential for bias is minimized. This can include 
making special provisions, such as segregating the data in question from view by the investigators, clinical team, or 
others as appropriate until the time of database lock and unblinding. 
Under normal circumstances, the blind should not be broken until all subjects have completed the study and the 
database is finalized. Otherwise, the blind should be broken only if specific emergency treatment/course of action 
would be dictated by knowing the treatment status of the subject. In such cases, the investigator may in an emergency 
determine the identity of the treatment by exposing the concealed area of the label attached to the subject's source 
documents, opening the sealed code. It is recommended that the investigator contact the sponsor or its designee if 
possible to discuss the particular situation, before breaking the blind. Telephone contact with the sponsor or its 
designee will be available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be 
informed as soon as possible. The date, time, and reason for the unblinding must be documented in the appropriate 
section of the CRF and in the source document. The documentation received from the IVRS, indicating the code break 
must be retained with the subject's source documents in a secure manner. 
Subjects who have had their treatment assignment unblinded are not required to return for scheduled evaluations. 
NCT03267576


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Approved   Date: 31 July 2017  
5.3.1.4. Dosage and Administration 
Table 5.  Description of Interventions  
Treatment name 
Canagliflozin (Invokana®) 
Sitagliptin (Januvia®) 
Test articles(s) 
Study tablets formulated to have 
equal 
appearance 
and 
other 
characteristics. 
Study tablets formulated to have 
equal appearance and other 
characteristics. 
Dose per delivery 
300 mg. 
100 mg. 
Frequency 
Once-daily. 
Once -daily. 
Total daily dose 
300 mg. 
100 mg. 
Delivery method 
Oral (p.o.). 
Oral (p.o.). 
Delivery instructions 
Blinded study drug will be taken 
orally and swallowed whole with 
liquid and not chewed, divided, 
dissolved, or crushed. One tablet 
will be taken daily, immediately 
before the first meal of the day (at 
approximately the same time of 
day). 
Blinded study drug will be taken 
orally and swallowed whole with 
liquid and not chewed, divided, 
dissolved, or crushed. One tablet 
will be taken daily, immediately 
before the first meal of the day (at 
approximately the same time of 
day). 
5.3.1.5. Treatment Compliance 
A single dose of study drug will be administered orally, by designated study-site personnel at the study sites, who will 
check the subject's mouth to confirm that the dose was swallowed. Study-site personnel will maintain a log of all study 
drug administered. Drug supplies for each subject will be inventoried and accounted for. 
 
When study drug is self-administered by subjects (i.e. between visits), the number of study drug dispensed will be 
recorded and compared with the number returned.  
 
Subjects will receive instructions on compliance with study drug administration at the screening visit. During the 
course of the study, the investigator or designated study-site personnel will be responsible for providing additional 
instruction to reeducate any subject who is not compliant with taking the study drug. 
5.3.1.6. Prestudy and Concomitant Therapy 
Prestudy therapies administered up to 30 days before the first dose of study drug must be recorded at screening. As 
mentioned above (Eligibility Criteria), patients must be taking MET monotherapy at stable daily doses of at least 
1,500 mg at screening to be enrolled in this trial.  
Concomitant therapies must be recorded throughout the study beginning with start of the first dose of study drug (Visit 
6) to the end-of-study visit (Visit 13). Concomitant therapies should also be recorded beyond Visit 1 only in 
conjunction with new or worsening adverse events (AEs) or serious AEs (SAEs) that meet the criteria outlined below. 
Allowed medications are the ones mentioned in the protocol (Canagliflozin, Sitagliptin during their respective periods 
and Metformin IR) and other medications unless among the prohibited concomitant medications. 
Prohibited concomitant therapies include any other SGLT2 inhibitor, any other DPP-4 inhibitor, other oral or 
injectable antidiabetic agent (including colesevelam and bromocriptine, GLP1 analogs or insulin/inslulin analog) 
different from the medications specified in the protocol (Canagliflozin, Sitagliptin or Metformin IR during the 
respective periods).  Subjects may not be in any other investigational drug during the study. Other prohibited 
concomitant medications are corticosteroids or immunosuppressive agents. 
The sponsor must be notified as soon as possible of any instances in which prohibited therapies are administered. 
 
Subjects must be on a stable blood pressure and lipid altering medication regimen for at least 4 weeks before baseline 
(Day 1). Adjustments to the blood pressure-lowering or lipid altering medication regimen that are considered to be 
NCT03267576


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Approved   Date: 31 July 2017  
clinically appropriate should be made during the pretreatment phase to avoid the need to adjustment in these drugs 
during the double-blind treatment phase. 
5.4. 
Study Procedures 
5.4.1. Evaluations 
5.4.1.1. Overview 
The Time and Events Schedule (Table 4) summarizes the frequency and timing of efficacy, safety, and other 
measurements applicable to this study. 
5.4.1.2. Study Procedures by Visit 
The following events are summarized in Table 4. 
5.4.1.2.1. 
Prerandomization Phase 
Beginning 16 days before planned randomization, potential candidates for the study will be advised of the study's 
purposes and potential benefits and risks, and provided with an ICF, which must be signed before any study assessment 
or other procedure. There is no initial washout period, in part because patients must continue to use MET at stable 
doses of at least 1,500 mg during the study. Subjects will be instructed to continue using MET throughout the study. 
Medical history, physical examination, vital signs, and collection of other (e.g. sociodemographic and clinical) data 
will be conducted, in part to determine eligibility for enrollment. Venous blood and urine will be collected to perform 
clinical laboratory safety assessments. Body weight will be evaluated at each study visit (Visits 1 through 12). 
Exceptional and limited retesting of abnormal screening values that lead to exclusion are allowed only once using an 
unscheduled visit during the screening period (to reassess eligibility). 
 
At the screening visit, the results of clinical laboratory tests performed at the central laboratory must be within normal 
limits according to local guidelines and reference ranges. The investigator may consider a subject eligible if previously 
abnormal laboratory test results are within the reference range on a repeat testing by the central laboratory. Only one 
repeat test is allowed, at an unspecified time during the screening interval. No repeat testing for baseline CGM data 
(see below) is allowed. 
 
Except for the tests specified above, if the results of other clinical laboratory tests are outside the normal reference 
ranges, the subject may be included only if the Investigator judges the abnormalities or deviations from normal to be 
not clinically significant or to be appropriate and reasonable for the population under study. This determination must 
be recorded in the subject's source documents and initialed by the Investigator. 
 
During the screening phase, each subject will be provided with the CGMS® Device: the Medtronic iPro2 (Medtronic 
Minimed, Northridge, CA; Figure 7).  
 
Figure 7. The CGMS® Device: Medtronic iPro2 (Medtronic Minimed, Northridge, CA). 
 
NCT03267576


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Approved   Date: 31 July 2017  
Study-site personnel will educate subjects in the use of the device, in part by reviewing the product manual with them. 
They will ask open-ended questions and attempt to anticipate any difficulties, in order to ensure that subjects are 
confident in using the device. Subjects will be provided with written instructions to obtain 24-hour technical support, 
if needed, to operate the device.  
The iPro2 measures interstitial-fluid glucose continuously, computing and storing PG readings every 5 min. for up to 
6 days. The device is cordless and requires minimum patient interaction or training. A wire with a glucose oxidase tip 
is inserted subcutaneously into the abdominal wall using the Senserter. In the presence of glucose and oxygen (O2), 
glucose oxidase catalyzes a biochemical reaction that transfers electrons to receiving molecule, creating electronic 
current measured by the device. 
After 6 days, the device is removed, docked, and the data downloaded by the investigator into the system in a few 
simple steps (Appendix 7A). The docking station can be connected to a computer that contains dedicated software 
(Carelink iPro Software) for use with the system. The computer can then generate a graph or a table of several days 
of glucose readings.  
Subjects will be advised and instructed to maintain separate diet, activity, and symptom diaries during the 6 days of 
monitoring (from which 72 hours of continuous data for readings will be taken), in order to assist in interpreting CGM 
data. To measure daily physical activity, each subject will also be provided with a wearable pedometer. Study-site 
personnel will train subjects in the use of the device, including instructions to capture the data according to the study 
design. Subjects will be provided with written instructions on how to obtain 24-hour technical support, if needed, for 
operation of the device. 
Glucometer readings data, the iPro2 device, completed diaries, and wearable pedometers will be returned by subjects 
and data collected/downloaded/stored by study-site personnel, within 3 days before the randomization visit (Visit 5).  
Study-site personnel will instruct subjects that they will return to study sites to receive the CGM device and repeat the 
6 day CGM procedure two more times during the study, at the end of: 1) active treatment phase 1 (days 22-27); and 
at the end of 2) active treatment phase 2 (days 66-71). 
5.4.1.2.2. 
Randomization Phase 
On Day 0 (Visit 5), subjects will be randomly allocated, to treatments and sequences, in a stratified manner based on 
gender-specific BMI tertiles, via permuted-block randomization. Physical examination and clinical laboratory 
evaluations will be conducted, vital signs assessed, and body weights measured. 
5.4.1.2.3.       Double-Blind Active Treatment Phase 1 
On Day 1 (Visit 6) subjects will report to study sites before their first meal to receive their blinded medication and 
take the first dose under supervision by study-site personnel. Study-site personnel will also remind each subject to 
return on Day 22 to receive their CGM iPro2 device and nutrition/activity/symptom diaries. Telephone reminders will 
also be done to subjects a few days prior   to remind them to return to study sites on Day 22.      
On Day 22, study-site personnel will reacquaint subjects in the use of the CGM iPro2 device and distribute / insert  it 
for use on Days 22-27. Study-site personnel will ask subjects about their first experiences with the device, attempt to 
address any difficulties from that initial experience, and ask open-ended questions to anticipate any difficulties, in 
order to ensure that subjects are confident in using the device. Subjects will be provided with written instructions to 
obtain 24-hour technical support, if needed, to operate the device. Subjects will be advised and instructed to maintain 
separate diet, activity, and symptom diaries and to perform and record Capillary Blood glucose readings with the 
Glucometer during the 6 days of monitoring, in order to assist in interpreting CGM data. 
To measure daily physical activity, each subject will also be provided with a wearable pedometer for concurrent use 
with the CGM iPro2 device (Days 22-27). Study-site personnel will train subjects in the use of the device, including 
instructions to capture the data according to the study design. Subjects will be reminded how to obtain 24-hour 
technical support, if needed, for operation of the device. 
The iPro2 device, the glucometer One Touch Ultra mini ™, completed diaries, and wearable pedometers will be 
returned by subjects, and data collected/downloaded/stored by study-site personnel, on Day 27, immediately before 
NCT03267576


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Approved   Date: 31 July 2017  
the MET washout visit (Visit 9). On Day 27, body weight will be measured, and study-site personnel will elicit any 
reports of AEs from subjects via open-ended questioning and record the data in CRFs. Tablet vials will be collected 
and pills counted to assess compliance. 
5.4.1.2.4. 
Metformin Washout Phase 
On Day 28 (Visit 9), subjects will be instructed to continue taking MET and to return to study sites on Day 44.  
5.4.1.2.5. 
Double-Blind Active Treatment Phase 2 
On Day 44 (Visit 10) subjects will report to study sites before their first meal to receive their blinded medication and 
take the first dose under supervision by study-site personnel. Study-site personnel will also remind each subject to 
return on Day 66 to receive their CGM iPro2 device and nutrition/activity/symptom diaries (patient log sheet). 
Telephone reminders will also be done to subjects a few days prior to remind them to return to study sites on Day 66.      
On Day 66, study-site personnel will reacquaint subjects in the use of the CGMS iPro2 device and distribute it for use 
on Days 66-71. Study-site personnel will ask subjects about their previous experiences with the device, attempt to 
address any difficulties from these experiences, and ask open-ended questions to anticipate any difficulties, in order 
to ensure that subjects are confident in using the device. Subjects will be reminded of instructions to obtain 24-hour 
technical support, if needed, to operate the device. Subjects will be advised and instructed to maintain separate diet, 
activity, and symptom diaries during the 6 days of monitoring, in order to assist in interpreting CGM data. 
To measure daily physical activity, each subject will also be provided with a wearable pedometer for concurrent use 
with the CGMS iPro2 device (Days 66-71). Study-site personnel will reacquaint subjects in the use of the device, 
including instructions to capture the data according to the study design.  
The iPro2 device, the OneTouch Ultra Mini ™ Glucometer, completed diaries, and wearable pedometers will be 
returned by subjects, and data collected/downloaded/stored by study-site personnel, on Day 71 (Visit 12). On Day 71, 
body weight will be measured, and study-site personnel will elicit any reports of AEs from subjects via open-ended 
questioning and record the data in CRFs. Bottles will be collected and pills counted to assess compliance. 
5.4.1.2.6. 
End-of-Study Phase/Early Withdrawal/Completion 
A subject will be considered to have completed the study if he or she has completed all study assessments (i.e. Visits 
1 through 12) or has experienced a clinical endpoint that precludes further continuation in the study (e.g. 
hospitalization for severe hypoglycemia).  Venous blood and urine will be collected to perform end-of-study clinical 
laboratory safety assessments. 
Subjects who prematurely discontinue study treatment for any reason before completion of the double-blind phase 
will not be considered to have completed the study. 
5.4.1.2.6.1. Withdrawal from the Study  
A subject will be automatically withdrawn from the study for any of the following reasons: 
• 
Lost to follow-up 
• 
Withdrawal of consent 
• 
Death 
• 
Noncompliance defined as returned pill counts with >20% (6 pills) of dispensed tablets remaining after 28 days 
of active treatment of subject   
• 
Disease-related events (e.g. hypoglycemia, microvascular events, macrovascular events) 
• 
Discontinuation of study treatment for any reason. A subject's study treatment will be automatically discontinued 
if the investigator or sponsor believes (e.g. that for safety or tolerability reasons (e.g. adverse event) it is in the 
best interest of the subject to discontinue treatment. 
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• 
The subject becomes pregnant (study therapy should be immediately interrupted based upon a positive [hCG], 
test).  
• 
The subject requires chronic dialysis or renal transplantation 
• 
The subject requires disallowed therapy, including need for rescue therapy due to poor glucose control:   
- 
After Day 1 through the end of the study, the investigator will withdraw the patient from the study in order 
to start the rescue therapy considered appropriate in patients that present with FPG measured by SMBG in 
repeated occasions over the course of 7 days, with a mean value equal or greater than 280 mg/dl and 
confirmed by the investigator with Laboratory FPG of equal or greater than 280 mg/dl. Subjects should have 
reinforcement of diet and exercise recommendations before obtaining the repeat FPG value. Subjects should 
be counseled to contact the site if their fasting self-monitored blood glucose (SMBG) consistently exceeds 
these values, and an FPG measurement to determine eligibility for glycemic rescue therapy should be 
obtained and therefore study withdrawal should be done. At the investigator’s discretion, based upon recent 
fasting SMBG values that are consistent with the initial FPG result meeting glycemic rescue criteria, this 
single FPG (ie, without a repeat FPG value) may be used to demonstrate eligibility for withdrawal from the 
study.  
• 
The subject experiences a serious adverse event of biochemically-confirmed (eg, pH, serum ketones, anion gap) 
DKA. 
• 
 The subject requires or has a programmed surgery or surgical procedure or presents with an infection which 
may transitorily alter glycemic control or which treatment may transitorily alter glycemic control. 
If a subject withdraws from the study for any reason before the end of any post-randomization study phase (i.e. Visits 
2-5), end-of-treatment and/or post-treatment assessments should be obtained.  
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel to contact the subject 
and determine the reason for discontinuation/withdrawal. The measures taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to be documented in the CRF and 
in the source document. Study drug assigned to the withdrawn subject may not be assigned to another subject. Subjects 
who withdraw will not be replaced. If a subject withdraws from the study before the end of any post-randomization 
study phase (i.e. Visits 2-5), end-of-treatment and post-treatment assessments should be obtained. 
5.4.1.2.7. 
Post-treatment Phase (Follow-Up)  
Visit 13 will be made to determine any resolution or other outcome of SAEs for up to 7 days after the last dose of 
study drug (days 72-80), unless the subject has died, is lost to follow-up, or has withdrawn consent. If the information 
on patient safety is obtained via telephone contact, written documentation of the communication must be available for 
review in the source documents. If the subject has died, the date and cause of death will be collected and documented 
on the CRF. 
Investigators may recontact the subject to obtain long-term follow-up information regarding the subject's safety or 
survival status as noted in the ICF (refer to Section 10.2.3, Informed Consent). 
Subjects will be instructed that study drug will not be made available to them after they have completed/discontinued 
study drug, that they should continue to take MET as they have done throughout the study, and that they should return 
to their primary physician to determine standard of care. 
5.5. 
Efficacy Evaluations  
CGM parameters will be measured using the CGM® Device: Medtronic iPro2 (Medtronic Minimed, Northridge, CA; 
Figure 7). Study-site personnel, including Investigators, will be centrally trained to calibrate and operate the device, 
instruct subjects in its use, and download and analyze data, according to the device's product manual.  
The following efficacy parameters will be evaluated:  
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Primary efficacy endpoint: Mean (SD) change from baseline in intrapatient coefficient of variation of glucose 
profiles (CV %; SD/mean glucose), as assessed using CGM over a 6-day period at baseline and after each active 
treatment. 
   
Secondary efficacy endpoints. Mean (SD) changes from baseline in: 
 
• 
Glycemic SD for 24-hour glucose (mg/dL). 
• 
Mean 24-hour glucose (mg/dL). 
• 
Preprandial glucose ( mg/dL). 
• 
2-hour PPG (mg/dL).  
• 
Time (minutes), percent of 24 hours, or area under the Glucose time curve for 24 hours (AUC24h) with glucose 
= 70−139 mg/dL (time spent with PG within reference range).   
• 
Time (minutes), percent of 24 hours, or AUC24h (mg/dL/hr) with glucose > 140 mg/dL (time spent with PG 
above reference range). 
• 
Time (minutes), percent of 24 hours, or AUC24h (mg/dL/hr) with glucose > 180 mg/dL (time spent with PG 
markedly above reference range).  
• 
Time (minutes), percent of 24 hours, or area over the PG time curve for 24 hours (AOC24h; mg/dL/hr) with 
glucose < 70 mg/dL.  
• 
Frequency (%) of 2+ consecutive glucose readings < 70 mg/dL (and/or of hypoglycemic symptoms requiring 
personal support). 
 
Exploratory efficacy endpoints. Mean (SD) changes from baseline in: 
 
• 
AUC for glycemic variability (mg/dL/hr) throughout the day (0−24 hours), after breakfast (0−5 hours), after 
lunch (5−11 hours), after dinner (11−15 hours), and during sleep (15−24 hours). 
• 
Peak glucose (mg/dL) throughout the day (0−24 hours), after breakfast (0−5 hours), after lunch (5−11 hours), 
after dinner (11−15 hours), and during sleep (15−24 hours). 
• 
Overall hyperglycemia: AUCtotal (mg/dL/hr). 
• 
Nadir glucose (mg/dL): lowest glucose level over 72 hours. 
• 
Continuous overlapping net glycemic action (CONGA): the SD of summed differences between observations 
separated by n hours. 
• 
Mean of daily differences in PG (MODD). 
5.6. 
Safety/Tolerability Evaluations  
5.6.1. Safety 
5.6.1.1. Physical Examination 
A medical history will be taken and physical examination conducted at the screening and end-of-study visits (Visits 1 
and 12), according to each investigator's usual practice and/or local/regional/global practice guidelines. 
At minimum, Investigators will collect the following information and conduct the following assessments. 
History: 
• 
Sociodemographic data: age, race/ethnicity, gender, height, and weight. Weight will also be measured at each 
study visit to assess and record any changes.  
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• 
History of T2DM: diagnosis date and time from this date to the screening visit (screening assessment only)  
• 
Past medical history: other major illnesses other than T2DM (history or ongoing), and previous surgeries 
• 
Family history (including of T2DM)  
• 
History of (and ongoing) medication use, including MET at stable dosages 
• 
Social history: marital or cohabitating status, number of children, employment status 
• 
Lifestyle history: behavioral risk factors, including physical activity, nutrition, tobacco/alcohol/substance use 
or abuse  
• 
Allergies 
• 
Sexual history 
 
Assessments of organ-systems: 
• 
Cardiovascular 
• 
Cranial-nerve 
• 
Cutaneous 
• 
Endocrine 
• 
Gastrointestinal 
• 
Genitourinary 
• 
Musculoskeletal 
• 
Nervous-system 
• 
Respiratory 
5.6.1.2. Vital Signs  
Vital signs will be measured at the screening and end-of-study visits (Visits 1 and 12), according to each Investigator's 
usual practice and/or local/regional/global practice guidelines. Oral temperature, pulse/heart rate, respiratory rate, and 
blood pressure will be assessed with a completely automated device. Manual techniques will be used only if an 
automated device is not available. Pulse rate and blood pressure will be measured at every clinic visit during the study. 
Blood pressure and pulse/heart rate measurements will be performed at every visit and should be preceded by at least 
5 minutes of rest in a quiet setting without distractions (e.g. television, cell phones) according to instructions 
(APPENDIX 5) 
5.6.1.3. Electrocardiogram (ECG)  
Twelve-lead ECGs will be conducted at the screening and end-of-study visits (Visits 1 and 12), according to each 
Investigator's usual practice and/or local/regional/global practice guidelines. During the collection of ECGs, subjects 
should be in a quiet setting without distractions (e.g. television, cell phones). Subjects should rest in a supine position 
for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. When performing 
safety evaluations, the investigator should adhere to the following sequences:  ECG, vital signs, blood draw, and urine 
collection. 
5.6.1.4. Clinical Laboratory Assessments 
Venous blood samples of approximately ≥5 mL will be collected for measurement of serum chemistries and complete 
blood count/hematology (APPENDIX 10). Estimated glomerular filtration rate (eGFR) will be computed using serum 
creatinine and other clinical data according to the abbreviated Modification of Diet in Renal Disease (MDRD) 
equation:  
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               eGFR = 186 x (Creat/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black)  
Blood samples for serum chemistry and hematology, and a random urine sample for urinalysis, will be collected at the 
screening and end-of-study visits for evaluation by a central laboratory. 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. Laboratory reports must be filed with the source documents. Subject confidentiality will be 
maintained. Additional information about the collection, handling, and shipment of biological samples can be found 
in the Laboratory Manual. 
Safety assessments will be based on medical review of adverse event reports and the results of vital-sign 
measurements, 12-lead ECGs, physical examinations, clinical laboratory tests, and other safety evaluations at 
specified time points as described in the Time and Events Schedule (Table 4). 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the CRF and laboratory requisition form. Refer 
to the Time and Events Schedule (Table 4) for the timing and frequency of all sample collections. 
Instructions for the collection, handling, storage, and shipment of samples are found in the laboratory manual that will 
be provided. Collection, handling, storage, and shipment of samples must be under the specified, and where applicable, 
controlled temperature conditions as indicated in the central laboratory manual. 
5.6.2.   Tolerability: Adverse Events 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally 
acceptable representative) for the duration of the study. Adverse events will be followed by the investigator as 
specified in Section 7, Adverse Event Reporting. 
5.6.3.    Other Evaluations  
At each study visit, body weight will be measured. 
6. 
STATISTICAL ANALYSIS PLAN 
6.1. 
Sample Size Determination 
Crossover trials yield more statistically efficient comparisons of treatments than parallel-group designs. (Shen, 2006; 
Wellek and Blettner, 2012) Because of these considerations, crossover studies achieve the same level of statistical 
power and precision while using smaller sample sizes than parallel-group studies.  Because each subject serves as his 
or her own control, data are paired rather than independent. 
 
To compute sample sizes in the CANA CGM Trial, the following software package was utilized: P/S (Power and 
Sample 
Size 
Calculation) 
version 
3.1.2 
(Biostatistics 
Department 
of 
Vanderbilt 
University 
(http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize). Raw data outputs on sample size computations using 
this software are presented in the Appendices.  
 
In the present Statistical Analysis Plan, sample size calculations are conducted using more than one set of assumptions 
because: 1) CANA 300 mg and SITA 100 mg have never been compared directly in a CGM study and 2) there are no 
available comparative data on the effects of CANA 300 mg versus SITA 100 mg on mean intrapatient glucose CV % 
(the primary outcome measure as specified by Janssen and principal investigator Dr. Fernando Javier Lavalle-
González). 
 
Although the effects of CANA 300 mg and SITA 100 mg on GV have never been directly compared in a clinical trial 
employing CGM, each active therapy has been compared with placebo using this methodology. The effects of the two 
therapies have been compared directly in non−CGM studies.   
 
In a Phase 2 trial (Janssen Study 28431754DIA2004), 18 weeks of treatment with CANA 300 mg were associated 
with a mean decrease in glycemic SD of 12.24 (SD: 13.90) mg/dL compared to placebo (Table 2). In the same study, 
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the change with placebo was a mean increase in glycemic SD of 1.62 (SD: 14.04) mg/dL. Hence, the mean treatment 
difference between CANA 300 mg and placebo in glycemic SD was 13.86 mg/dL.  
 
In a similar population, subjects received either SITA 100 or placebo. Compared to placebo, SITA 100 mg was 
associated with a mean decrease in glycemic SD of 2.52 (SD: 2.34) mg/dL (Ellis et al., 2011). Comparing the effects 
of CANA 300 mg and SITA 100 mg with placebo across these studies, the net decrease in glycemic SD (vs. placebo) 
between CANA 300 mg and SITA 100 mg is hence 13.86 – 2.52 = 11.36.  
 
Using a two-sided α = 0.05 and a power of 80%, a total of 12 subjects are needed to detect a mean difference of 11.36 
mg/dL in glycemic SD between CANA 300 mg and SITA 100 mg, assuming a common SD of 13.00 mg/dL (Appendix 
1).  
 
Because the above sample size calculation on mean glycemic SD involves indirect comparisons between CANA 300 
mg (and SITA 100 mg) and placebo, a second sample size calculation is conducted using data from a direct-comparator 
(CANA 300 mg vs. SITA 100 mg) trial that did not employ CGM but did involve a Latin American population 
(CANTATA-D) (Table 1) (Lavalle-Gonzalez et al., 2013b).  
 
To compute sample size using studies that directly compared the effects of CANA 300 mg or SITA 100 mg on glucose 
profiles, we translated HbA1c to estimated average glucose (eAG) using the formula of formula of Nathan et al 
(Nathan et al., 2008) Values computed in this way are normally distributed. Using least–squares regression analysis 
with HbA1c as the independent variable and mean eAG as the dependent variable, there was no deviation from 
linearity when fitting higher-order polynomial terms (Wilson et al., 2011). When examining residual values, no 
outliers or other overly consequential values were identified that modified the normal distribution. There was no 
meaningful divergence from the assumption of homoscedasticity when plotting residuals versus predicted values 
(Wilson et al., 2011). 
 
In the Latin American subpopulation of the CANTATA-D trial, the mean (SD) difference between the two treatments 
in eAG was −41.00 (−38.55) mg/dL (Lavalle-Gonzalez et al., 2016). According to a two-sided α = 0.05 and power of 
80%, a total of 9 subjects with paired data are needed to detect a mean (SD) difference of 41.00 (38.55) mg/dL 
between CANA 300 mg and SITA 300 mg with a power of 80% (Appendix 2).  
 
Finally, effects of CANA 300 mg and SITA 100 mg were directly compared in the overall CANTATA-D trial (all 
patients). The mean (SD) difference in eAG between groups was 11.11 (26.28) mg/dL. According to a two-sided α = 
0.05 and power of 80%, a total of 46 subjects with paired data are needed to detect a mean (SD) difference of 11.11 
(16.28) mg/dL between CANA 300 mg and SITA 300 mg with a power of 80% (Appendix 3). 
 
Using this, most conservative sample size (N = 46) and a conservative subject attrition rate of 20% for an 
approximately 12-week study, the required sample size for this crossover trial is 46 + 13.8 = 60subjects, each 
randomly allocated in a double-blind manner to two treatments, two periods, and two sequences involving 
CANA 300 mg compared with SITA 100 mg as add-ons to MET in T2DM subjects with glucose inadequately 
controlled on the biguanide as monotherapy who meet all eligibility criteria. 
6.2. 
Overall Statistical Methods 
Subjects will be randomized 1:1 to each treatment sequence. The CANTATA-D study found that treatment with 
CANA 300 mg was associated with a 2.1% to 2.9% reduction in body weight compared to SITA 100 mg when each 
was added to ongoing MET over 52 weeks (Lavalle-Gonzalez et al., 2013; Lavalle-Gonzalez et al., 2016). It is also 
possible that, once subjects lose weight while randomized to CANA 300 mg, they will become more physically active. 
To minimize the effects of this potentially important covariate with relation to GV, randomization will be stratified 
according to gender-specific tertiles of body mass index (BMI) (Kriska et al., 2003). For men, tertile 1 ranges from 
17 to <28; 2, from 28 to <33; and 3 from 33 to <66, kg/m2. For women, tertile 1 ranges from 16 to <30; 2, from 30 to 
<36; and 3, from 36 to <69 kg/m2. Because the eligibility criteria in this trial require a range of BMI = 22 to 45 kg/m2 
for study entry, the tertiles are redefined as follows. For men, tertile 1 ranges from 22 to <28; 2, from 28 to <33; and 
3 from 33 to <45, kg/m2. For women, tertile 1 ranges from 22 to <30; 2, from 30 to <36; and 3, from 36 to <45 kg/m2. 
 
This stratified randomization method will control for any influence of the covariate of baseline BMI (surrogate for 
body weight). One potential limitation of stratified randomization is that the covariate must be measured (and known) 
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at baseline. If it is not feasible to determine all subjects’ BMI (or body weight) values at baseline, an analysis of 
covariance (ANCOVA) model controlling for the covariate of baseline BMI (and/or body weight) can be constructed. 
6.2.1.   Efficacy Outcome Measures and Hypothesis Testing 
Three null hypotheses (NH) will be tested: 
H0A: There is no statistically significant difference between CANA 300 mg and SITA 100 mg in terms of 
their effects on mean intrapatient glucose CV % from baseline as measured by CGM over a continuous 72 
hour period at baseline and after each active treatment. 
H1A [Alternative hypothesis (AH)]: There is a statistically significant difference between CANA 300 mg and 
SITA 100 mg in terms of their effects on mean intrapatient glucose CV % from baseline as measured by 
CGM over a continuous 72 hour period at baseline and after each active treatment. 
H0B: There is no statistically significant difference between CANA 300 mg and SITA 100 mg in terms of 
their effects on mean intrapatient glycemic SD for 24-hour PG from baseline as measured by CGM over a 
continuous 72 hour period at baseline and after each active treatment. 
H1B: There is a statistically significant difference between CANA 300 mg and SITA 100 mg in terms of their 
effects on mean intrapatient glycemic SD for 24-hour PG from baseline as measured by CGM over a 
continuous 72 hour period at baseline and after each active treatment. 
H0C: There is no statistically significant difference between CANA 300 mg and SITA 100 mg in terms of 
their effects on mean 24-hour PG from baseline as measured by CGM over a continuous 72 hour period at 
baseline and after each active treatment. 
H1C: There is no statistically significant difference between CANA 300 mg and SITA 100 mg in terms of 
their effects on mean 24-hour PG from baseline as measured by CGM over a continuous 72 hour period at 
baseline and after each active treatment. 
 
Descriptive statistics will be presented as mean (SD) for normally distributed continuous variables, median 
[interquartile range (IQR)] for non-normally distributed continuous variables, and numbers (%) for categorical 
variables. Baseline sociodemographic and other characteristics will be compared using Fisher’s Exact test for 
categorical variables and Student’s t-test for normally distributed continuous variables.  
Efficacy analyses will be conducted using intent-to-treat and per-protocol populations. Although a previous 
randomized controlled trial compared effects of another SGLT2 inhibitor (and also open-label SITA 100 mg) using a 
modified last observation carried forward approach (with linear interpolation) to missing data,(Rosenstock et al., 2013) 
no data imputation will be performed in the present study, which has a limited number of visits (six). 
As in a previous CGM study, the distribution of each glycemic indicator (except for SD; see below), as well as body 
weight will be assessed for normality via the Shapiro-Wilk test (Nomura et al., 2011). For normally distributed data, 
the mean (SD) value will be presented and, for non-normally distributed data, the median and IQR. Most between-
treatment differences will be assessed using a paired Fisher’s Exact test for baseline categorical variables and paired 
t-tests or Wilcoxon signed rank sum tests for normally and non-normally distributed continuous efficacy endpoints 
(respectively), according to the Shapiro-Wilk test results. 
Also paralleling a previous CGM study involving SITA 100 mg, data for analyses of the CANA CGM Trial's 
secondary endpoints related to AUC24hr (and AOC24hr for hypoglycemia) will be included per subject only if >70% of 
his or her CGM readings are available during each assessment period (3-day CGM at the end of the baseline and each 
of two treatment intervals); and AUC values will be adjusted for preprandial PG (FPB) readings (Ellis et al., 2011). 
Some of these variables (e.g. percentage of time with PG in different ranges) are known to be non-normally distributed 
and, as in previous CGM studies, will be evaluated using paired Wilcoxon rank sum tests on median and IQR values 
(Nomura et al., 2011; Nishimura et al., 2015).  
Body weight will be assessed at each visit. In the event of a significant mean (SD) [or median (IQR)] difference in 
change from baseline in body weight or physical activity between CANA 300 mg and SITA 100 mg (according to a 
statistical assessment informed by the Shapiro-Wilk test) a statistical approach similar to a prior SGLT2 (vs. SITA) 
trial will be taken (Rosenstock et al., 2013). A sensitivity analysis using either: 1) a repeated-measures mixed-effect 
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model with baseline CGM values as fixed effects and on-treatment body weight, and subject as random effects; or 2) 
an ANCOVA with visit-wise body weights and physical activity as covariates.  
The primary efficacy analysis will be conducted on the intent-to-treat population, which comprises all subjects who 
received at least one dose of medication and in whom CGM recordings at baseline and after each active treatment 
were successful. A secondary efficacy analysis will be conducted on the per-protocol population, which will include 
all intent-to-treat subjects without a major protocol violation. 
To evaluate carry-over effects, Grizzle’s two-stage model will be employed to statistically test for treatment x period 
interactions (Shen, 2006) (Appendix 4). In the event of a significant carryover effect, the methodology enables 
comparison of the effects of CANA 300 mg versus SITA 100 mg on parameters of GV in one of the two treatment 
periods. 
 
All tests will be conducted at a two-sided α = 0.05 (i.e. a priori significance level of p < 0.05). 
6.2.2.   Safety/Tolerability Measures 
Subjects receiving at least one dose of active treatment will comprise the safety population. Safety will be assessed 
according to mean values for vital signs, 12-lead ECGs, and laboratory examinations at screening and the end of each 
active treatment period. Adverse events will be elicited by open-ended questioning at each visit and coded as to 
system-organ class and preferred term using the Medical Dictionary of Regulatory Activities (MedDRA) version 14 
or higher.  Safety and tolerability parameters will be summarized by descriptive statistics only; no hypotheses will be 
tested. Continuous variables will be expressed as mean (SD; for normally distributed) or median (IQR; for non-
normally distributed) and categorical variables as numbers (%). 
7. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies are crucial for the 
protection of subjects, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The 
sponsor has established Standard Operating Procedures in conformity with regulatory requirements worldwide to 
ensure appropriate reporting of safety information; all clinical studies conducted by the sponsor or its affiliates will 
be conducted in accordance with those procedures. 
Care will be taken not to introduce bias when detecting adverse events (AEs) or serious AEs (SAEs). Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE event occurrence.  
7.1    Definitions 
7.1.1    Adverse Event Definitions and Classifications 
7.1.1.1. Adverse Events 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal (noninvestigational) 
product. An AE does not necessarily have a causal relationship with the treatment. An AE 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 Harmonization [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition, 
or abnormal results of diagnostic procedures, including laboratory test abnormalities. 
Note: The sponsor collects adverse events starting with the signing of the ICF. 
7.1.1.2. Serious Adverse Events 
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal Products for Human Use 
is any untoward medical occurrence that at any dose: 
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• 
Results in death. 
• 
Is life threatening. 
 
(The subject was at risk of death at the time of the event. It does not refer to an event that hypothetically might 
have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is a suspected transmission of any infectious agent via a medicinal product. 
• 
Is medically important.* (*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes listed in the definition above. These should usually be considered serious.) 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal relationship between 
the study drug and the event, the event must be reported as a serious and unexpected suspected adverse reaction even 
if it is a component of the study endpoint. In the CANA CGM Trial, the chief SAE that may also be a study endpoint 
is an event of hypoglycemia (according to both symptoms and signs of PG < 70 mg/dL) that requires medical attention 
or other assistance from a caregiver.   
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal relationship between 
the drug and the event, the event must be reported under § 312.32(c)(1)(i) as a serious and unexpected suspected 
adverse reaction even if it is a component of the study endpoint unless contradicted by local regulations. Refer to 21 
CFR 312.32(c)(5) for further guidance as appropriate. 
7.1.1.3. Unlisted (Unexpected) Adverse Events/Reference Safety Information 
An AE is considered unlisted if its nature or severity is not consistent with the applicable product reference safety 
information. For CANA, the expectedness of an AE event will be determined by whether or not it is listed in the full 
prescribing information [package insert (PI)]. For SITA and MET, with marketing authorization, the expectedness of 
an AE will be determined by whether or not it is listed in each product's PI. 
7.1.1.4. Adverse Events Associated With the Use of the Drug 
An adverse event is considered associated with the use of the drug if the attribution is [possible, probable, or very 
likely by the definitions listed in the following section (Attribution Definitions). 
7.1.1.5. Attribution Definitions 
7.1.1.5.1. 
Not Related 
An AE that is not related to the use of the drug. 
7.1.1.5.2. 
Doubtful 
An AE for which an alternative explanation is more likely, such as concomitant drug(s), concomitant disease(s), or 
the relationship in time suggests that a causal relationship is unlikely. 
7.1.1.5.3. 
Possible 
An AE that might be due to the use of the drug. An alternative explanation, such as concomitant drug(s) or concomitant 
disease(s), is inconclusive. The relationship in time is reasonable; therefore, the causal relationship cannot be excluded. 
7.1.1.5.4. 
Probable 
An AE that might be due to the use of the drug. The relationship in time is suggestive (e.g. confirmed by dechallenge). 
An alternative explanation, such as concomitant drug(s) or concomitant disease(s), is less likely. 
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7.1.1.5.5. 
Very Likely 
An AE event that is listed as a possible adverse reaction and cannot be reasonably explained by an alternative 
explanation, such as concomitant drug(s) or concomitant disease(s). The relationship in time is very suggestive (e.g. it 
is confirmed by dechallenge and rechallenge). 
7.2. Severity Criteria 
An assessment of severity grade will be made using the following general categorical descriptors: 
• 
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not interfering with 
everyday activities. 
• 
Moderate: Sufficient discomfort is present to cause interference with normal activity. 
• 
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. Prevents normal, 
everyday activities. 
The investigator should use clinical judgment in assessing the severity of events not directly experienced by the subject 
(e.g. laboratory abnormalities). 
7.3    Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting or safety evaluation include, 
but are not limited to: 
• 
Overdose of a sponsor or other study drug (overdose being the ingestion of one or more tablet from the dose 
indicated in the protocol.  Investigators should take the actions considered appropriate for the situation,  ensuring 
the patient’s best interest and wellbeing.    
• 
Suspected abuse/misuse of a sponsor or other study drug 
• 
Accidental or occupational exposure to a sponsor or other study drug 
• 
Any failure of expected pharmacologic action (i.e. lack of effect) of a sponsor or other study drug 
• 
Unexpected therapeutic or clinical benefit from use of a sponsor study drug 
• 
Medication error involving a sponsor product (with or without subject exposure to the sponsor study drug, such 
as name confusion) 
• 
Exposure to a sponsor study drug from breastfeeding 
• 
Amputation 
Special reporting situations should be recorded in the CRF. Any special reporting situation that meets the criteria of a 
SAE should be recorded on the SAE page of the CRF. 
7.3.1. Procedures 
7.3.1.1. All Adverse Events 
All AEs and special reporting situations, whether serious or nonserious, will be reported from the time a signed and 
dated ICF is obtained until completion of the subject's last study-related procedure, which may include contact for 
follow-up of safety. Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using the Serious Adverse Event Form. The sponsor will evaluate 
any safety information that is spontaneously reported by an investigator beyond the time frame specified in the 
protocol. 
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they are protocol-specific 
assessments.  
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All AEs, regardless of seriousness, severity, or presumed relationship to study drug, 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 (e.g. 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 AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions. 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. The sponsor will 
also report to the investigator (and the head of the investigational institute where required) all suspected unexpected 
SAEs (SUSARs). 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. A SUSAR will be reported to regulatory authorities unblinded. Participating 
investigators and the IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified.  
For all studies with an outpatient phase, the subject must be provided with a "wallet (study) card" and instructed to 
carry this card with them for the duration of the study, indicating the following:  
• 
Study number 
• 
Statement, in Spanish or English, that the subject is participating in a clinical study 
• 
Investigator's name and 24-hour contact telephone number 
• 
Local sponsor's name and 24-hour contact telephone number (for medical staff only) 
• 
Site number 
• 
Subject number 
• 
Any other information that is required to do an emergency breaking of the blind 
Consistent with standard diabetes treatment guidelines, all study subjects should be provided with routine preventative 
foot care and early intervention for foot problems. Specifically: 
• 
Provide or ensure that all subjects have had general foot self-care education. 
• 
Perform a comprehensive foot evaluation at each visit to identify risk factors for ulcers and amputations. The 
examination should include inspection of the skin, assessment of foot deformities, neurological assessment 
including pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment including pulses 
in the legs and feet. 
• 
Subjects who have a history of prior lower extremity complications, loss of protective sensation, structural 
abnormalities, or peripheral arterial disease should be referred to foot care specialists for ongoing preventive 
care. 
Study research staff should make study subjects aware of potential signs and symptoms of DKA such as difficulty 
breathing, nausea, vomiting, abdominal pain, feeling confused, fruity-smelling breath, and unusual fatigue or 
sleepiness. Study subjects should be instructed to contact the site if they experience such symptoms. If the investigator 
suspects these symptoms may be related to DKA (even if the subject’s blood glucose levels are less than 250 mg/dL 
(13.9 mmol/L), testing for urine or blood ketones should be considered. 
For all study subjects, there should be a clinical evaluation at every visit to assess the presence of any sign or symptom 
suggestive of volume depletion (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and 
dehydration), which if present should be adequately treated either by decreasing dose or eliminating use of diuretics 
or other antihypertensive medications or interrupting study drug until the condition resolves. However, consider 
withdrawal of other antihypertensive agents prior to adjusting dose of ACE inhibitors or ARBs. 
7.3.1.2. Serious Adverse Events 
All SAEs 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. 
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Information regarding SAEs 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 an SAE should be made by facsimile (fax). 
All SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation of the subject's 
participation in the study, must be followed until any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health care practitioner refusal 
to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. Any event requiring 
hospitalization (or prolongation of hospitalization) that occurs during the course of a subject's participation in a study 
must be reported as an SAE, except hospitalizations for the following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g. 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). [Note: 
Hospitalizations that were planned before the signing of the ICF, and where the underlying condition for which 
the hospitalization was planned has not worsened, will not be considered SAEs. Any AE that results in 
prolongation of the originally planned hospitalization is to be reported as a new SAE.] 
• 
For convenience the investigator may choose to hospitalize the subject for the duration of the treatment period.  
The cause of death of a subject in a study within 30 days of the last dose of study drug, whether or not the event is 
expected or associated with the study drug, is considered an SAE. 
7.3.1.3. Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to the sponsor by the 
study-site personnel within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered serious adverse events and must be reported using the Serious Adverse Event Form. If a 
subject becomes pregnant during the study, a determination regarding study drug discontinuation must be made by 
the investigator in consultation with the sponsor. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects included in the 
study will be reported as noted above. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. 
7.4. Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted regarding safety issues 
or questions regarding the study are listed in the Contact Information page(s), which will be provided as a separate 
document. 
7.5. Product Quality Complaint Handling 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to manufacturing, labeling, 
or packaging ( i.e. 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, 
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accurate, and complete reporting and analysis of PQC information from studies are crucial for the protection of 
subjects, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of PQC 
information; all studies conducted by the sponsor or its affiliates will be conducted in accordance with those 
procedures. 
7.5.1.   PQC 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 6.1.1.2, Serious Adverse Events). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor. 
7.5.1.1. 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. 
8. 
STUDY DRUG INFORMATION 
8.1. 
Physical Description of Study Drugs 
CANA is formulated as 300-mg tablets and SITA as matched 100-mg tablets. Subjects will continue to use their own 
MET (at stable entry doses) throughout the study. CANA will be manufactured and provided under the responsibility 
of the sponsor.  
8.2. 
Packaging 
The study drug will be packaged in individual subject kits. Each kit will consist of study drug for the first phase; diaries 
to record daily nutrition, physical activity, and any clinical symptoms (e.g. suggestive of hypoglycemia). Subjects will 
return to study sites 4 days before the end of their active-treatment and washout phases to receive their CGM and then 
return to these sites 3 to 4 days later to return the devices (and to allow study-site personnel to download the data). All 
study drug will be dispensed in child-resistant packaging. 
8.3. 
Labelling 
Study drug labels will contain information to meet the applicable regulatory requirements. 
8.4. 
Preparation, Handling, and Storage 
Subjects will be instructed to store CANA at an approximate temperature of 25°C (77°F). Excursions from 15°C to 
30°C (59°F to 86°F) are allowed. 
Subjects will be instructed to store SITA at an approximate temperature of at 20°C to 25°C (68°F to 77°F). Excursions 
from 15°C to 30°C (59°F to 86°F) are allowed. 
Subjects will store and use MET (at stable doses) in the same manner as at the screening visit. 
8.5. 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried and accounted for 
throughout the study. The dispensing of study drug to the subject, and the return of study drug from the subject, must 
be documented on the drug accountability form. Subjects must be instructed to return all original containers, whether 
empty or containing study drug.  
Study drug must be handled in strict accordance with the protocol and the container label, and must be stored at the 
study site in a limited-access area or in a locked cabinet under appropriate environmental conditions. Unused study 
drug, and study drug returned by the subject, must be available for verification by the sponsor's study site monitor 
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during on-site monitoring visits. The return to the sponsor of unused study drug will be documented on the drug return 
form. When the study site is an authorized destruction unit and study drug supplies are destroyed on-site, this must 
also be documented on the drug return form. 
Initial dispensing of study drugs (CANA and SITA) will be under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to subjects 
participating in the study. Returned study drug must not be dispensed again, even to the same subject. Whenever a 
subject brings his or her study drug to the study site for pill count, this is not seen as a return of supplies. Study drug 
may not be relabeled or reassigned for use by other subjects. The investigator agrees neither to dispense the study drug 
from, nor store it at, any site other than the study sites agreed upon with the sponsor. 
9. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
• 
Package inserts for CANA, SITA, and MET. 
• 
Approved study protocol 
• 
User's manual (with technical support contact information) for the CGMS® Device: the Medtronic iPro2 
(Medtronic Minimed, Northridge, CA [Laboratory manual] 
• 
Example subject Patient Log Sheet used to record nutrition, physical activity, and any important clinical 
symptoms (e.g. of hypoglycemia) 
• 
IVRS Manual, including contact information   
• 
DMC and other central-study administrative contact information 
• 
Sample ICF 
• 
Health care related materials for the randomized subjects, distributed within the protocol visits, with the aim to 
encourage subject retention in the protocol will be provided. These materials are non-returnable to the site.   
10. 
ETHICAL ASPECTS 
10.1. 
Study-Specific Design Considerations 
Potential subjects will be fully informed of the risks and requirements of the study and, during the study, subjects will be 
given any new information that may affect their decision to continue participation. They will be told that their consent to 
participate in the study is voluntary and may be withdrawn at any time with no reason given and without penalty or loss 
of benefits to which they would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, 
and potential adverse events of the study, and provide their consent voluntarily, will be enrolled. 
10.2. 
Regulatory Ethics Compliance 
10.2.1. 
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 subjects. Compliance with this standard provides public 
assurance that the rights, safety, and well-being of study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki, and that the study data are credible. 
10.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB with current and 
complete copies of the following documents (as required by local regulations): 
• 
Final protocol and, if applicable, amendments 
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• 
Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
• 
Full prescribing information (PIs) of study drugs 
• 
Sponsor-approved subject recruiting materials 
• 
Investigator's curriculum vitae or equivalent information (unless not required, as documented by the IEC/IRB) 
• 
Information regarding funding, name of the sponsor, institutional affiliations, other potential conflicts of interest, 
and incentives for subjects 
• 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, amendments (if 
any, excluding the ones that are purely administrative, with no consequences for subjects, data or study conduct, unless 
required locally), the ICF, applicable recruiting materials, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being approved. 
During the study, the investigator (or sponsor where required) will send the following documents and updates to the 
IEC/IRB for their review and approval, where appropriate: 
• 
Protocol amendments (excluding the ones that are purely administrative, with no consequences for subjects, data 
or study conduct) 
• 
Revision(s) to ICF and any other written materials to be provided to subjects 
• 
If applicable, new or revised subject recruiting materials approved by the sponsor 
• 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at least annually) 
• 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug 
• 
New information that may adversely affect the safety of the subjects or the conduct of the study 
• 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
• 
Report of deaths of subjects under the investigator's care 
• 
Notification if a new investigator is responsible for the study at the site 
• 
Development Safety Update Report and Line Listings, where applicable 
• 
Any other requirements of the IEC/IRB 
 
For all protocol amendments (excluding the ones that are purely administrative, with no consequences for subjects, 
data or study conduct), the amendment and applicable ICF revisions must be submitted promptly to the IEC/IRB for 
review and approval before implementation of the change(s).  
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about the study 
completion.  
10.2.3. Informed Consent  
Each subject must give written consent according to local requirements after the nature of the study has been fully 
explained. Because the total duration of this study is 80 days (and of active treatment 56 days), the potential benefits 
and risks are of a short-term nature. The potential clinical benefits include enhanced glucose control (and overall care 
in the setting of a clinical study) using either active treatment in conjunction with MET (compared to MET 
monotherapy). A potential (but very small) risk of the study is hypoglycemia. In part because time with hypoglycemia 
represents a secondary efficacy endpoint, subjects will receive diaries to record any signs or symptoms of 
hypoglycemia, as well their nutrition and physical activity. 
The ICF must be signed before performance of any study-related activity. The ICF that is used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and understand. The 
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informed consent will be in accordance with ethical tenets originating in the Declaration of Helsinki, current ICH and 
GCP guidelines, applicable regulatory requirements, and sponsor policy. 
Before any assessment or other procedure, including enrollment in the study, the investigator or an authorized member 
of the study-site personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, and 
potential hazards of the study, and any discomfort participation in the study may entail. Subjects will be informed that 
their participation is voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment of his or her disease. 
Subjects will be told that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject identification register 
for the purposes of long-term follow up if needed and that their records may be accessed by health authorities and 
authorized sponsor personnel without violating the confidentiality of the subject, to the extent permitted by the 
applicable law(s) or regulations.  
By signing the ICF, the subject is authorizing such access. It also denotes that the subject agrees to allow his or her 
study physician to recontact the subject for the purpose of obtaining consent for additional safety evaluations, and 
subsequent disease-related treatments, if needed. 
The subject 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 the subject's personally dated 
signature. After having obtained the consent, a copy of the ICF must be given to the subject. 
If the subject is unable to read or write, an impartial witness/legally acceptable representative 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 subject or legally acceptable representative is obtained. 
The blood volume taken for safety testing, at the screening and end-of-study visits, is necessary to assess and ensure 
the safety of each subject. This volume is much less than would be required for standard blood donation (500 mL over 
60 days). 
10.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be limited to data necessary to 
fulfill the objectives of the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality and compliance with 
applicable data privacy protection laws and regulations. Appropriate technical and organizational measures to protect 
the personal data against unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss or 
alteration must be put in place. Sponsor personnel whose responsibilities require access to personal data agree to keep 
the identity of subjects confidential. 
The informed consent obtained from the subject (or his or her legally acceptable representative) includes explicit 
consent for the processing of personal data and for the investigator/institution to allow direct access to his or her 
original medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory 
inspection. This consent also addresses the transfer of the data to others. 
11. 
ADMINISTRATIVE REQUIREMENTS 
11.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by the sponsor. All 
protocol amendments must be issued by the sponsor, and signed and dated by the investigator. Protocol amendments 
must not be implemented without prior IEC/IRB approval, or when the relevant competent authority has raised any 
grounds for non-acceptance, except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the change(s) involves 
only logistic or administrative aspects of the study, the IEC/IRB (where required) only needs to be notified. 
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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. 
11.2. 
Regulatory Documentation 
11.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities in each respective 
country, if applicable. A study may not be initiated until all local regulatory requirements are met. 
11.2.2. 
Required Prestudy Documentation 
The following documents must be provided to the sponsor before shipment of study drug to the study site: 
• 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
• 
A copy of the dated and signed (or sealed), written IEC/IRB approval of the protocol, amendments, ICF, any 
recruiting materials, and if applicable, subject compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed) by the chairman or authorized designee. 
• 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their function, with a 
statement that it is organized and operates according to GCP and the applicable laws and regulations. If 
accompanied by a letter of explanation, or equivalent, from the IEC/IRB, a general statement may be substituted 
for this list. If an investigator or a member of the study-site personnel is a member of the IEC/IRB, documentation 
must be obtained to state that this person did not participate in the deliberations or in the vote/opinion of the 
study. 
• 
Regulatory authority approval or notification, if applicable 
• 
Signed and dated statement of investigator (e.g. Form FDA 1572), if applicable 
• 
Documentation of investigator qualifications (e.g. curriculum vitae) 
• 
Completed investigator financial disclosure form from the principal investigator, where required 
• 
Signed and dated clinical trial agreement, which includes the financial agreement 
• 
Any other documentation required by local regulations 
 
The following documents must be provided to the sponsor before enrollment of the first subject: 
• 
Completed investigator financial disclosure forms from all subinvestigators 
• 
Documentation of subinvestigator qualifications (e.g. 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 (e.g. accreditation/license), if 
applicable 
11.2.3. Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy identification of each 
subject during and after the study. This document will be reviewed by the sponsor study-site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed by the investigator in the 
study file. To ensure subject confidentiality, no copy will be made. All reports and communications relating to the 
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study will identify subjects by subject identification and date of birth. In cases where the subject is not randomized 
into the study, the date seen and date of birth will be used. 
The investigator must also complete a subject screening log, which reports on all subjects who were seen to determine 
eligibility for inclusion in the study. 
11.2.4. 
Source Documentation 
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: subject 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; drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if applicable.  
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). 
The following individual subject-level data will be recorded directly into the CRF and will be considered source data:   
• 
Age 
• 
Gender 
• 
Race/ethnicity 
• 
Body weight/height/BMI 
• 
Date of diabetes diagnosis (i.e. to compute duration of diabetes) 
• 
History of smoking 
• 
Blood pressure and pulse rate 
• 
Details of physical examination 
• 
Concomitant medications (apart from MET) 
• 
Relevant data from clinical laboratory assessments  
The minimum source documentation requirements for Inclusion Criteria and Exclusion Criteria that specify a need for 
documented medical history are as follows: 
• 
Referral letter from treating physician  
• 
Complete history of medical notes at the site 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a minimum by subject 
interview or other protocol required assessment (e.g. physical examination, laboratory assessment) and documented 
in the source documents. 
An electronic source system may be utilized, which contains data traditionally maintained in a hospital or clinic record 
to document medical care (e.g. electronic source documents) as well as the clinical study-specific data fields as 
determined by the protocol. These data are electronically extracted for use by the sponsor. If the electronic source 
system is utilized, references made to the CRF in the protocol include the electronic source system, but information 
collected through the electronic source system may not be limited to that found in the CRF. Data in this system may 
be considered source documentation. 
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11.2.5. 
Case Report Form Completion 
Case report forms are prepared and provided by the sponsor for each subject in printed or electronic format. 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. 
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. 
In the event that electronic CRFs (eCRFs) are used, 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 subject's source documents. Data must be entered into the CRF in Spanish or English. The CRF 
must be completed as soon as possible after a subject visit and the forms should be available for review at the next 
scheduled monitoring visit. 
Corrections to paper CRFs 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).] 
In the event that eCRFs are utilized, the following conditions must be met. If necessary, queries will be generated in 
the eDC tool. If corrections to an eCRF are needed after the initial entry into the eCRF, 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). 
• 
The sponsor or a sponsor delegate can generate a query for resolution by the investigator and study-site 
personnel. 
An electronic audit trail will be established to document all changes to the data after they leave the eCRF collection 
device. 
 
11.2.6. Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified investigators and 
appropriate study sites, review of protocol procedures with the investigator and study-site personnel before the study, 
and direct transmission of clinical laboratory data from a central laboratory (or other data source) into the sponsor's 
data base. 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. 
In the event of paper CRF use, the sponsor will review CRFs 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.  
In the event of eCRF use, the sponsor will review eCRFs for accuracy and completeness during on-site monitoring 
visits and after transmission to the sponsor; any discrepancies will be resolved with the investigator or designee, as 
appropriate. After download of the data into the study database they will be verified for accuracy and consistency with 
the data sources.  
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11.2.7. 
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 subject, as well as all study documents as specified in ICH/GCP 
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. 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 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. 
11.2.8. Monitoring 
The sponsor will use a combination of monitoring techniques (central, remote, 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. The first post-initiation visit will be made as soon as 
possible after enrollment has begun. At these visits, the monitor will compare the data entered into the CRF with the 
source documents (e.g. 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. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that, during these remote contacts, 
study-site personnel will be available to provide an update on the progress of the study at the site.  
Central monitoring will take place for data identified by the sponsor as requiring central review. 
11.2.9. 
Study Completion/Termination 
11.2.9.1. Study Completion/End of Study 
The study is considered completed with the last visit (Visit 13; scheduled study assessment as shown in the Time and 
Events Schedule) for the last subject participating in the study. The final data from the study site will be sent to the 
sponsor (or designee) after completion of the final subject assessment at that study site, in the time frame specified in 
the Clinical Trial Agreement. 
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11.2.9.2. Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any reason at the sole 
discretion of the sponsor. Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and sufficient notice is 
given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or local health 
authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
 
• 
Discontinuation of further study drug development 
11.2.9.3. 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. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part of a national GCP 
compliance program or to review the results of this study in support of a regulatory submission. The investigator 
should immediately notify the sponsor if he or she has been contacted by a regulatory agency concerning an upcoming 
inspection. 
11.3. 
Use of Information and Publication 
All information, including but not limited to information regarding CANA or the sponsor's operations (e.g. 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 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 CANA, 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. 
Results of exploratory analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will not be used in 
publication of results. Any work created in connection with performance of the study and contained in the data that 
can benefit from copyright protection (except any publication by the investigator as provided for below) shall be the 
property of the sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal Editors guidelines, the 
sponsor shall have the right to publish such 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 
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abstracts, poster presentations, or other materials. If requested by the sponsor in writing, the investigator will withhold 
such publication for up to an additional 60 days to allow for filing of a patent application. In the event that issues arise 
regarding scientific integrity or regulatory compliance, the sponsor will review these issues with the investigator. The 
sponsor will not mandate modifications to scientific content and does not have the right to suppress information. For 
substudy approaches, secondary results generally should not be published before the primary endpoints of a study 
have been published. Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
which state that the named authors must have made a significant contribution to the design of the study or analysis 
and interpretation of the data, provided critical review of the paper, and given final approval of the final version. 
11.4. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12. 
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APPENDICES: SAMPLE SIZE CALCULATIONS. RAW DATA FROM PS (POWER AND SAMPLE SIZE 
CALCULATION) VERSION 3.1.2  
 
APPENDIX 1. SAMPLE SIZE CALCULATION BASED ON MEAN (SD) DIFFERENCE IN 
GLYCEMIC SD (SD OF 24-HOUR GLUCOSE PROFILE) IN PATIENTS RECEIVING 
CANAGLIFLOZIN 300 MG/SITAGLIPTIN 100 MG, EACH AS RELATED TO PLACEBO, ON 
CGM  
 
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APPENDIX 2. SAMPLE SIZE CALCULATION BASED ON MEAN (SD) DIFFERENCE IN 
ESTIMATED AVERAGE GLUCOSE BETWEEN CANAGLIFLOZIN 300 MG/SITAGLIPTIN 100 
MG IN MEAN (SD) ESTIMATED AVERAGE GLUCOSE (EAG) IN DIRECT COMPARATIVE 
TRIALS WITHOUT CGM (CANTATA-D TRIAL, LATIN AMERICAN POPULATION)  
 
 
 
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APPENDIX 3.  SAMPLE SIZE CALCULATION BASED ON MEAN (SD) DIFFERENCE IN 
ESTIMATED 
AVERAGE 
GLUCOSE 
BETWEEN 
CANAGLIFLIZIN 
300 
MG 
AND 
SITAGLIPTIN 100 MG IN MEAN (SD) ESTIMATED AVERAGE GLUCOSE (EAG) IN DIRECT 
COMPARATIVE TRIALS WTIHOUT CGM CANTATA-D TRIAL, TOTAL POPULATION)  
 
 
 
 
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APPENDIX 4.  GRIZZLE'S TWO-STAGE MODEL TEST OF CARRYOVER: FORMULAS 
(Shen, 2006)  
 
 
 
 
 
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APPENDIX 5.  METHOD OF BLOOD PRESSURE MEASUREMENT 
 
Subject Preparation 
The subject should remove all clothing that covers the location of cuff placement. (The sleeve should not be rolled up 
so that it has a tourniquet effect.) The subject should be comfortably seated with legs uncrossed, and back and arm 
supported, so that the upper arm is at the level of the right atrium (midpoint of the sternum). The subject should be 
instructed to relax and not talk; approximately 5 minutes should pass before the reading is taken.  
 
Blood Pressure Measurement  
 
Device  
Blood pressure readings should be taken manually with a mercury sphygmomanometer or an automated blood pressure 
monitor.  
 
Cuff Size  
A cuff should be chosen that is appropriate for the individual, based upon the upper arm circumference in centimeters. 
The bladder of the cuff should encircle ≥ 80% of the arm circumference.  
 
Arm circumference (cm) 
Arm Circumference (cm) Size 22-26 Small Adult 27-34 Adult 35-44 Large Adult 45-52 Adult Thigh For the subject 
with an arm circumference >52 cm when the thigh cuff cannot be fitted over the arm, an appropriately sized cuff 
should be placed on the subject’s forearm, the forearm should be supported at heart level, and the radial pulse at the 
wrist should be used.  
 
Cuff Placement 
Palpate the brachial artery in the antecubital fossa. Place the midline of the bladder of the cuff so that it is over the 
arterial pulsation on the subject’s bare upper arm. The lower end of the cuff should be 2 to 3 cm above the antecubital 
fossa to allow space for the stethoscope. Pull the cuff snugly around the bare upper arm. Neither the observer nor the 
subject should talk.  
 
Inflation/Deflation  
Inflate the cuff to ≥30 mmHg above the point at which the radial pulse disappears. Deflate the mercury column at 2 
to 3 mmHg per second. The first and last audible sounds should be taken as systolic and diastolic blood pressure. 
  
Number of Measurements  
One reading should be taken, and the results recorded on the CRF. Blood pressure should be measured at the screening 
visit in both arms. If there is an interim difference of  >10 mmHg in either the systolic or diastolic blood pressure, the 
arm with the higher pressure should be used for all subsequent blood pressure measurement during the study. If 
possible, if the blood pressure is measured manually, it should be taken by the same individual, using the same 
equipment, at each visit so as to reduce interobserver variability (American Heart Assoc Council on High Blood 
Pressure 2005). 
 
 
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Appendix 6.  ONE-TOUCH ULTRA MINI USER GUIDE  
 
 
(This is the cover of the document which will be available in the investigator regulatory binder) 
 
 
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APPENDIX 7.    
APPENDIX 7.A.  I PRO 2 USER GUIDE 
 
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(This is the cover of the document which will be available in the investigator regulatory binder) 
 
APPENDIX 7.B.   CLINIC (SITE) CHECKLIST 
 
 
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APPENDIX 7.C.  PATIENT INSTRUCTIONS: 
 
 
 
 
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APPENDIX 8.   PATIENT LOG SHEET 
 
 
 
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APPENDIX 9.  INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will conduct the 
study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist in the 
conduct of this study. I will discuss this material with them to ensure that they are fully informed regarding the study 
drug, the conduct of the study, and the obligations of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
Fernando Javier Lavalle-González, MD  
Institution and Address: 
Facultad de Medicina de la Universidad Autónoma de Nuevo León 
 
Madero y Dr. Aguirre Pequeño, Col. Mitras Centro sin número 
 
 Mexico 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
Patricia Cabrera, MD, Regional Therapeutics Area Manager, Metabolics 
Institution: 
Janssen Research & Development/Janssen Latin America 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 
 
 
 
 
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Approved   Date: 31 July 2017  
APPENDIX 10: CLINICAL LABORATORY TESTS 
Blood samples for serum chemistry and hematology, and a random urine sample for urinalysis will be collected.  
The following tests will be performed by the central laboratory: 
o 
Hematology Panel 
-hemoglobin 
 -platelet count 
-hematocrit 
-red blood cell (RBC) count 
-white blood cell (WBC) count with differential 
 
o 
Serum Chemistry Panel 
-sodium                                                                   -alkaline phosphatase 
-potassium                                                               -creatine phosphokinase (CPK) 
-chloride                                                                  -lactic acid dehydrogenase (LDH) 
-bicarbonate                                                            -uric acid 
- blood urea nitrogen (BUN)                                  -calcium 
-creatinine                                                               -phosphate 
-aspartate aminotransferase (AST)                         -albumin 
-alanine aminotransferase (ALT)                            -total protein 
-gamma-glutamyltransferase (GGT)                      -magnesium 
-total bilirubin 
 
o 
Follicle-stimulating hormone only for women >45 years of age who have had amenorrhea for at least 6 months 
and <18 months before screening.  
 
o 
Fasting serum lipid profile (triglycerides, LDL-C, HDL-C, total cholesterol). LDL-C will not be measured but 
will be calculated using the Friedewald equation 
 
o 
HbA1c 
 
o 
Fasting plasma glucose 
 
o 
C-peptide 
 
o 
Urinalysis. Dipstick done at central laboratory 
-specific gravity 
-pH 
-protein 
-blood 
-ketones 
-bilirubin 
-urobilinogen 
-nitrite 
-leukocyte esterase 
If dipstick result is abnormal, microscopic examination will be performed. 
 
o 
Urine pregnancy testing, unless a serum pregnancy test is preferred at the discretion of the investigator or if 
required by local regulations, for all women unless they are surgically sterile or unless there is a documented 
history of their postmenopausal status. 
 
Subjects must be fasting for at least 8 hours before blood sample collections, except for the screening visit when 
nonfasting blood samples may be collected. 
 
Central laboratory will report the eGFR according to the Modification of Diet in Renal Disease Study (MDRD) 
equation (Levey 1995; Myers 2005; Stevens 2006) at study visits when serum creatinine is measured. 
 
The 4-variable MDRD eGFR includes serum creatinine, age, race, and sex according to the equation below: 
For creatinine in mg/dL: 
eGFR (mL/min/1.73 m2) = 175 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.21 if black) 
NCT03267576

SAP_001.pdf: 
1
Statistical Analysis Plan 
COMETA Study
COMETA study carried out for Janssen México 
Innoval study coordinator
Janssen, México,
August 13, 2018
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Version 1.0
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General 
This document describes the tasks that form part of the statistical analysis to be 
carried out by Innoval S.A. de C.V. for the COMETA study, approved by Janssen 
México (hereinafter Janssen) 
Background 
We have established that sixty patients will the form the basis of comparing the effect 
of four weeks’ daily treatment with canaglifozin and sitagliptin by measuring the 
change in the level of glucose. The sample size was estimated for an ongoing response
variable of compared study patient pairs. 
The study is a multi-center, 2 x 2 randomized, double blind, crossed, actively 
controlled study on Diabetes Mellitus 2 patients whose glucose is not properly 
controlled, using stable doses of metformin (MET) monotherapy (1,500 mg/day) as oral 
treatment once a day, plus canagliflozin 300 mg or the dipeptidyl peptidase-4 inhibitor 
(DPP-4): stable doses of sitagliptin phosphate 100 mg once a day for 28 days, with a for 
sixteen-day washout period with MET monotherapy. Therefore, the interval between 
the first and last dose of adjuvant treatment is 72 days. With a pre-study interval of 
sixteen days (optional pre-selection period of six days; selection lasting three days; 
selection lasting seven days) and a post-treatment monitoring period of up to nine 
days. The maximum duration of the study for each patient who tolerates the drug and 
who does not withdraw his or her consent is, therefore, 97 days. A window of ±3 days 
was taken into account for each of these visits, so that individual patients could be 
programmed. Patients are randomized double blind to treatment, the period and the 
sequence.
Objectives of the study. 
The main objective of the study is to compare four weeks of treatment with CANA 300 
mg with SITA 100 mg as a complement to metformin at a stable dose on glycemic 
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variability (GV), measured using continuous glucose measurements (CGM), when each 
drug is added to MET treatment, in stable doses in patients receiving type 2 DM 
treatment (T2DM) whose glucose is not properly controlled with MET monotherapy. 
The measurement of the primary efficacy result is the coefficient of variation of the CV 
intra-patient mean (SD)/fasting plasma glucose (FPG) mean.
Other study objectives include comparisons between the effect that this adjuvant 
treatment has on the following changes from the baseline: 
1. Mean 24-hour glucose level (mg/dL). 
2. Mean pre-prandial glucose (SD) [fasting plasma glucose (FPG)].
3. Mean two-hour postprandial glucose (PPG) (SD).
4. Time, percentage of time or AUC24h (or AOC24h for hypoglycemia) with glucose in 
euglycemic, hyperglycemic and hypoglycemic ranges. 
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Statistical analysis plan.
To make sure that the data gathering protocol is adhered to, Janssen will set up a 
clinical monitoring procedure so that certain action may be to deal with any problem 
that may arise regarding any missing or doubtful data, by means of a data enquiry 
process. 
Following are the stages of the statistical analysis process:
1. Once Janssen has completed the data enquiry process, it must notify Innoval 
accordingly so that it may close the database and begin the statistical data 
analysis. 
2. Innoval will carry out an exploratory data analysis in three weeks, consisting 
of the following stages: 
Week one
a. Data encoding. A list will be drawn up that specifies all variables of the 
electronic patient case report form (eCRF), their characteristics and the 
parameter range assigned to each answer given on the eCRF. 
b. Data compiled from the sample will be organized and ordered 
according to the type of variable and type of measurement, whether
quantitative (numerical) or qualitative (nominal or categorical). 
Weeks two and three 
a. Patient information will be summarized and specified according to the type 
of variable, using the descriptive data analysis. 
i.
Frequencies and percentages (tables and graphs) will be 
analyzed for nominal and categorical variables.
ii.
Summary methods will be used for quantitative variables 
(numerical data): central trend measurements
(mean and 
median); 
dispersion 
measurements 
(interquartile 
range, 
deviation and range) and position measurements (percentiles 
and quartiles). 
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b. Assessment of analysis of study groups and attributes of interest. 
i.
Patients whose glucose is not properly controlled during the 
screening visit.
The number of patients that meet this criterion will be 
established. The numerical HbA1c variable of the eCRF will be 
assessed as a categorical value: 
Category
Hemoglobin values 
(HbA1C)
Glucose not properly controlled
7.5 to 10.5%
Glucose properly controlled
≤ 7.4%
Glucose not properly controlled, 
more than 10.5% of HbA1C)
> 10.6%
ii.
Stable dose of metformin. The number of patients who meet this criterion 
will be established. Numerical variable metformin: Doses per day will be 
assessed as a categorical variable: 
Category
Dose of metformin mg/day
Patients with a stable dose of 
metformin 
≥ 1,500 mg/day
Patients without a stable dose of 
metformin
> 1,500 mg/day
iii.
Body mass index by tercile according to sex. The number of patients who 
meet this criterion will be established. The numerical BMI variable will be 
assessed as a categorical variable: 
Tercile Category 
BMI men (kg/m2)
BMI women (kg/m2)
Tercile 1
22 to <28
22 to <30
Tercile 2
28 to <33
30 to <36
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Tercile 3
33 to <45
36 to <45
iv.
Glucose in the euglycemic, hyperglycemic and hypoglycemic 
ranges. The numerical variables with glucose values are: Glucose (serum 
chemistry Panel visit 1 and visit 13), CGM Report (visits 4, 8 and 12), 
Glucometer (visits 4, 8 and y 12) will be assessed as a variable. 
IMPORTANT: the ranges and parameters for these ranges are not specified 
in the protocol. 
2. The above analysis will form the basis of a meeting to be held between Janssen and 
Innoval at which Innoval will submit the findings of its exploratory analysis, such as: 
a. Missing data,
b. Possible unusual distribution patterns
c. Potential extreme values that may affect distribution of the variable of interest. 
d. Based on the results of the exploratory analysis submitted, Janssen will establish: 
i. Additional associations of variables that reflect results desired.
ii. Confirmation of multi-varied analysis (proposed on point 6). 
iii. Possible alternative analyses.
3. After the meeting, analysis agreements will be documented. 
4. Janssen must confirm and approve the analyses that Innoval will carry out in the final 
statistical analysis.
5. As soon as Janssen gives its confirmation and approval, Innoval carry out a final statistical 
data analysis in two weeks. 
If the exploratory analysis does not come up with values that may influence distribution of 
the variable of interest, objectives will be assesses as follows: 
Weeks four and five
a. The primary objective will be assessed in terms of efficacy using:
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i. Glucose values CGM Report (interstitial glucose). Visit 4 (Baseline), Visit 8 (First 
Treatment) and Visit 12 (Second treatment) obtained during a period of six months 
after each active treatment. 
ii. Glucose variable values Glucometer (plasma glucose). Visit 4 (Baseline), Visit 8 
(First Treatment) and Visit 12 (Second treatment) obtained during a period of six 
months after each active treatment. 
The mean change of these variables will be assessed (standard deviation) with regard 
to the baseline point using the intra-patient variation coefficient of glucose profiles, 
calculated as follows: (DS/mean glucose x 100).
b. The same variables as those above will be used to assess secondary efficacy objectives, the 
only difference being that normality will be assessed using the Shapiro-Wilk test. The value of 
the mean (standard deviation) will be presented for normally distributed data and the median 
and interquartile range will be presented for data not distributed normally.
i. Average value (mean or median) of 24-hour glucose levels (mg/dL). 
ii. Average value (mean or median) and standard deviation or interquartile range of 
pre-prandial glucose (mg/dL) (fasting plasma glucose) and two-hour postprandial 
glucose (PPG)).
iii. Time and percentage of time or AUC24h or (AOC24h for hypoglycemia). 
1. Time (minutes), percentage of 24 hours or area under the glucose curve – time of 
24 hours (AUC24h) with glucose = 70−139 mg/dL (time elapsed with PG within the 
reference range). 
2. Time (minutes), percentage of 24 hours or area under the glucose curve – time of 
24 hours (AUC24h) with glucose = 70−180 mg/dL (time elapsed with PG within the 
reference range). 
3. Time (minutes), percentage of 24 hours or AUC24h (mg/dL/h) with glucose >140 
mg/dL (time elapsed with PG above reference range). 
4. Time (minutes), percentage of 24 hours or AUC24h (mg/dL/h) with glucose >180 
mg/dL (time elapsed with PG substantially above reference range). 
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5. Time (minutes), percentage of 24 hours or area above the PG curve – time of 24 
hours (AOC24h; mg/dL/h) with glucose <70 mg/dL. 
c. The paired exact Fisher test will be used for all other differences between treatments that 
Janssen wants to be assessed for categorical baseline variables and paired t tests or Wilcoxon 
tests for ongoing efficacy assessment criteria distributed normally and abnormally 
(respectively), according to the results of the Shapiro-Wilk test. All other tests will be carried 
out using a bilateral α bilateral value = 0.05 (in other words, an a priori signification level of p 
< 0.05). 
6. Once this has been done, Innoval will submit the following documents:
a. A final statistical analysis. 
b. Original database.
c. Encoded database.
d. Working database and carrying out of statistical analysis.
END OF DOCUMENT. 
Document approval
Date
FELIX 
RODRIGUEZ 
GUTIERREZ
Date
PATRICIA 
CABRERA 
JARAMILLO
Signature 
Maria Félix Rodriguez Gutierrez
Associate Director- Global Trial 
Manager
Signature
Patricia Cabrera
Regional Medical Director
Date
Signature
Salvador Duran Coyote
Clinical Research and Scientific Analysis 
Manager
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