A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled Clinical Study to Evaluate the Safety and Efficacy of Ertugliflozin (MK-8835/PF-04971729) in Pediatric Participants (Ages 10 to 17 Years, Inclusive) With Type 2 Diabetes Mellitus
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04029480 
Document Date: 
14-Nov-2024
A Phase 3, Multicenter, Double-blind, Randomized, Placebo-
controlled Clinical Study to Evaluate the Safety and Efficacy of 
Ertugliflozin (MK-8835/PF-04971729) in Pediatric Participants 
(ages 10 to 17 years, inclusive) with Type 2 Diabetes Mellitus

PRODUCT: MK-8835  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled 
Clinical Study to Evaluate the Safety and Efficacy of Ertugliflozin (MK-8835/PF-04971729) 
in Pediatric Participants (ages 10 to 17 years, inclusive) with Type 2 Diabetes Mellitus
Protocol Number: 059-04
Compound Number: MK-8835
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Ertugliflozin (MK-8835/PF-04971729) is being co-developed by MSD and Pfizer.
Regulatory Agency Identifying Number(s):
IND
106,447
EudraCT
2017-003455-35
EU CT: 2022-501085-21-00
UTN: U1111-1279-3984
MSD Protocol Number: 059-00
Pfizer Protocol Number: B1521066
Approval Date: 14 November 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 4
14-NOV-2024
Health Authority feedback to update the primary 
treatment policy analysis.
Amendment 3
14-MAR-2024
This protocol is being amended to address Health 
Authority feedback to change the primary analysis 
methodology.
Amendment 2
16-FEB-2023
To align with EU CTR and update Sponsor’s name 
and address change. 
Amendment 1
11-JUN-2020
Amendment created to fulfill requests from 
regulatory agencies. Changes also include 
corrections and clarifications.
Original Protocol
01-APR-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 4 
Overall Rationale for the Amendment:
Health Authority feedback to update the primary treatment policy analysis.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 9.6.1, 
Statistical 
Methods for 
Efficacy Analysis
Changed the primary analysis from a single 
value imputation to multiple imputation with a 
Bayesian Rubin’s rule methodology.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 9.1, 
Statistical 
Analysis Plan 
Summary
Statistical Methods for Key 
Efficacy/Immunogenicity/ Pharmacokinetic 
Analyses: Updated the weight given to the adult 
prior distribution for the primary hypothesis 
test. 
Sample Size and Power: Changed TP estimand 
power measurement from Highest Posterior 
Density to posterior credible intervals. 
Section 9.4.1, 
Efficacy 
Endpoints
Homeostasis Model Assessments were removed 
as exploratory endpoints.
Section 9.5.1, 
Efficacy Analysis 
Populations
Information on classification of the incorrect 
stratum for insulin use was added.
Section 9.6.1, 
Statistical 
Methods for 
Efficacy Analysis 
The mixture parameter was changed from 0.299 
to 0.134.
Changed TP estimand power measurement from 
highest posterior density to posterior credible 
intervals.
The RD imputation analysis steps were revised 
based on the new Rubin’s rule multiple 
imputation methodology.
Details on the computation of the SD for the WI 
approach were revised to align with the RD 
imputation analysis.
Updated the analyses for hypotheses H2 and H3 
from the bootstrap to Rubin’s rule.
CCI
CCI
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Section Number 
and Name
Description of Change
Brief Rationale
Section 9.6.2, 
Statistical 
Methods for 
Safety Analyses
Added details on number of days after last dose 
of therapy for Tanner staging, growth velocity, 
and safety vital signs.
Section 9.9, 
Sample Size and 
Power 
Calculations
Changed TP estimand power measurement from 
highest posterior density to posterior credible 
intervals.
CCI
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................26
2.1
Study Rationale....................................................................................................26
2.2
Background ..........................................................................................................26
Pharmaceutical and Therapeutic Background .............................................26
Information on Other Study-related Therapy ..............................................27
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................29
4
STUDY DESIGN............................................................................................................31
4.1
Overall Design......................................................................................................31
4.2
Scientific Rationale for Study Design.................................................................32
Rationale for Endpoints ...............................................................................33
4.2.1.1
Efficacy Endpoints.............................................................................33
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Pharmacokinetic Endpoints ...............................................................34
4.2.1.4
Pharmacodynamic Endpoints.............................................................34
4.2.1.5
Future Biomedical Research..............................................................34
Rationale for the Use of Placebo .................................................................34
4.3
Justification for Dose...........................................................................................35
Maximum Dose/Exposure for This Study ...................................................35
Rationale for Dose Interval..........................................................................35
4.4
Beginning and End of Study Definition .............................................................35
Clinical Criteria for Early Study Termination .............................................36
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................36
5.2
Exclusion Criteria................................................................................................40
5.3
Lifestyle Considerations......................................................................................45
Meals and Dietary Restrictions....................................................................45
Caffeine, Alcohol, and Tobacco Restrictions ..............................................45
Activity Restrictions ....................................................................................45
5.4
Screen Failures.....................................................................................................45
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5.5
Participant Replacement Strategy......................................................................45
6
STUDY INTERVENTION............................................................................................46
6.1
Study Intervention(s) Administered...................................................................46
6.2
Preparation/Handling/Storage/Accountability .................................................50
Dose Preparation..........................................................................................50
Handling, Storage, and Accountability........................................................50
6.3
Measures to Minimize Bias: Randomization and Blinding..............................51
Intervention Assignment..............................................................................51
Stratification.................................................................................................51
Blinding........................................................................................................52
6.4
Study Intervention Compliance..........................................................................52
6.5
Concomitant Therapy..........................................................................................52
Rescue Medications and Supportive Care ...................................................53
6.6
Dose Modification (Escalation/Titration/Other)...............................................57
6.7
Intervention After the End of the Study............................................................57
6.8
Clinical Supplies Disclosure................................................................................57
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................57
7.1
Discontinuation of Study Intervention...............................................................57
7.2
Participant Withdrawal From the Study...........................................................60
7.3
Lost to Follow-up .................................................................................................60
8
STUDY ASSESSMENTS AND PROCEDURES........................................................61
8.1
Administrative and General Procedures ...........................................................61
Informed Consent/Assent.............................................................................61
8.1.1.1
General Informed Consent/Assent.....................................................61
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................62
Inclusion/Exclusion Criteria ........................................................................62
Participant Identification Card.....................................................................63
Medical History ...........................................................................................63
Prior and Concomitant Medications Review...............................................63
8.1.5.1
Prior Medications...............................................................................63
8.1.5.2
Concomitant Medications..................................................................63
Assignment of Screening Number...............................................................63
Assignment of Treatment/Randomization Number.....................................63
Study Intervention Administration ..............................................................64
8.1.8.1
Timing of Dose Administration.........................................................64
8.1.8.2
Witnessed Dose..................................................................................64
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8.1.8.3
Dispense Single-Blind Placebo Treatment ........................................64
8.1.8.4
Dispense Double-Blind Study Treatment ..........................................64
8.1.8.5
Evaluation of Study Treatment Compliance......................................64
Discontinuation and Withdrawal .................................................................65
8.1.9.1
Withdrawal From Future Biomedical Research ................................65
Participant Blinding/Unblinding..................................................................66
Calibration of Equipment.............................................................................67
Dispense Glucose Meters, Blood Glucose Assessment Tools, and 
SMBG Instructions ......................................................................................67
Instruct on Hypoglycemia Symptoms and Management.............................67
Second Randomization ................................................................................68
8.2
Efficacy Assessments ...........................................................................................69
Body Weight................................................................................................69
Waist Circumference ...................................................................................69
Height...........................................................................................................70
BMI Percentile.............................................................................................70
Vital Signs....................................................................................................71
Laboratory Measurements for Efficacy .......................................................71
8.3
Safety Assessments...............................................................................................72
Physical Examinations.................................................................................72
Diet and Exercise Counseling and Monitoring............................................72
Tanner Staging.............................................................................................72
Abdominal Ultrasound.................................................................................72
Electrocardiograms ......................................................................................73
Review of SMBG Measurements and Blood Glucose Assessment Tools...73
Review Rescue Criteria and Assess Need for Glycemic Intensification .....73
Clinical Safety Laboratory Assessments .....................................................74
8.3.8.1
Site FFSG and FS A1C Measurements..............................................75
8.3.8.2
Site Measured Urine Ketones ............................................................75
8.3.8.3
Urine Pregnancy Test.........................................................................75
8.3.8.4
Archive Urine Sample........................................................................76
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................76
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................76
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......78
Follow-up of AE, SAE, and Other Reportable Safety Event Information...78
Regulatory Reporting Requirements for SAE .............................................78
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Pregnancy and Exposure During Breastfeeding ..........................................79
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................79
Events of Clinical Interest (ECIs)................................................................79
Other Safety Topics of Interest....................................................................80
Monitor for Adverse Events.........................................................................80
8.5
Treatment of Overdose........................................................................................80
8.6
Pharmacokinetics.................................................................................................81
Blood Collection for Plasma Ertugliflozin ..................................................81
8.7
Pharmacodynamics..............................................................................................81
8.8
Future Biomedical Research Sample Collection...............................................81
8.9
Health Economics.................................................................................................82
8.10
Visit Requirements...............................................................................................82
General Information for Study Visits ..........................................................82
Screening Visit / Visit 1...............................................................................83
Single-Blind Placebo Run-in - Visit 2/Week -1 ..........................................83
Double-Blind Treatment Period – Phase A - Visit 3/Day 1/ 
Randomization to Visit 6/Week 24..............................................................84
Double-Blind Treatment Period – Phase B - Visit 6/Week 24 Through 
Visit 8/Week 54 ...........................................................................................84
Study Visits Performed at Home .................................................................85
Rescue/ Intensification Visit........................................................................85
Discontinuation Visit ...................................................................................85
Mandatory Poststudy Telephone Follow-up................................................86
Follow Up of Participants Who Have Discontinued Study Medication 
Prior to Study Completion ...........................................................................86
9
STATISTICAL ANALYSIS PLAN .............................................................................86
9.1
Statistical Analysis Plan Summary.....................................................................86
9.2
Responsibility for Analyses/In-house Blinding .................................................88
9.3
Hypotheses/Estimation ........................................................................................89
9.4
Analysis Endpoints...............................................................................................89
Efficacy Endpoints.......................................................................................89
Safety Endpoints..........................................................................................91
9.5
Analysis Populations............................................................................................91
Efficacy Analysis Populations.....................................................................91
Safety Analysis Populations ........................................................................92
9.6
Statistical Methods...............................................................................................92
Statistical Methods for Efficacy Analyses...................................................92
Statistical Methods for Safety Analyses ....................................................100
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Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................104
9.7
Interim Analyses ................................................................................................104
9.8
Multiplicity .........................................................................................................105
9.9
Sample Size and Power Calculations ...............................................................105
9.10
Subgroup Analyses.............................................................................................106
9.11
Compliance (Medication Adherence)...............................................................107
9.12
Extent of Exposure.............................................................................................108
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................109
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......109
Code of Conduct for Interventional Clinical Trials ...................................109
Financial Disclosure...................................................................................113
Data Protection...........................................................................................113
10.1.3.1
Confidentiality of Data ....................................................................115
10.1.3.2
Confidentiality of Participant Records.............................................115
10.1.3.3
Confidentiality of IRB/IEC Information..........................................116
Committees Structure.................................................................................116
10.1.4.1
Scientific Advisory Committee........................................................116
10.1.4.2
Executive Oversight Committee......................................................116
10.1.4.3
External Data Monitoring Committee .............................................116
10.1.4.4
Internal Case Review Committee for Ketoacidosis.........................116
Publication Policy......................................................................................117
Compliance with Study Registration and Results Posting Requirements .117
Compliance with Law, Audit, and Debarment ..........................................117
Data Quality Assurance .............................................................................118
Source Documents .....................................................................................119
Study and Site Closure...............................................................................119
10.2
Appendix 2: Clinical Laboratory Tests............................................................120
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................122
Definitions of Medication Error, Misuse, and Abuse................................122
Definition of AE ........................................................................................122
Definition of SAE ......................................................................................123
Additional Events Reported.......................................................................124
Recording AE and SAE .............................................................................125
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................128
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collections, and Documentation ................................130
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................131
Definitions..................................................................................................131
Contraception Requirements......................................................................131
Pregnancy Testing......................................................................................133
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................134
10.7
Appendix 7: Country-specific Requirements..................................................139
Saudi Arabia and United Arab Emirates Requirements ............................139
Serum Pregnancy Requirements................................................................139
10.8
Appendix 8: BMI for Age Charts.....................................................................140
10.9
Appendix 9: Blood Pressure Tables .................................................................142
10.10 Appendix 10: Management of Participants with Elevated Liver Enzymes 
(ALT or AST ≥3x ULN) ....................................................................................144
10.11 Appendix 11: Mapping of Relative Day Ranges to Weeks.............................149
10.12 Appendix 12: Interim PK Analysis ..................................................................150
10.13 Appendix 13: Tanner Staging...........................................................................154
10.14 Appendix 14: Abbreviations .............................................................................156
11
REFERENCES.............................................................................................................159
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LIST OF TABLES
Table 1
Study Medications .....................................................................................48
Table 2
Glycemic Rescue/Intensification Strategy.................................................55
Table 3
Glycemic Rescue Criteria (Phase A) .........................................................56
Table 4
Glycemic Intensification Criteria (Phase B)..............................................56
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................77
Table 6
Efficacy Variables/Endpoints ....................................................................90
Table 7
Analysis Strategy for Efficacy Variables at Week 24 and at Week 54 ...100
Table 8
Analysis Strategy for Safety Endpoints by Study Phase .........................101
Table 9
Analysis Strategy for Safety ....................................................................103
Table 10
Contraceptive Methods ............................................................................132
Table 11
Blood Pressure Table for Gender/Age/Height for Boys Age 10 to 17 ....142
Table 12
Blood Pressure Table for Gender/Age/Height for Girls Age 10 to 17 ....143
Table 13
Relative Day Ranges to Weeks for A1C..................................................149
Table 14
Relative Day Ranges to Weeks for FPG, Lab, and Lipid Endpoints.......149
Table 15
Simulation Results: Estimated Probability that the 15 mg Dose Could 
be Discontinued Based on the PK IA ......................................................153
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................18
Figure 2
BMI for Age Girls, 5 to 19 Years (Percentiles).......................................140
Figure 3
BMI for Age Boys, 5 to 19 Years (Percentiles).......................................141
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled 
Clinical Study to Evaluate the Safety and Efficacy of Ertugliflozin (MK-8835/PF-04971729) 
in Pediatric Participants (ages 10 to 17 years, inclusive) with Type 2 Diabetes Mellitus
Short Title: Ertugliflozin T2DM Pediatric Study (MK-8835/PF-04971729) 
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
In pediatric patients (ages 10 to 17 years, inclusive) with T2DM on a stable dose of 
metformin ≥1500 mg/day ± stable insulin:
Primary Objectives
Primary Endpoints
- Objective: To compare the addition of 
ertugliflozin with the addition of placebo on 
the change from baseline in A1C at 
24 weeks.
Hypothesis (H1): The addition of 
ertugliflozin reduces A1C more than the 
addition of placebo after 24 weeks of 
treatment.
- A1C
- Objective: To assess the safety and 
tolerability of ertugliflozin over 24 weeks 
and 54 weeks. 
- Adverse Events (AEs)
- Discontinuation of study medication due 
to AEs
Secondary Objectives
Secondary Endpoints
- Objective: To compare the addition of 
ertugliflozin, with dosing optimized 
according to A1C response, to the addition of 
placebo on the change from baseline in A1C 
at 24 weeks. 
Hypothesis (H2): The addition of 
ertugliflozin, with dosing optimized 
according to A1C response, reduces A1C 
more than the addition of placebo after 24 
weeks of treatment.
- A1C
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- Objective: To compare the addition of 
ertugliflozin 5 mg with the addition of 
placebo on the change from baseline in A1C 
at 24 weeks.
Hypothesis (H3): The addition of 
ertugliflozin 5 mg reduces A1C more than 
the addition of placebo after 24 weeks of 
treatment.
- A1C  
- Objective: To compare the effect of the 
addition of ertugliflozin to the addition of 
placebo on the change from baseline in 
fasting plasma glucose (FPG) at 24 weeks.
- FPG
- Objective: To assess the within-group 
(ertugliflozin and placebo) changes from 
baseline at 54 weeks for A1C and FPG. 
- A1C 
- FPG
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
T2DM
Population
Pediatric patients who are 10 to 17 years of age (inclusive) with 
T2DM and inadequate glycemic control on metformin ± insulin.
Study Type
Interventional
Intervention Model
Parallel
multi-site
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Sponsor
Investigator
Participant
Estimated Duration 
of Study
The Sponsor estimates that the study will require approximately 6
years from the time the first participant signs the informed 
consent/assent until the last participant’s last study-related telephone 
call or visit.
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Number of Participants:
Approximately 165 participants will be enrolled. 
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
Ertugliflozin
5 mga
Ertugliflozin
5 mg
qd
Oral
Double-
blind 
treatment 
period
Test 
Product
Ertugliflozin 
15 mgb
Ertugliflozin
15 mg
qd
Oral
Double-
blind 
treatment 
period
starting 
Visit 5
/Week 12
Test 
Product
Placeboa
Placebos
matching 
ertugliflozin 
5 mg and 
15 mg
0 mg
qd
Oral
Double-
blind 
treatment 
period
Placebo
Abbreviations: mg=milligram; qd= once daily.
a.  At the first randomization (R1) participants in the ertugliflozin arm will receive ertugliflozin 
5 mg and placebo to ertugliflozin 15 mg. Participants in the placebo arm will receive placebos to 
both ertugliflozin 5 mg and ertugliflozin 15 mg. 
b.  At the second randomization (R2), Visit 5/Week 12, approximately half of the participants in the 
ertugliflozin 5 mg arm with A1C ≥7.0% (53 mmol/mol) will up-titrate to receive ertugliflozin 
15 mg and placebo to ertugliflozin 5 mg. Participants in the placebo group with A1C ≥7.0% 
(53 mmol/mol) at Visit 5/Week 12 will be mock titrated. Note: The up-titration criteria for 
participants on insulin will include a fasting fingerstick glucose (FFSG) of ≥110 mg/dL 
(6.1 mmol/L) in addition to A1C ≥7.0% (53 mmol/mol) at Visit 5/Week 12. Participants who do 
not meet the threshold(s) for a second randomization will continue on ertugliflozin 
5 mg/placebo.
Participants will remain on their background metformin ± insulin
treatment throughout the course of the study.
Total 
Number
2 treatment groups at Day 1, changing to 3 treatment groups at 
Visit 5/Week 12.
Duration of 
Participation
Each participant will participate in the study for approximately 58 weeks
from the time the participant signs the Informed Consent Form (ICF) 
through the final contact. After a screening period of approximately 1 week 
and a single-blind placebo run-in period of approximately 1 week, each 
participant will receive assigned treatment for approximately 54 weeks. 
Participants will be contacted by telephone 14 days (Week 56) after the last 
dose of study medication to assess and collect information on AEs, and any 
other reportable safety events. To minimize missing data, participants who 
discontinue study medication prior to study completion will remain in the 
study and complete all remaining scheduled visits.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Internal Ketoacidosis Case Review
Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 14.
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1.2
Schema
The study design is depicted in Figure 1. 
Figure 1
Study Design
A1C=glycosylated hemoglobin; AHA=anti-hyperglycemic agent; FFSG=fasting fingerstick glucose; 
FPG=fasting plasma glucose; FS=fingerstick; FSG=fingerstick glucose; Pbo=placebo; R=randomization; 
SCR=screening; T2DM=type 2 diabetes mellitus; TC=telephone call; V=Visit; Wk=Week.
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1.3
Schedule of Activities (SoA)
Schedule of Activities
Screen
Single-
Blind 
Placebo 
Run-In
Random-
ization
Double-Blind Treatment 
Period Phase A
Double-Blind Treatment 
Period Phase B
Visit 
Rescue -
Intensific-
ation,/ 
Discon
Post-
Study
Phone 
Contact
Comment
Visit 
1
Visit 
2
Visit
3
Visit 
4a
Visit 
5
TC
Visit 
6
TC
Visit 
7a
TC
Visit 
8
No 
earlier 
than -4 
weeks
Week -1
Week 0/ 
Day 1
Wk 
6
± 1 
wk
Wk 
12
± 1 
wk
Wk
18
± 1 
wk
Wk 
24
± 1 
wk
Wk 
30
± 1 
wk
Wk 
38
± 2 
wks
Wk 
44
± 1 
wk
Wk 
54
± 2 
wks
Wk 56 
OR
14 days 
after last 
dose
See Note 1 below
Study Procedures
See Note 1 below
Obtain informed consent 
and assent
X
Obtain informed consent 
and assent for Future 
Biomedical Research
X
Can also be obtained 
any time prior to 
collecting the 
samples.
Assignment of screening 
number
X
Evaluate
Inclusion/Exclusion criteria
X
X
X
Dispense participant 
identification card
X
X
Collect medical history
X
Review prior/concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
CCI
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PRODUCT: MK-8835
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Schedule of Activities
Screen
Single-
Blind 
Placebo 
Run-In
Random-
ization
Double-Blind Treatment 
Period Phase A
Double-Blind Treatment 
Period Phase B
Visit 
Rescue -
Intensific-
ation,/ 
Discon
Post-
Study
Phone 
Contact
Comment
Visit 
1
Visit 
2
Visit
3
Visit 
4a
Visit 
5
TC
Visit 
6
TC
Visit 
7a
TC
Visit 
8
No 
earlier 
than -4 
weeks
Week -1
Week 0/ 
Day 1
Wk 
6
± 1 
wk
Wk 
12
± 1 
wk
Wk
18
± 1 
wk
Wk 
24
± 1 
wk
Wk 
30
± 1 
wk
Wk 
38
± 2 
wks
Wk 
44
± 1 
wk
Wk 
54
± 2 
wks
Wk 56 
OR
14 days 
after last 
dose
See Note 1 below
CCI
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PRODUCT: MK-8835
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Schedule of Activities
Screen
Single-
Blind 
Placebo 
Run-In
Random-
ization
Double-Blind Treatment 
Period Phase A
Double-Blind Treatment 
Period Phase B
Visit 
Rescue -
Intensific-
ation,/ 
Discon
Post-
Study
Phone 
Contact
Comment
Visit 
1
Visit 
2
Visit
3
Visit 
4a
Visit 
5
TC
Visit 
6
TC
Visit 
7a
TC
Visit 
8
No 
earlier 
than -4 
weeks
Week -1
Week 0/ 
Day 1
Wk 
6
± 1 
wk
Wk 
12
± 1 
wk
Wk
18
± 1 
wk
Wk 
24
± 1 
wk
Wk 
30
± 1 
wk
Wk 
38
± 2 
wks
Wk 
44
± 1 
wk
Wk 
54
± 2 
wks
Wk 56 
OR
14 days 
after last 
dose
See Note 1 below
CCI
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PRODUCT: MK-8835
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PROTOCOL/AMENDMENT NO.: 059-04
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Schedule of Activities
Screen
Single-
Blind 
Placebo 
Run-In
Random-
ization
Double-Blind Treatment 
Period Phase A
Double-Blind Treatment 
Period Phase B
Visit 
Rescue -
Intensific-
ation,/ 
Discon
Post-
Study
Phone 
Contact
Comment
Visit 
1
Visit 
2
Visit
3
Visit 
4a
Visit 
5
TC
Visit 
6
TC
Visit 
7a
TC
Visit 
8
No 
earlier 
than -4 
weeks
Week -1
Week 0/ 
Day 1
Wk 
6
± 1 
wk
Wk 
12
± 1 
wk
Wk
18
± 1 
wk
Wk 
24
± 1 
wk
Wk 
30
± 1 
wk
Wk 
38
± 2 
wks
Wk 
44
± 1 
wk
Wk 
54
± 2 
wks
Wk 56 
OR
14 days 
after last 
dose
See Note 1 below
CCI
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PRODUCT: MK-8835
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PROTOCOL/AMENDMENT NO.: 059-04
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Schedule of Activities
Screen
Single-
Blind 
Placebo 
Run-In
Random-
ization
Double-Blind Treatment 
Period Phase A
Double-Blind Treatment 
Period Phase B
Visit 
Rescue -
Intensific-
ation,/ 
Discon
Post-
Study
Phone 
Contact
Comment
Visit 
1
Visit 
2
Visit
3
Visit 
4a
Visit 
5
TC
Visit 
6
TC
Visit 
7a
TC
Visit 
8
No 
earlier 
than -4 
weeks
Week -1
Week 0/ 
Day 1
Wk 
6
± 1 
wk
Wk 
12
± 1 
wk
Wk
18
± 1 
wk
Wk 
24
± 1 
wk
Wk 
30
± 1 
wk
Wk 
38
± 2 
wks
Wk 
44
± 1 
wk
Wk 
54
± 2 
wks
Wk 56 
OR
14 days 
after last 
dose
See Note 1 below
CCI
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PRODUCT: MK-8835
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PROTOCOL/AMENDMENT NO.: 059-04
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Schedule of Activities
Screen
Single-
Blind 
Placebo 
Run-In
Random-
ization
Double-Blind Treatment 
Period Phase A
Double-Blind Treatment 
Period Phase B
Visit 
Rescue -
Intensific-
ation,/ 
Discon
Post-
Study
Phone 
Contact
Comment
Visit 
1
Visit 
2
Visit
3
Visit 
4a
Visit 
5
TC
Visit 
6
TC
Visit 
7a
TC
Visit 
8
No 
earlier 
than -4 
weeks
Week -1
Week 0/ 
Day 1
Wk 
6
± 1 
wk
Wk 
12
± 1 
wk
Wk
18
± 1 
wk
Wk 
24
± 1 
wk
Wk 
30
± 1 
wk
Wk 
38
± 2 
wks
Wk 
44
± 1 
wk
Wk 
54
± 2 
wks
Wk 56 
OR
14 days 
after last 
dose
See Note 1 below
CCI
08XTGG

PRODUCT: MK-8835
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PROTOCOL/AMENDMENT NO.: 059-04
MK-8835-059-04 FINAL PROTOCOL
14-NOV-2024
Schedule of Activities
Screen
Single-
Blind 
Placebo 
Run-In
Random-
ization
Double-Blind Treatment 
Period Phase A
Double-Blind Treatment 
Period Phase B
Visit 
Rescue -
Intensific-
ation,/ 
Discon
Post-
Study
Phone 
Contact
Comment
Visit 
1
Visit 
2
Visit
3
Visit 
4a
Visit 
5
TC
Visit 
6
TC
Visit 
7a
TC
Visit 
8
No 
earlier 
than -4 
weeks
Week -1
Week 0/ 
Day 1
Wk 
6
± 1 
wk
Wk 
12
± 1 
wk
Wk
18
± 1 
wk
Wk 
24
± 1 
wk
Wk 
30
± 1 
wk
Wk 
38
± 2 
wks
Wk 
44
± 1 
wk
Wk 
54
± 2 
wks
Wk 56 
OR
14 days 
after last 
dose
See Note 1 below
CCI
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2
INTRODUCTION
Ertugliflozin (MK-8835/PF-04971729), a sodium glucose co-transporter 2 (SGLT2) 
inhibitor, is approved for the treatment of T2DM in adults (18 years and older) and is being 
developed for pediatric patients (10 to17 years of age).
2.1
Study Rationale
The purpose of this 54-week (24 weeks Phase A + 30 weeks Phase B) study is to evaluate the 
safety and efficacy of ertugliflozin in pediatric patients (10 to 17 years of age, inclusive) with 
T2DM. The study design uses a dose titration scheme to optimize the dose for participants in 
a manner consistent with the ertugliflozin label/Investigator’s Brochure (IB). 
Metformin and insulin remain the only pharmaceutical agents approved for pediatric patients 
with T2DM. However, both agents may have issues with acceptability (for metformin, 
difficulty in swallowing tablets and gastrointestinal side-effects, and for insulin, difficulty 
with accepting injections and hypoglycemia) that limit their use, making it important to 
develop a more acceptable alternative therapy.  
Furthermore, glycemic control on metformin monotherapy is not durable, and insulin is the 
only agent approved for use in pediatric patients with T2DM and inadequate glycemic 
control on metformin. Pediatric patients with T2DM on insulin (± metformin) often have 
poor glycemic control, likely due to poor compliance, as well as difficulty with accepting 
insulin therapy. Therefore, there is a need to assess additional treatment options for pediatric 
patients with T2DM, including those who are on metformin ± insulin.  
2.2
Background
Ertugliflozin has been approved for use in adults; refer to the IB/approved labeling for 
detailed background information on ertugliflozin. Refer to product labeling for information 
on metformin and insulin.  
Pharmaceutical and Therapeutic Background
The incidence and prevalence of T2DM in the pediatric population is increasing worldwide. 
T2DM is associated with the development of microvascular complications, particularly 
nephropathy [Bogdanovic, R. 2007] [Krakoff, J., et al 2003] [Pavkov, M. E., et al 2006] 
[Eppens, M. C., et al 2006], as well as the presence of several cardiovascular risk factors that 
increase the likelihood of early macrovascular complications in this population [Fagot-
Campagna, A., et al 2000] [Eppens, M. C., et al 2006] [Petitti, D. B., et al 2007] [Sanders, B. 
H., et al 2006] [Gungor, N., et al 2005][Fagot-Campagna, A., et al 2000] [Eppens, M. C., et 
al 2006] [Petitti, D. B., et al 2007] [Sanders, B. H., et al 2006] [Gungor, N., et al 2005]. As in 
adults, blood glucose levels likely influence the development and progression of both the 
microvascular and possibly macrovascular complications of T2DM [Bogdanovic, R. 2007] 
[DCCT/EDIC Study Research Group 2005]. Therefore, given the substantial lifelong 
cumulative exposure to hyperglycemia for this population, the availability of effective 
therapies is necessary.
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While lifestyle modification is effective [Urakami, T. 2005], it is difficult to implement and 
maintain, and tends to benefit a relative minority of youths with T2DM [American Diabetes 
Association 2000] [Urakami, T. 2005]. Metformin is the only broadly approved oral agent for 
first-line therapy in youths with T2DM [Pinhas-Hamiel, O. and Zeitler, P. 2007] [Bobo, N., 
et al 2004] [Canadian Diabetes Association 2003]. Although initially effective in lowering 
A1C, studies suggest that 35 to 50% of pediatric patients need an additional agent within a 
year of diagnosis [Hannon, T. S., et al 2005]. Since the evolution of T2DM in youths is 
characterized by a rapid and progressive decrease in insulin secretion and progressive 
increase in insulin resistance, along with overproduction of hepatic glucose, and excessive 
levels of glucagon [Weiss, R., et al 2006] [Caprio, S. 2002] [Weiss, R., et al 2005] [Weiss, 
R., et al 2003] [Yeckel, C. W., et al 2005], an orally administered pharmacological agent that 
lowers glucose while also reducing other risks factors, represents a major advantage in the 
treatment of diabetes.
Ertugliflozin is a potent inhibitor of SGLT2 and possesses a high selectivity over glucose 
transport via SGLT1 and several other glucose transporters (GLUT1-4). Ertugliflozin inhibits 
renal glucose reabsorption resulting in urinary glucose excretion and thereby reducing 
plasma glucose and A1C in patients with T2DM with a low risk of hypoglycemia, and 
without increasing insulin secretory burden on pancreatic beta cells. Adult studies have also 
shown that ertugliflozin achieves clinically meaningful improvements in body weight and 
systolic blood pressure (SBP).
The purpose of this study is to evaluate the safety and efficacy of ertugliflozin in pediatric 
patients with T2DM on metformin ± insulin. Ertugliflozin could potentially represent a 
valuable therapeutic option across the typical disease progression of T2DM, including those 
with inadequate glycemic control on metformin with or without insulin. 
Information on Other Study-related Therapy
Metformin
Clinical recommendations for treatment of pediatric patients with T2DM are to integrate 
metformin monotherapy with lifestyle modifications (ie, diet and exercise) [Copeland, K. C., 
et al 2013]. Close monitoring for glycemic deterioration is also recommended, with the early 
addition of insulin or another pharmacologic agent as needed. 
Insulin
Insulin is approved for use in pediatric patients with T2DM. Use of basal insulin is associated 
with less hypoglycemia in patients with T2DM compared to intermediate-acting insulin 
[Klingensmith, G. J., et al 2015]. The procedure and dose for initiation of insulin glargine, 
and for titration of background insulin, will be at the discretion of the investigator, based on 
local/regional/country guidelines. 
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine. However, based on the available 
ertugliflozin adult data, it is predicted that the benefit/risk will be favorable in the patient 
population studied.
In adults, ertugliflozin provides the benefit of inhibiting renal glucose reabsorption resulting 
in urinary glucose excretion and thereby reducing plasma glucose and A1C in patients with 
T2DM without increasing the risk of hypoglycemia. In adult studies of participants with 
T2DM, ertugliflozin treatment improved glucose control, and led to reductions in body 
weight and blood pressure. However, it is not known if these effects will be the same in the 
pediatric population.
Adverse reactions with ertugliflozin treatment in adults include genital mycotic infections in 
males and females, increased urination, thirst, vulvovaginal pruritus, volume depletion 
(particularly in patients with impaired renal function [estimated glomerular filtration rate 
(eGFR) <60 mL/min/1.73 m2], elderly patients [≥65 years], or patients on diuretics), 
ketoacidosis, hypoglycemia in combination with insulin and/or insulin secretagogues, and 
increased low-density lipoprotein cholesterol (LDL-C). In adult studies, use of ertugliflozin 
was associated with transient increases in serum creatinine and decreases in eGFR. Please 
refer to the latest version of the ertugliflozin IB/approved labeling for the most current risk
information related to ertugliflozin treatment. 
A risk to the participants in the placebo group is inadequate glycemic control leading to 
hyperglycemia. The medical risk of inadequate glycemic control has been considered and 
efforts to limit this risk will be implemented in this protocol. To ensure that participants (in 
both treatment groups) will not be exposed to poor glycemic control for an undue period of 
time, the following have been included in the protocol design: diet and exercise counseling
specifically designed for pediatric patients with T2DM, frequent blood glucose monitoring, 
protocol-specified progressively stricter glycemic rescue/intensification procedures, and 
glycemic discontinuation criteria. 
Participants being treated with glucose lowering medications have the risk of developing 
hypoglycemia, which is even greater in participants taking insulin. Hypoglycemia will be 
mitigated by frequent blood glucose monitoring, down-titration, and discontinuation of 
insulin (if needed). 
Additional details regarding specific benefits and risks for participants of this clinical study 
may be found in the accompanying IB and Informed Consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In pediatric patients (ages 10 to 17 years, inclusive) with T2DM on a stable dose of
metformin ≥1500 mg/day ± stable insulin:
Objectives
Endpoints
Primary

Objective: To compare the addition of 
ertugliflozin with the addition of placebo on 
the change from baseline in A1C at 
24 weeks.
Hypothesis (H1): The addition of ertugliflozin 
reduces A1C more than the addition of placebo 
after 24 weeks of treatment.

A1C

Objective: To assess the safety and 
tolerability of ertugliflozin over 24 weeks 
and 54 weeks. 

Adverse Events (AEs)

Discontinuation of study medication 
due to AEs
Secondary

Objective: To compare the addition of 
ertugliflozin, with dosing optimized 
according to A1C response, to the addition 
of placebo on the change from baseline in 
A1C at 24 weeks. 
Hypothesis (H2): The addition of ertugliflozin, 
with dosing optimized according to A1C 
response, reduces A1C more than the addition 
of placebo after 24 weeks of treatment.

A1C

Objective: To compare the addition of 
ertugliflozin 5 mg with the addition of 
placebo on the change from baseline in A1C 
at 24 weeks.
Hypothesis (H3): The addition of ertugliflozin 
5 mg reduces A1C more than the addition of 
placebo after 24 weeks of treatment.

A1C  
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Objectives
Endpoints

Objective: To compare the effect of the 
addition of ertugliflozin to the addition of 
placebo on the change from baseline in 
fasting plasma glucose (FPG) at 24 weeks.

FPG

Objective: To assess the within-group 
(ertugliflozin and placebo) changes from 
baseline at 54 weeks for A1C and FPG. 

A1C 

FPG
Tertiary/Exploratory

Objective: To assess the within-group 
(ertugliflozin and placebo) mean changes 
from baseline for A1C at Week 12.  

A1C 

Objective: To assess the within-group 
(ertugliflozin and placebo) proportion of 
participants at 24 weeks and 54 weeks for 
the following endpoints:

Initiating glycemic rescue/glycemic 
intensification

At the following A1C treatment targets: 

<7.0% (53 mmol/mol)

<6.5% (48 mmol/mol)

<7.0% (53 mmol/mol) among 
participants with baseline A1C 
≥7.0% (53 mmol/mol)

Acceptability and palatability of 
ertugliflozin

Use of glycemic rescue or glycemic 
intensification therapy 

A1C

AEs

Objective: Among those who up-titrated 
from ertugliflozin 5 mg/day to ertugliflozin 
15 mg/day, to assess the within-group 
(ertugliflozin and placebo) proportion of 
participants with A1C <7.0% 
(53 mmol/mol) at 24 weeks. 

A1C
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Objectives
Endpoints

Objective: To assess the within-group 
(ertugliflozin and placebo) mean changes 
from baseline at 24 weeks and 54 weeks for 
the following endpoints:

Body weight and body mass index 
(BMI) percentile

Systolic and diastolic blood pressure

Bone biomarkers

Body weight and BMI percentile

Systolic and diastolic blood pressure

Bone biomarkers

Objective: To assess the within-group 
(ertugliflozin and placebo) mean 
ertugliflozin exposure at 24 weeks. 

Steady state ertugliflozin exposure 
levels
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind study of 
ertugliflozin in pediatric participants (10 to 17 years of age, inclusive) with T2DM, including 
a randomly assigned up-titration of eligible participants after a second randomization at 
Visit 5/Week 12 (Section 8.1.14). Participants will take part in the study for approximately 
58 weeks, including an approximately 1-week screening period (Visit 1/Screening to Visit
2/Week -1), an approximately 1-week single-blind placebo run-in period (Visit 2/Week -1 to
Visit 3/Day 1/Randomization), an approximately 54-week double-blind treatment period 
(including a 24-week Phase A + 30-week Phase B), and a telephone contact 14 days after the 
last dose of study medication. All participants will continue to receive metformin ± insulin 
background therapy during the course of the study. The primary efficacy endpoint for the 
study will be evaluated using data from Phase A. The 30-week Phase B will provide a 
longer-term evaluation of ertugliflozin safety and efficacy in this pediatric population.   
The mitigation strategies for managing participants with poor glycemic control differ 
between the Phase A and Phase B periods (Section 6.5.1). During the 24-week Phase A 
period, participants meeting progressively lower FPG thresholds (Table 3) will be rescued. In 
Phase B, therapy for participants meeting even lower glycemic thresholds will be intensified 
(Table 4) to prevent prolonged exposure to hyperglycemia.
At Visit 3/Day 1/Randomization, eligible participants will be randomized in a 2:1 ratio to 
ertugliflozin 5 mg or placebo. At Visit 5/Week 12, eligible participants in the ertugliflozin 
5 mg treatment group (Section 6.1) will undergo a second randomization in a 1:1 ratio to 
either continue on ertugliflozin 5 mg or up-titrate to ertugliflozin 15 mg. Similarly, eligible 
participants in the placebo group will be mock-titrated (Section 6.1) to maintain the blind. 
Participants who do not meet the threshold(s) for a second randomization will continue on 
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ertugliflozin 5 mg/placebo. Additional details are provided in Section 9. If a participant 
discontinues study medication before Visit 5/Week 12, the second randomization should not 
be performed.  
Approximately 165 participants will be randomized (at Visit 3/Day 1/Randomization) such 
that at least 156 participants are likely to have complete data at Visit 6/Week 24 as described 
in Section 9.9. At least 30% of randomized participants will be between the ages of 10 and 
14 years of age, and at least 30% of participants will be recruited from European Union (EU) 
member states, or countries with ethnicity, lifestyle, and diabetes care similar to those in EU 
countries. Further, at least 1/3 of the participants and not more than 2/3 of the participants 
will be female.
Sparse sampling to assess the pharmacokinetics (PK) of ertugliflozin will be performed. An
interim analysis (IA) is planned to confirm ertugliflozin exposure in this population, and to 
limit potentially exceeding the exposures observed with the highest dose used in adult 
Phase 2 clinical studies. The IA will be conducted when ~30 participants on study 
medication (~20 participants on ertugliflozin) have completed Visit 4/Week 6.
If the IA exposure result exceeds the threshold described in Section 9.7, the second 
randomization will be discontinued, and ongoing participants who have up-titrated to
ertugliflozin 15 mg/day will have an Unscheduled Visit as soon as possible to be down-
titrated to ertugliflozin 5 mg/day in a blinded manner; participants in the placebo group who 
have been mock up-titrated will also be mock down-titrated. If the ertugliflozin 15 mg dose is 
continued, the second randomization at Visit 5/Week 12 will be monitored by the unblinded 
DMC statistician so that ~30 participants are up-titrated to ertugliflozin 15 mg/day.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The purpose of this study is to evaluate the safety and efficacy of ertugliflozin in pediatric 
patients (10 to 17 years of age, inclusive) with T2DM. In addition, the study design 
incorporates a dose titration scheme through a second randomization at Visit 5/Week 12. 
This design element aligns ertugliflozin administration in the study with clinical practice and 
the ertugliflozin product label and IB. 
Population
Pediatric participants 10 to 17 years (inclusive) of age were selected for evaluation because 
T2DM does not occur in infants or toddlers and has rarely been reported in prepubertal 
children less than 10 years of age [Pettitt, D. J., et al 2014] [American Diabetes Association 
2000] [Cefalu, W. T. 2015] [NA 2009]. In individuals less than 18 years of age, the onset of 
T2DM usually occurs during or following the onset of puberty. For this reason, this study 
will focus on participants 10 to 17 years of age (inclusive).
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Primary Endpoint
A1C reflects average glucose concentrations in the past 3 to 4 months and, therefore, will 
provide a useful index of glycemic control at the end of the 24-week treatment period. A1C 
is a standard efficacy endpoint used to assess the glycemic efficacy of AHAs, and 
improvements in A1C correlates with reduction of risk of diabetic complications [Freinkel, 
N. 2017]. 
Run-in placebo period
The placebo run-in period has the explicit purpose of familiarizing the participants with the 
study treatment regimen and excluding participants who are not compliant with the blinded 
placebo prior to randomization. 
Phase A: (Visit 3/Day 1/Randomization to Visit 6/Week 24) 
The length of the placebo-controlled Phase A (24 weeks) was chosen to provide the optimal 
duration to assess the safety and efficacy profile of ertugliflozin versus placebo. An A1C 
threshold of ≥7.0% (53 mmol/mol) was chosen for up-titration of ertugliflozin at 
Visit 5/Week 12 based on the definition of glycemic control in the clinical practice guideline 
for the management of pediatric patients with T2DM [American Diabetes Association 2018] 
[DiMeglio, L. A., et al 2018]. The up-titration schema is described in Section 8.1.14.   
Phase B: (Visit 6/Week 24 to Visit 8/Week 54)
The 30-week treatment period should provide longer-term safety and efficacy data for the use 
of ertugliflozin in pediatric patients.
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
To assess longer-term glucose-lowering efficacy (weeks to months), A1C will be measured.
Since A1C reflects average glucose concentrations over the past 3-4 months, this measure 
provides a more useful index of the glycemic efficacy of ertugliflozin than FPG alone. 
Moreover, A1C is the key glycemic parameter which correlates with reduction of risk of 
diabetic complications. FPG will be measured to characterize the time course of glucose 
control.
4.2.1.2
Safety Endpoints
General safety and tolerability will be evaluated by clinical review of relevant parameters, 
including AEs, vital signs, laboratory safety studies (blood chemistry, hematology, lipid 
panel, urinalysis, and urine pregnancy testing for all females [for exceptions, see Section 
10.7]), bone turnover biomarkers, assessment of growth and development, and 
nephrocalcinosis evaluation. For this study, prespecified AEs of interest (Tier 1) are 
symptomatic hypoglycemia, hypovolemia, genital mycotic infections (gender specific), and 
urinary tract infection (UTI). 
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4.2.1.3
Pharmacokinetic Endpoints
The PK data from this study may be combined with data from other studies for population 
PK analysis using nonlinear mixed effects modeling. If data permit, estimates of population 
PK parameters such as apparent oral clearance (CL/F) as well as estimates of inter-individual 
and residual variability will be determined. In addition, effects of demographic or 
physiologic factors (eg, age, race, weight, gender, renal function) on PK parameters will be 
assessed if possible. The results of this population PK analysis will be summarized in a 
separate report.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic analysis is being conducted for this study.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
Rationale for the Use of Placebo
The placebo control group is an essential arm in this study, as it supports the evaluation of 
the safety and efficacy of ertugliflozin in pediatric participants 10 to 17 years of age 
(inclusive). 
Glucose concentrations can change over time related to changes in diet, activity, and other 
factors, and hence a comparison to pre-treatment baseline glucose concentrations, rather than 
to glucose levels in another treatment group, would not accurately characterize the glucose-
lowering efficacy of ertugliflozin in this population. Non-placebo controlled, 
active-comparator studies provide important information, but the efficacy profile of a new 
agent is best characterized by comparison to placebo.  
Similarly, the safety profile of any drug is best characterized versus placebo, especially when 
it is first being studied in a particular population (eg, pediatric participants with T2DM).
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4.3
Justification for Dose
The proposed ertugliflozin doses to be evaluated in this study are 5 mg and 15 mg qd to be 
taken in the morning with or without food. 
The 5 mg and 15 mg doses of ertugliflozin were studied in the adult Phase 3 program and 
have been approved for use in adults. Since pediatric PK and pharmacodynamic responses 
are anticipated to be comparable to those of adults, the same adult doses were selected for 
evaluation in this study. Results from the adult Phase 3 program showed that the 5 mg and 
15 mg doses of ertugliflozin have similar safety profiles, and both lead to clinically 
meaningful improvements in glycemia, blood pressure, and body weight. Due to the 
consistent effects of both doses, primary safety and efficacy analyses for this study will pool 
results from the 2 ertugliflozin dose groups. 
Maximum Dose/Exposure for This Study
Based on 3 Phase 1 PK/Pharmacodynamic studies for canagliflozin, empagliflozin, and 
dapagliflozin, the PK/pharmacodynamic relationship for SGLT2 inhibitors appears to be 
similar in pediatric T2DM patients (aged 10-17 years of age) and adult T2DM patients 
[Tamborlane, W. V., et al 2018] [Laffel, L. M. B., et al 2018] [Tirucherai, G. S., et al 2016].
The maximum dose of 15 mg qd was selected because it was the highest ertugliflozin dose 
studied in adults with T2DM in the Phase 3 studies and is the higher of 2 approved doses for 
use in adults. Population PK analysis predicts that ertugliflozin exposure in T2DM pediatric 
participants would be similar to that of adults when the same dose is administered. For the 
15 mg dose, the population PK model predicted a median steady state AUC24 of 
1207 ng•hr/mL in the T2DM pediatric population, which is comparable to the model 
predicted steady state AUC24 in adults with T2DM (1329 ng•hr/mL). The threshold for 
stopping the 15 mg dose is described in Section 9.7.
Rationale for Dose Interval
The PK of ertugliflozin in adults supports once daily dosing and the approved dosing 
regimen in adults is ertugliflozin 5 mg qd or ertugliflozin 15 mg qd without regards to food. 
Since the population PK model has predicted comparable exposures between adults and 
pediatric patients 10 to 17 years of age, a similar dosing regimen (dose and dose interval) is 
proposed for this study. 
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form.
End of study will be declared after (1) all participants in the study have completed Week 54 
or have discontinued from study prior to Week 54, (2) the database has been locked (after 
medical and scientific reviews of the data have been completed), and (3) the data have been 
unblinded. Note: Fifty-six weeks after the last participant is randomized, any participant with 
an outstanding status will be declared as “lost to follow-up”.
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If the study includes countries in the European Economic Area (EEA), the local start of the
study in the EEA is defined as First Site Ready (FSR) in any Member State.
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
However, the clinical study may be terminated early if the risk/benefit ratio to the study 
population is viewed as unacceptable. In addition, further recruitment in the study or at (a) 
particular study site(s) may be stopped due to insufficient compliance with the protocol, 
Good Clinical Practice (GCP), and/or other applicable regulatory requirements, procedure-
related problems or an unacceptably high number of discontinuations or withdrawals due to 
administrative reasons.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Male/Female participants with T2DM between the ages of 10 and 17 years (inclusive) will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
All laboratory measures (to determine eligibility) must be performed after an overnight fast 
≥10 hours in duration. Participants with laboratory screening values/findings not meeting 
protocol inclusion criteria may, at the discretion of the investigator, have 1 repeat 
determination performed by the central laboratory. If the repeat value satisfies the criterion,
the participant may continue in the screening process. Only the specific laboratory test not 
meeting the inclusion criterion should be repeated (not the entire panel). 
Note: If the period of time between Screening Visit/Visit 1 (ie, date when the screening 
laboratory measurements were obtained) and the Visit 3/Day 1/Randomization date exceeds 
28 days, participants must have all screening laboratory measurements repeated (this includes 
participants who have had their metformin and/or insulin doses adjusted). If screening 
laboratory values are repeated, the last laboratory draw/result should be used to evaluate 
eligibility.
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To be eligible for inclusion in this study, the participant must meet all of the following 
criteria:
At Screening Visit/Visit 1
1. Have T2DM as indicated by “yes” answers to all of the following:
i.
Participant has diabetes diagnosed by one of the following American Diabetes 
Association (ADA) criteria, eg:
a.
Laboratory determinations of FPG ≥126 mg/dL (7.0 mmol/L), OR
b.
Random plasma glucose ≥200 mg/dL (11.1 mmol/L), OR
c.
2-hour oral glucose tolerance test (OGTT) plasma glucose 
≥200 mg/dL (11.1 mmol/L), OR
d.
A1C ≥6.5% (48 mmol/mol) test performed using a method that is 
National Glycohemoglobin Standardization Program (NGSP) certified 
and standardized to the Diabetes Control and Complications Trial 
(DCCT) assay.
ii.
Participant has BMI ≥85th percentile at screening OR
participant has a history of being overweight or obese at time of diagnosis of 
T2DM.  
Note: If the participant does not have a BMI ≥85th percentile at the time of 
screening, the documentation of overweight or obesity at the time of diagnosis 
of T2DM must be included in the source documents at the site.
2. Have:
i.
T2DM for ≥2 years, OR
ii.
T2DM for <2 years and a fasting C-peptide value >0.6 ng/mL at Screening 
Visit/Visit 1.
Note: All participants on background insulin must have a fasting C-peptide 
value >0.6 ng/mL with a concurrent FPG >100 mg/dL (5.56 mmol/L) at 
Screening Visit/Visit 1 regardless of duration of T2DM. If FPG ≤100 mg/dL 
(5.56 mmol/L) C-peptide levels should be measured at an Unscheduled
Visit/Visit 2/Week -1, at least 30 minutes, but no longer than 2 hours after a 
meal. Participants must have a C-peptide value >1.5 ng/mL in the post-meal 
period.
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3. Be:
i.
On stable metformin monotherapy (≥1500 mg/day, for ≥8 weeks prior to 
Screening Visit/Visit 1), OR
ii.
On a stable metformin dose (≥1500 mg/day, for ≥8 weeks prior to Screening 
Visit/Visit 1) and a stable dose of insulin (of any type, variance in dose to be 
≤15% of total daily dose for ≥8 weeks prior to Screening Visit/ Visit 1). 
Note: This stable dose can include: (1) a stable dose of basal insulin (±15%) 
AND/OR (2) stable prescribed doses of bolus insulin (±15%) (a) for each 
fingerstick glucose (FSG) range for participants on sliding scale OR, if 
applicable, (b) for corrective doses and carbohydrate coverage. 
Notes:
a.
Participants on stable doses of metformin ≥1000 and <1500 mg/day 
(± insulin) for ≥8 weeks can participate if there is documentation that they 
cannot tolerate higher doses of metformin.
b.
Participants on metformin doses ≥1000 and <1500 mg/day (± insulin) can 
have their metformin doses up-titrated to ≥1500 mg/day and be eligible to 
participate after their dose remains stable for ≥8 weeks, if they meet eligibility 
criteria when they are rescreened. If up-titration of metformin is not tolerated, 
it must be documented, and the participant will be eligible if they meet all 
other Screening Visit/Visit 1 eligibility criteria. 
c.
At Screening Visit/Visit 1, participants on insulin doses that are not stable 
can have the insulin doses adjusted and be eligible to participate after their 
dose remains stable for ≥8 weeks, if they meet eligibility criteria when they 
are rescreened. 
4. Have an A1C ≥6.5% and ≤10.0% (48 mmol/mol and 86 mmol/mol) at Screening 
Visit/Visit 1 if on metformin monotherapy, OR an A1C ≥7.0% and ≤10.0% (53 
mmol/mol and 86 mmol/mol) at Screening Visit/Visit 1 if on metformin + insulin.
Demographics
5. Be male or female, ≥10 years and ≤17 years of age, when the informed consent is signed 
by the legally acceptable representative, and randomization (Visit 3/Day 
1/Randomization) will occur prior to the participant’s 18th birthday.
Male Participants
6. Contraceptive use by male participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
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Female Participants
7. Contraceptive use by female participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
8. Be a female participant who is unlikely to conceive as indicated by at least 1 “yes”
response to the following which will remain consistent for the projected duration of the 
study and for 14 days after the last dose of study treatment:
i.
Participant is a non-sterilized female who is currently not sexually active and 
agrees to follow statement “iii” if heterosexual activity is initiated, OR
ii.
Participant is a non-sterilized female who agrees to abstain from heterosexual 
activity. Note: If abstinence (see Appendix 5) is not a locally acceptable method 
of contraception, then 1 other adequate birth control method must be used, OR
iii.
Participant is a non-sterilized female who agrees to start contraception prior to
initiating sexual activity and who agrees to use an adequate method of 
contraception (Appendix 5). Note: Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. Participants initiating hormonal contraception during 
the study should use 1 additional contraceptive method.
Informed Consent/Assent
9. Have a legally acceptable representative who understands the study procedures, 
alternative treatments available and risks involved with the study, and voluntarily agrees 
to the child's participation by giving informed written consent, and the participant has an 
age-appropriate understanding of the same by giving informed written assent. If the 
legally acceptable representative is illiterate see Section 8.1.1.1 for details. In addition, 
the legally acceptable representative may also consent to have the child participate in 
Future Biomedical Research (FBR) by signing a separate consent (Section 8.1.1.2). 
Otherwise eligible participants will be able to participate in the main study even if they 
opt to not participate in FBR.
10. Have a family member or adult who, along with the participant, will be closely involved 
in the participant’s daily activities (in the opinion of the investigator) and in the 
participant's treatment and study procedures (ie, available for telephone calls, study visits 
and administration of study medication as needed).
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At Visit 3/Day 1/Randomization
11. Have ≥80% compliance with placebo treatment during the single-blind run-in as 
measured by site-performed tablet count.
Note: The minimum interval between Visit 2/Week -1 and Visit 3/Day 
1/Randomization should be 6 days. In this case, 100% compliance with single-blind 
placebo treatment will be required for randomization. The maximum interval between 
Visit 2/Week -1 and Visit 3/Day 1/Randomization should be 14 days, with ≥80% 
compliance with single-blind placebo treatment required for randomization. 
5.2
Exclusion Criteria
All laboratory measures (to determine eligibility) must be performed after an overnight fast 
≥10 hours in duration. Participants with laboratory screening values outside the ranges 
described in the protocol may, at the discretion of the investigator, have 1 repeat 
determination performed by the central laboratory. If the repeat value satisfies the criterion,
the participant may continue in the screening process. Only the specific out-of-range 
value/finding should be repeated (not the entire panel).
Note:  If the period of time between Screening Visit/Visit 1 (ie, date when the screening 
laboratory measurements were obtained) and the date of Visit 3/Day 1/Randomization
exceeds 28 days, participants must have all screening laboratory measurements repeated (this 
includes participants who have had their metformin and/or insulin doses adjusted). If 
screening laboratory values are repeated, the last laboratory draw/result should be used to 
evaluate eligibility.
The participant must be excluded from the study if the participant meets any of the following 
criteria:
At Screening Visit/Visit 1
1. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
Medical Conditions
2. Has known type 1 diabetes mellitus or documented evidence of positive diabetes 
auto-antibodies performed when participant was diagnosed with diabetes.
3. Has known monogenic diabetes, or secondary diabetes.
4. Has symptomatic hyperglycemia and/or moderate to large ketonuria requiring 
immediate initiation of another antihyperglycemic agent, including insulin.
5. Has active, obstructive uropathy or indwelling urinary catheter. 
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6. Has history of malignancy ≤5 years prior to signing informed consent, except for 
adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
Note (a):  A participant with a history of malignancy >5 years prior to signing 
informed consent should have no evidence of residual or recurrent disease.
Note (b):  A participant with any history of melanoma, leukemia, lymphoma, or 
renal cell carcinoma is excluded (cannot participate).
7. Has a known hypersensitivity or intolerance to any SGLT2 inhibitor.
8. Has active liver disease (other than non-alcoholic hepatic steatosis) by history, 
including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic 
gallbladder disease.
9. Has active nephropathy (ie, nephrotic syndrome or glomerulonephritis) or 
abnormalities of genitourinary tract that predispose to recurrent urinary tract 
infections. Note:  Participants with diabetic nephropathy will be eligible if they meet 
all other eligibility criteria.
10. Meets any of the following criteria:
i.
Participant is on a weight-loss program and is not weight-stable.
ii.
Participant is on a weight-loss medication (eg, orlistat, 
phentermine/topiramate, lorcaserin) and is not weight-stable.
iii.
Participant is on other medications associated with weight changes (eg, anti-
psychotic agents) and is not weight-stable.
iv.
Participant had bariatric surgery at any time in the past. 
Note: Weight-stable is defined as <5% change in body weight in the last 3 
months.
11. Has been previously diagnosed with disorders of growth or bone metabolism.
12. Has a clinically significant hematological disorder (such as aplastic anemia, 
thrombocytopenia, myeloproliferative or myelodysplastic syndrome). 
13. Is pregnant, or breast feeding or is expecting to conceive or donate eggs during the 
study, including 14 days following the last dose of study medication.
Prior/Concomitant Therapy
14. Has been treated with a sulfonylurea, meglitinide, alpha glucosidase inhibitor, DPP-4 
inhibitor, or incretin-based agent in the 8 weeks prior to Screening Visit/Visit 1. 
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15. Has been treated with a thiazolidinedione in the 16 weeks prior to 
Screening Visit/Visit 1. 
16. Is taking blood pressure medication(s) and will not be on a stable dose for at least 4 
weeks prior to Visit 3/Day 1/Randomization.
17. Is currently being treated for hyperthyroidism.
18. Is on, or likely to require treatment with, ≥14 consecutive days or repeated courses of 
pharmacologic doses of corticosteroids. 
Note: Inhaled, nasal, and topical corticosteroids are permitted. 
Prior/Concurrent Clinical Study Experience
19. Has previously taken an SGLT2 inhibitor (such as canagliflozin, dapagliflozin, 
empagliflozin, or ertugliflozin) or was enrolled in a study for these agents. 
Note:  Participants who have been enrolled in single-dose studies with these agents 
≥12 weeks prior to screening are eligible to participate.
Diagnostic Assessments
20. Has a Screening Visit/Visit 1 SBP or diastolic blood pressure (DBP) ≥95th percentile 
for age, height percentile, and gender (see Table 11 and Table 12) and is not 
considered likely to have values <95th percentile for age, height percentile and 
gender by Visit 3/Day 1/Randomization even with appropriate antihypertensive 
therapy. 
Note: Investigators are encouraged to maximize blood pressure control according to 
current guidelines. Participants may have blood pressure medications adjusted and 
may be enrolled if the participant’s blood pressure no longer meets exclusion criteria. 
21. Has fasting serum triglyceride >500 mg/dL (5.65 mmol/L) at Screening Visit /Visit 1, 
confirmed by a single repeat if deemed necessary. Participants with elevated 
triglycerides may be rescreened with the permission of the Sponsor’s Clinical 
Director if they have a normal triglyceride level (<150 mg/dL [1.7 mmol/L]) after 
they have been on a triglyceride-lowering diet or a stable lipid-lowering medication 
regimen for at least 4 weeks prior to rescreening with no further dose changes during 
the pre-randomization period. 
22. Has an eGFR <45 mL/min/1.73m2 at Screening Visit/ Visit 1.
Note:  The eGFR cutoff for exclusion should be consistent with the local label for 
ertugliflozin if it is different from above.   
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23. Has an aspartate transaminase (AST) or alanine transaminase (ALT) >2.5X the upper 
limit of normal (ULN) at Screening Visit/ Visit 1, or a total bilirubin >1.5X the ULN 
unless the participant has a history of Gilbert syndrome.
24. Has hemoglobin levels below normal range for age and sex at Screening Visit/
Visit 1.
25. Has thyroid-stimulating hormone (TSH) levels outside normal range at Screening 
Visit/ Visit 1. Participants with elevated TSH must be excluded and may be 
rescreened with the permission of the Sponsor’s Clinical Director if they have a 
normal TSH after they have been on a stable thyroid replacement regimen for at least 
6 weeks prior to rescreening with no further dose changes during the pre-
randomization period. 
Note: Participants already on thyroid replacement therapy at Screening Visit/Visit 1
should have a normal TSH and be on a stable dose for at least 6 weeks prior to 
randomization.
26. Has a history of idiopathic acute pancreatitis or chronic pancreatitis.
27. Has a history of severe hypoglycemia (hypoglycemia associated with altered 
sensorium, seizures, or loss of consciousness) while on insulin. 
Other Exclusions
28. Has a known history of recreational or illicit drug use, or of alcohol abuse or 
dependence (within the past year).
29. Has donated blood products or has had phlebotomy of >10% of estimated total blood 
volume within 8 weeks of signing informed consent or intends to donate blood 
products or receive blood product within the projected duration of the study.
30. Is unlikely to adhere to the study procedures and appointment schedule, is planning to 
relocate outside of the geographic area during the study (including attending school at 
a remote location), or has poor mental function, or legally acceptable representative is 
in the opinion of the investigator, mentally or legally incapacitated preventing 
informed consent from being obtained. 
31. Has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance which, in the opinion of the investigator, might pose a risk to the 
participant, make participation not in the participant’s best interest, might confound 
the results of the study, or interfere with the participant’s involvement for the full 
duration of the study. 
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At Visit 2/Week -1
32. Has symptomatic hyperglycemia or ketonuria.
33. Has a clinically significant ECG abnormality that requires further diagnostic 
evaluation or intervention (eg, new, clinically significant arrhythmia or a conduction 
disturbance) which, in the opinion of the investigator, exposes the participant to risk 
by enrolling in the study. Or participant has a prolonged QTc interval for age. Note: 
The same criterion will apply if the ECG is performed at Visit 3/
Day 1/Randomization instead of Visit 2/Week -1.
34. Requires initiation of concomitant medications listed in Section 6.5. The current Visit 
should be changed to an Unscheduled Visit and the participant should be rescheduled 
for a Visit 2/Week -1 (and Visit 3/Day 1/Randomization) to occur in accordance with 
the guidance in Section 6.5.
Note: If the duration between Visit 1/Screening and Visit 3/Day 1/Randomization is 
greater than 28 days, participants must have all screening laboratory measurements 
repeated as described at the beginning of Section 5.2. 
At Visit 3/Day 1/Randomization
35. Has symptomatic hyperglycemia, and/or ketonuria, requiring immediate change to 
his/her antihyperglycemic therapy.
36. Has developed a new medical condition, suffered a change in status of an established 
medical condition, developed a laboratory abnormality, or required a new treatment 
or medication during the run-in which meets any previously described study 
exclusion criterion. 
Note:  If a participant requires initiation of a new medication (with the exception of 
medications prohibited in the exclusion criteria) at Visit 3/Day 1/Randomization, the 
current visit should be changed to an "Unscheduled Visit" and the participant should 
be rescheduled for a Visit 3/Day 1/Randomization to occur 1 to 2 weeks later. 
Additional single-blind placebo run-in treatment should be dispensed at this 
Unscheduled Visit.
37. Is female with a positive pregnancy test.
38. Has a site fasting fingerstick glucose (FFSG) >240 mg/dL (13.3 mmol/L).
Note: If the investigator believes that the value does not reflect the participant’s 
recent glycemic control, then the participant should not be excluded at this time. The 
current visit should be changed to an Unscheduled Visit and the participant should 
be rescheduled for Visit 3/Day 1/Randomization. If at the rescheduled visit, the 
participant meets this exclusion criterion, the participant MUST be excluded.
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39. Has a FFSG <130 mg/dL (7.2 mmol/L) if on insulin 
Note: If the investigator believes that the value does not reflect the participant’s 
recent glycemic control, then the participant should not be excluded at this time. The 
current visit should be changed to an Unscheduled Visit and the participant should 
be rescheduled for Visit 3/Day 1/Randomization. If at the rescheduled visit, the 
participant meets this exclusion criterion, the participant MUST be excluded.
5.3
Lifestyle Considerations
Participants will be advised to adhere to the recommended dietary and activity regimen for 
the duration of the study, with the objective of maintaining consistency.
Meals and Dietary Restrictions
The participant and legally acceptable representative will receive individualized diet 
counseling for weight maintenance consistent with the standard guidelines of the country of 
the investigational site (or other similar guidelines such as those from the ADA) for youths 
with T2DM from a dietitian or other qualified health care professional. Detailed dietary 
information will not be captured in the study database.
Caffeine, Alcohol, and Tobacco Restrictions
Participants should not have any caffeine or tobacco within 30 minutes of blood pressure 
measurements.
Activity Restrictions
Participants must not engage in physically strenuous exercise (eg, heavy lifting, weight 
training, calisthenics, and aerobics) within 48 hours before each blood sample collection for 
clinical laboratory tests for the duration of participation in the study.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
Participants who discontinue from study medication or withdraw from the study will not be 
replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies of blinded study medications provided by the Sponsor will be packaged to 
support enrollment in the study. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study medications to be used in this study are outlined in Table 1.
First Randomization at Visit 3/Day 1/Randomization:
All qualified participants will be randomized to receive 2 tablets per day of either:

Ertugliflozin 5 mg and placebo matching ertugliflozin 15 mg –OR-

Placebo matching ertugliflozin 5 mg and placebo matching ertugliflozin 15 mg
Second Randomization at Visit 5/Week 12:
Eligible participants in the ertugliflozin 5 mg group 

Treated with ertugliflozin 5 mg: FS A1C ≥7.0% (53 mmol/mol)

Treated with ertugliflozin 5 mg and insulin: FS A1C ≥7.0% (53 mmol/mol) and
FFSG ≥110 mg/dL (6.1 mmol/L)
will have a second randomization to receive 2 tablets per day of either:

Ertugliflozin 5 mg and placebo matching ertugliflozin 15 mg OR-

Ertugliflozin 15 mg and placebo matching ertugliflozin 5 mg.
Eligible participants in the placebo group

Treated with placebo alone: FS A1C ≥7.0% (53 mmol/mol)

Treated with placebo and insulin: FS A1C ≥7.0% (53 mmol/mol) and a FFSG
≥110 mg/dL (6.1 mmol/L) 
will undergo a mock second randomization to maintain blinding, with no change in study 
medication. Participants who do not meet the threshold(s) for a second randomization will 
continue on ertugliflozin 5 mg/placebo.
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If a participant discontinues study medication before Visit 5/Week 12, the second 
randomization should not be performed.  
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Table 1
Study Medications
Arm Name
Arm Type
Medication
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Placebo Run-in
Other
Placebo 
matching 
ertugliflozin 
5 mg
Other
Tablet
0 mg
1 Tablet qd
Oral
Visit 2 to Visit 3 
(Placebo Run-in 
Period)
Placebo
IMP
Provided 
centrally by 
Sponsor
Placebo Run-in
Other
Placebo 
matching 
ertugliflozin 
15 mg
Other
Tablet
0 mg
1 Tablet qd
Oral
Visit 2 to Visit 3 
(Placebo Run-in 
Period)
Placebo
IMP
Provided 
centrally by
Sponsor
Ertugliflozin 
5 mg
Experimental
Ertugliflozin 
5 mg
Drug
Tablet
5 mg
1 Tablet qd
Oral
Visit 3 to Visit 
5/8 (Double-
blind Treatment 
Period)
Test 
Product
IMP
Provided 
centrally by 
Sponsor
Ertugliflozin 
5 mg
Experimental
Placebo 
matching 
ertugliflozin 
15 mg
Other
Tablet
0 mg
1 Tablet qd
Oral
Visit 3 to Visit 
5/8 (Double-
blind Treatment 
Period)
Placebo
IMP
Provided 
centrally by 
Sponsor
Placebo
Placebo 
Comparator
Placebo 
matching 
ertugliflozin 
5 mg
Other
Tablet
0 mg
1 Tablet qd
Oral
Visit 3 to Visit 8 
(Double-blind 
Treatment 
Period)
Placebo
IMP
Provided 
centrally by 
Sponsor
Placebo
Placebo 
Comparator
Placebo 
matching 
ertugliflozin 
15 mg
Other
Tablet
0 mg
1 Tablet qd
Oral
Visit 3 to Visit 8 
(Double-blind 
Treatment 
Period)
Placebo
IMP
Provided 
centrally by 
Sponsor
Ertugliflozin 
15 mg (a)
Experimental
Ertugliflozin 
15 mg
Drug
Tablet
15 mg
1 Tablet qd
Oral
Visit 5 to Visit 8 
(Double-blind 
Treatment 
Period)
Test 
Product
IMP
Provided 
centrally by 
Sponsor
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Arm Name
Arm Type
Medication
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Ertugliflozin 
15 mg (a)
Experimental
Placebo 
matching 
ertugliflozin 
5 mg
Other
Tablet
0 mg
1 Tablet qd
Oral
Visit 5 to Visit 8 
(Double-blind 
Treatment 
Period)
Placebo
IMP
Provided 
centrally by 
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note: Standard of care medication to be sourced locally and to follow local guidelines and regulations. Rescue/intensification medication to be sourced locally and administration 
to be consistent with those specified in the protocol. Drug handling, storage, and accountability of blinded study medication, metformin, and insulin will be conducted per Section 
6.2.2, as applicable.
(a) The ertugliflozin 15 mg dose will be administered to a portion of the participants who qualify for the second randomization (Section 8.1.14).
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. 
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. At Visit 3/Day 1/Randomization, there will be 2 study 
intervention arms. Participants will be assigned randomly in a 2:1 ratio to ertugliflozin 5 mg 
or placebo. 
At Visit 5/Week 12, all eligible participants (Section 6.1) will undergo a second 
randomization. Eligible participants in the ertugliflozin 5 mg group will be randomized in a 
1:1 ratio to either stay on ertugliflozin 5 mg or up-titrate to ertugliflozin 15 mg
(Section 8.1.14). Eligible participants in the placebo group will participate in the second 
randomization, but all will remain on placebo and be mock-titrated to preserve blinding.
If the PK IA (Section 9.7) results in a decision to drop the 15 mg dose, then:
1. The second randomization at Visit 5/Week 12 will be discontinued and the 
corresponding FS A1C and FFSG should not be performed (the central laboratory A1C 
will still be performed).
2. Ongoing participants who have reached Visit 5/Week 12 or beyond on study medication 
will return to the site to have blinded study medication redispensed through IRT to 
maintain blinding. Participants receiving placebo or ertugliflozin 5 mg will continue to 
receive the same medication. Participants who are receiving ertugliflozin 15 mg will be 
down-titrated to the ertugliflozin 5 mg dose for the remainder of the study.
If the ertugliflozin 15 mg dose is continued, the second randomization at Visit 5/Week 12
will be monitored by the unblinded DMC statistician so that ~30 participants are up-titrated 
to ertugliflozin 15 mg/day.   
Stratification
Treatment allocation/randomization at Visit 3/Day 1/Randomization will be stratified 
according to the following factors collected at Screening Visit/Visit 1:
1. Age: 10 to 14 years of age OR 15 to 17 years of age 
2. Insulin use: Yes OR No
Treatment allocation/randomization at Visit 5/Week 12 will be stratified according to the 
following factor collected at Visit 5/Week 12:
3. Insulin use: Yes OR No
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Blinding
For the double-blind phase of the study, double-blinding technique with in-house blinding 
will be used. Ertugliflozin 5 mg and ertugliflozin 15 mg will be packaged identically relative 
to their matching placebos so that blind is maintained. The participant, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention administration or 
clinical evaluation of the participants are unaware of the intervention assignments.
At Visit 5/Week 12, eligible participants in the ertugliflozin 5 mg treatment group 
(Section 6.1) will undergo a second randomization in a 1:1 ratio to either continue on 
ertugliflozin 5 mg or up-titrate to ertugliflozin 15 mg. Similarly, eligible participants in the 
placebo group will be mock-titrated (Section 6.1) to maintain the blind. Participants who do 
not meet the threshold(s) for a second randomization will continue on ertugliflozin 
5 mg/placebo.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted. 
6.4
Study Intervention Compliance
Every effort will be made to maintain 100% medication adherence. If a participant is found 
to have compliance <85%, site personnel should begin frequent contacts (at least once a 
week, until the next site visit) with the participant and the legally acceptable representative to 
reinforce compliance with study medication.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study if the participant is on double-blind study medication. If the participant is 
being followed up in the study off-study medication, these prohibited medications may be 
used at the discretion of the investigator.  
Note: It is the responsibility of the investigator to ensure that participants with concomitant 
medical conditions (such as hypothyroidism, hypertension, and dyslipidemia) are treated 
according to local guidelines.
Antihyperglycemic Medications
Double-blind study treatment and metformin (as background) and insulin (as background or 
rescue/intensification therapy when appropriate), are the only AHAs permitted in the study. 
Participants who discontinue study medication may be treated with antihyperglycemic 
medication as considered clinically appropriate.
Lipid, Blood Pressure, and Thyroid Hormone Medications
Concurrent lipid-lowering, antihypertensive, and thyroid hormone replacement medications 
are permitted. However, it is the responsibility of the investigator to ensure that participants 
are on a stable dose of thyroid medication regimen for at least 6 weeks  and/or a stable dose 
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of lipid-lowering and antihypertensive medications for at least 4 weeks prior to Visit 3/Day 
1/Randomization.
Note: Medications to treat hyperthyroidism are prohibited.
Birth Control Medications
These medications are allowed, but participants should be on a stable regimen during placebo 
run-in and are expected to remain on a stable regimen during the double-blind treatment 
period (refer to Appendix 5 for further detail regarding contraceptive agents).
Note: Participants who initiate heterosexual activity during the study may begin hormonal 
contraception as detailed in Appendix 5.
Corticosteroids
Treatment for ≥14 consecutive days of pharmacologic doses of corticosteroids (oral, 
injectable/parenteral) is not permitted during the study. Oral corticosteroids used for 
physiologic replacement therapy (ie, in participants with adrenal insufficiency) and inhaled, 
nasal, and topical corticosteroids are allowed.
Note: Use or need for use of excluded medications will require consultation with the study 
investigator and the Sponsor.
Supplements
The use of herbal supplements and other so-called “natural products” should be discouraged 
for the duration of the study. Participants who do not discontinue the use of such supplements 
prior to the Screening Visit should be instructed not to change the use or dose of the 
supplement for the duration of the study. Participants should be instructed not to initiate new 
supplements for the duration of the study.
Imaging with contrast
Metformin should be temporarily discontinued at the time of, or prior to, iodinated contrast 
imaging procedures, and restarted if renal function is normal 48 hours after the imaging 
procedure.
Rescue Medications and Supportive Care
After randomization (Visit 3/Day 1/Randomization), participants who have ≥80% 
compliance with study medication (and diet/exercise recommendations) and meet protocol-
specified glycemic thresholds will be eligible for glycemic rescue therapy during Phase A 
(Table 3) or glycemic intensification during Phase B (Table 4). Participants, who, in the 
investigator’s judgment, are not compliant (<80%) with study medication and/or 
diet/exercise recommendation, should be retrained by site personnel on compliance with 
medication and diet/exercise (Section 6.4). The participant should be contacted a week later 
to assess if FFSG values still meet rescue/intensification criteria. 
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The participant and legally acceptable representatives will be (1) instructed on FFSG values 
that meet the threshold corresponding to the participant’s duration in the study (eg, a 
participant has 3 consecutive days of FFSG values >240 mg/dL [13.3 mmol/L] between Visit 
3/Day 1/Randomization and Visit 4/Week 6) and (2) instructed to call the site if the 
participant has 3 consecutive days of FFSG values that exceed the specified thresholds. For 
reference, site personnel will instruct the legally acceptable representative/participant of the 
threshold level for rescue for the specific time period in the study. 
Participants and legally acceptable representatives will be counseled that if 1 FFSG value is 
above the threshold for rescue/intensification, the FFSG value must be checked the following 
morning. If the FFSG value is above the threshold for rescue/intensification on 2 consecutive 
days, the FFSG has to be checked on the third day as well, and the site called if all 3 values 
are above the threshold for rescue/intensification.    
The participant will attend an Unscheduled Visit if the FFSG value exceed thresholds for 
3 consecutive days and has been compliant with study medication, diet, and exercise 
recommendations.  
During Phase A:
At the Unscheduled Visit, an FPG will be drawn for local and central laboratory evaluation. 
The FPG value reported from the local laboratory should be used to assess rescue criteria and 
must be recorded on the relevant electronic case report form (eCRF). If the local lab FPG 
value is less than the rescue threshold, but the central laboratory FPG value is greater than 
the rescue threshold, the participant will have to return to the site to complete a Rescue Visit
(Section 8.10.7) and initiate rescue therapy.
Participants should also initiate glycemic rescue therapy if a central laboratory FPG alone 
meets rescue criteria during a routine site visit, even if the participant does not report 
3 consecutive FFSG values above the threshold. In this situation, the participant will need to 
come to the site for an Unscheduled Visit to initiate glycemic rescue.
Participants on metformin alone who meet glycemic rescue criteria should initiate insulin 
glargine (dose at the investigator’s discretion based on accepted local, national or 
international guidelines). If the participant is on metformin + insulin, the insulin dose should
be increased by ≥15% (Table 2).
No participant should undergo glycemic rescue at an Unscheduled Visit between Week 10
and Visit 5/Week 12.
Additionally, at Visit 5/Week 12, participants who are eligible for the second randomization
should NOT undergo glycemic rescue even if they meet the specified criteria. Instead, these 
participants should be advised to check FFSG measurements every day for the next 2 weeks
and glycemic rescue therapy should be initiated 2 weeks after Visit 5/Week 12 if they
continue to meet the prespecified thresholds (Table 3). 
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During Phase B (for participants not rescued in Phase A):
Starting from Visit 6/Week 24, FFSG and FS A1C will be measured at scheduled and 
unscheduled site visits, and glycemic intensification will be initiated if the participant meets 
criteria (Table 4). Between site visits, participants with FFSG >130 mg/dL (7.2 mmol/L) at 
home for 3 consecutive days will come to the site for an Unscheduled Visit if, in the 
investigator’s judgment, the participant has been compliant with study medication and 
diet/exercise recommendations. At the unscheduled site visit, the participant’s FFSG and FS 
A1C will be measured, and the participant will initiate glycemic intensification if both values 
meet criteria (Table 4). If the participant is on metformin alone, insulin glargine will be 
initiated (dose at the investigator’s discretion based on accepted local, national or 
international guidelines). If the participant is on metformin + insulin the total daily insulin 
dose will be increased by ≥15% (Table 2).
Table 2
Glycemic Rescue/Intensification Strategy
Participant’s Background 
Therapy
Phase A Rescue Therapy OR 
Phase B Intensification Therapy (for participants not rescued in Phase A)
Metformin alone
Insulin glargine
Metformin + Insulin  
Increase insulin dose ≥15%
Note: In Phase A and Phase B, participants requiring transient (ie, <14 days) initiation of 
insulin or an increase in insulin (≥15% of the dose at baseline), for participants on 
background insulin therapy (eg, an intercurrent illness) will not be considered as having 
initiated rescue/intensification. Down-titration or weaning of insulin after a temporary 
initiation or increase in dose should occur at the investigator’s discretion.
Note that participants rescued or intensified with basal insulin for 6 weeks or more, can have 
prandial insulin added at the investigator’s discretion. The choice, dose, and titration of 
prandial insulin will be the investigator's responsibility.  
Participants <18 years of age, who refuse to initiate insulin or up-titrate their background 
insulin (or for whom it is considered inappropriate) when glycemic thresholds for 
rescue/intensification are met will be discontinued from study medication (see Section 7.1).  
Participants ≥18 years of age can be rescued or undergo glycemic intensification using any of 
the antihyperglycemic agents approved for use with ertugliflozin.
Insulin (background, rescue, and intensification) will be sourced locally and administered 
subcutaneously based on instructions provided by the investigator (based on accepted, local, 
national or international guidelines for the indication and use of insulin or alternate 
medication). 
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Table 3
Glycemic Rescue Criteria (Phase A)
Time in Study
FFSG Thresholds for 
Rescue1
FPG Thresholds1,2
Day 1 through Week 6
>240 mg/dL (13.33 mmol/L)
>240 mg/dL (13.33 mmol/L)
After Week 6 through Week 12
>225 mg/dL (12.50 mmol/L)
>225 mg/dL (12.50 mmol/L)
After Week 12 through Week 18
>200 mg/dL (11.11 mmol/L)
>200 mg/dL (11.11 mmol/L)
After Week 18 through Week 24
>180 mg/dL (10.00 mmol/L)
>180 mg/dL (10.00 mmol/L)
FFSG = fasting fingerstick glucose; FPG = fasting plasma glucose.
1 The initial FFSG value will trigger a repeat FFSG measurement(s). An FPG measurement will be triggered 
when FFSG values meet rescue criteria for 3 consecutive days, and rescue will be initiated if the FPG is 
above threshold.
2 Perform confirmatory FPG (central and local lab) if FFSG value is greater than the defined threshold on 3 
consecutive days (after assessing for study medication compliance).
Table 4
Glycemic Intensification Criteria (Phase B)
Time in Study
FFSG Threshold for 
Intensification
FS A1C threshold for 
Intensification
From Week 24 through Week 54
>130 mg/dL (7.2 mmol/L)
>7.5% (58 mmol/mol)
A1C = glycosylated hemoglobin; FFSG = fasting fingerstick glucose; FS = fingerstick.
Note: If at any time a participant has
1.
FSG value >400 mg/dL (22.2 mmol/L) with or without ketonuria/ketonemia, OR
2.
Moderate to large ketonuria, positive test for ketonemia, or a flag from the Central 
Laboratory for ketonuria, regardless of blood glucose levels after a workup of 
ketoacidosis,
Note: Participants will be instructed to check for ketones if they meet the following 
criteria: 
a.
Fever
b. Nausea or vomiting
c.
Abdominal pain (unrelated to menstrual cramps in females)
d. Fasting
e.
Unusual calorie restriction (eg, during an intercurrent illness or in preparation for 
surgery/procedure) 
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the investigator should consider initiating insulin for participants not on insulin treatment at 
Screening Visit/Visit 1 OR should consider up-titrating insulin therapy for those participants
on insulin treatment at Screening Visit/Visit 1. If after 14 days, the dose of insulin cannot be 
reduced (to the participant’s previous dose) or weaned off, the participant should be 
considered as having initiated glycemic rescue or glycemic intensification. In addition, if the 
participant has ketonuria or ketonemia, study intervention should be interrupted, and 
guidelines in Section 7.1 for a suspected event of ketoacidosis should be followed.
6.6
Dose Modification (Escalation/Titration/Other)
Participants with A1C ≥7.0% (53 mmol/mol) at Visit 5/Week 12 will be eligible for a second 
randomization at Visit 5/Week 12.  Eligible participants in the ertugliflozin 5 mg treatment 
group will be re-randomized in a 1:1 ratio to up-titrate to ertugliflozin 15 mg or remain with 
ertugliflozin 5 mg. Similarly, eligible participants in the placebo group will undergo a mock-
titration to maintain the blind (Section 6.1).
If the ertugliflozin 15 mg group is dropped after the PK IA, participants in the ertugliflozin 
15 mg group will be down-titrated to ertugliflozin 5 mg (Section 6.3.1) and participants in 
the placebo group who have been mock up-titrated will also be mock down-titrated.  
6.7
Intervention After the End of the Study
There is no study-specified medication following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3.
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Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and Section 
8.10.8. Participants who discontinue study medication without withdrawing consent will 
have their diabetes managed as considered clinically appropriate by their primary doctor. 
Initiation of other AHAs will not be considered as prohibited medication in these 
participants. Participants who discontinue study medication before Visit 5/Week 12 will not 
have the second randomization performed.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
Hyperglycemia: The participant meets the criteria for rescue/intensification and 
rescue/intensification therapy is refused by the participant or deemed clinically inappropriate 
by the investigator. 

Hypoglycemia: 

Repeated (2 or more episodes since the prior study visit)

FSG <54 mg/dL (3.0 mmol/L) with or without symptoms of 
hypoglycemia, OR

FSG 54 to 70 mg/dL (3.0 to 3.9 mmol/L) with symptoms of 
hypoglycemia, and without a reasonable explanation (such as increased 
physical activity and/or skipped meal).
Note: Participants who are on insulin (background, rescue, or intensification therapy) and 
who meet either of the hypoglycemia discontinuation criteria may have their insulin dose 
reduced or interrupted at the investigator’s discretion and may continue in the study on 
study medication.
Note: The investigator or site personnel should make sure the participant’s glucose meter 
and test strips are functioning accurately and that the test procedure is being correctly 
performed by the participant prior to discontinuation from study medication.
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
Abnormal liver function tests meeting criteria (see Appendix 10 for additional details on 
management and discontinuation of blinded investigational product for participants with 
elevated liver enzymes): 

ALT or AST ≥3X ULN with total bilirubin ≥2X ULN and alkaline phosphatase 
(ALP) <2X ULN, and without established etiology; OR

ALT or AST ≥8X ULN or ≥3X ULN with symptoms consistent with liver injury 
and without an established etiology; OR

ALT or AST ≥5X ULN for 2 weeks or longer; OR

ALT or AST ≥3X ULN and participant is unwilling or unable to undergo repeat 
ALT and AST testing at the frequency defined in Appendix 10

eGFR is consistently <45 mL/min/1.73 m2 with no other explanation.
Note 1: The eGFR cutoff for discontinuing study medication should be consistent with 
the local label for ertugliflozin if it is different from above.
Note 2: A consistent value is defined as a repeat measurement within 14 days of 
notification from the central laboratory.

Requirement for 1 of the excluded medications listed in Section 6.5.

Pregnancy
Note: A positive urine pregnancy test requires immediate interruption of study 
medication until serum hCG can be performed and found to be negative. Participant must 
be permanently discontinued from study medication and followed per Section 8.4.5, if 
pregnancy is confirmed by a positive serum pregnancy test. If the serum pregnancy test is 
negative, blinded study medication should be resumed and the participant should be 
counseled about appropriate contraceptive measures.

Participant develops any condition for which ertugliflozin, metformin, or insulin is 
contraindicated according to the approved labels in the country in which the study site is 
located.

Participant has a clinically confirmed event of ketoacidosis
Note: If the participant has a suspected event of ketoacidosis, study medication should be 
interrupted. 

Consider interrupting blinded study medication in clinical situations known to predispose 
to ketoacidosis (refer to the IB). 
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
If study medication is interrupted, it should be re-initiated if the clinical situation resolves 
in ≤14 days. If resolution takes more than 14 days, consultation with the Sponsor is 
required prior to re-initiating study medication. 

Participant develops a hypersensitivity reaction to study medication. 

Participant develops any medical condition or personal circumstance which, in the 
opinion of the investigator, exposes the participant to risk by continuing on study 
medication or does not allow the participant to adhere to the requirements of the protocol.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study-site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).

All study-related medical decisions must be made by an investigator who is a qualified 
physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent, and assent if applicable, be obtained from 
the participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
8.1
Administrative and General Procedures
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical study or 
future biomedical research. If there are changes to the participant’s status during the study 
(eg, health or age of majority requirements), the investigator or medically qualified designee 
must ensure the appropriate consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form, and any written information provided to the participant must receive the 
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Institutional Review Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable 
opinion in advance of use. The participant or his/her legally acceptable representative should 
be informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent/assent form or 
addendum to the original consent/assent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
If the participant’s legally acceptable representative is illiterate, an impartial witness will be 
present when the entire ICF and other written information are read and explained. The 
impartial witness will sign and date the ICF indicating that the explanation of the written 
information was accurate, consent by the participant’s legally acceptable representative was 
given freely and the participant’s legally acceptable representative verbally acknowledged 
that they understood the information. Assent must be documented by the dated signature of 
the participant along with the dated signature of the person conducting the assent discussion.  
When the study population includes non-English speaking people, the information in the 
consent and assent forms will be translated and communicated to the participant in language 
understandable to the participant and participant’s legally acceptable representative. Either 
the investigator or Sponsor may take the responsibility for the translation; however, 
documentation must exist to demonstrate who performed the translation and the translation 
was verified by an individual other than the person who performed the translation. 
Accurately translated consent and assent forms will be provided with a written statement by 
the translator (whether the translator is the investigator or a professional translator), 
indicating that the consent and assent forms are an accurate translation of the accompanying 
English version.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant, answer all of his/her questions, and obtain written informed 
consent/assent before performing any procedure related to future biomedical research. A 
copy of the informed consent/assent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator to ensure that the 
participant qualifies for the study.
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Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent/assent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. The use of 
tobacco will be collected as part of medical history. Additionally, for male participants, sites 
must indicate if the participant is circumcised or uncircumcised.
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use. The site may rely on 
the participant’s report for this information. Please refer to the data entry guidelines for 
details on entering prior medications.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication taken by the participant during 
the study.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the Screening Visit/Visit 1
requirements are provided in Section 8.10.2.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
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participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
Study Intervention Administration
Study medication will begin on the day of treatment randomization or as close as possible to 
the date on which the participant is assigned. 
8.1.8.1
Timing of Dose Administration
Participants will be instructed to take study medication orally at approximately the same time 
of the morning with or without food from Visit 3/Day 1/Randomization through Visit 
8/Week 54 or discontinuation of study medication. Participants will be instructed NOT to 
take study medication the morning of each site visit.  
If a participant misses a dose of study medication, he/she will be instructed to take it as soon 
as he/she remembers unless it is time for the next dose. Participants will be instructed NOT
to ‘make up’ for the missed dose by taking 2 doses at the same time.
8.1.8.2
Witnessed Dose
Administration of study medication will be witnessed and documented at select study visits 
(including time of administration – see Section 1.3) by the investigator and/or study staff 
after completion of all study procedures including collection of all fasting blood samples. 
8.1.8.3
Dispense Single-Blind Placebo Treatment
Eligible participants will be dispensed single-blind placebo and instructed to take 1 tablet 
orally per day from each row (total of 2 tablets) at approximately the same time of day in the 
morning with or without food. The last dose of single-blind placebo will be taken on the day 
prior to Randomization. Refer to Section 8.10.3 for further details. 
8.1.8.4
Dispense Double-Blind Study Treatment
Participants will be dispensed double-blind study treatment (ertugliflozin or matching 
placebo) at study visits outlined in the SoA and instructed to take the double-blind study 
treatment once a day, orally, at approximately the same time of the morning with or without 
food (refer to Section 8.1.8.1). 
8.1.8.5
Evaluation of Study Treatment Compliance 
Participants will be directed to bring any unused study medication to the Visit 3/Day 
1/Randomization Visit. The investigator must maintain a complete and current 
accountability record for the blinded study treatment. 
Compliance with the single-blind placebo treatment will be monitored by study personnel at 
the site at the end of the single-blind placebo run-in period by comparing the returned 
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product with the amount dispensed and the information reported by the participant. The 
number of tablets issued minus the number of tablets returned will be used to calculate 
tablets taken according to the formula below. 
Compliance (%) = 
100 × (tablets dispensed – tablets returned)             
No. of days between visits × No. of tablets taken per day
Participants who are <80% compliant based on pill count with the single-blind placebo 
treatment are ineligible for randomization (Visit 3/Day 1/Randomization). 
During the remainder of the study, compliance with ertugliflozin and matching placebo will 
be assessed by site review of the blister cards and participant report. Every effort should be 
made to maintain adherence as close to 100% as possible.
The investigator or designee will counsel participants who report taking <85% of the blinded 
study treatment following randomization. The investigator or designee will determine factors 
that resulted in <85% compliance with the blinded study treatment and will take steps to 
improve compliance (Section 6.4). Participants will be counseled on the importance of taking 
their medication as prescribed. Participants counseling will be documented in the source 
documents.   
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
will complete all applicable activities scheduled for the Discontinuation Visit (Section 
8.10.8) and should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.10.8.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Discontinuation Visit (Section 8.10.8) should be performed (at the time of 
withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
Discontinuation Visit procedures need not be performed if the participant has had Visit 6 or a 
Discontinuation Visit (due to discontinuation of study intervention) within the last 4 weeks.  
8.1.9.1
Withdrawal From Future Biomedical Research
A participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate) and their specimens and 
all derivatives destroyed. A participant’s consent may be withdrawn at any time by 
contacting the principal investigator for the main study. If medical records for the main study 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's consent for 
future biomedical research will be withdrawn. A letter will be sent from the Sponsor to the 
investigator confirming the withdrawal. It is the responsibility of the investigator to inform 
the participant of completion of withdrawal. Any analyses in progress at the time of request 
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for withdrawal or already performed prior to the request being received by the Sponsor will 
continue to be used as part of the overall research study data and results. No new analyses 
would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
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At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Dispense Glucose Meters, Blood Glucose Assessment Tools, and SMBG 
Instructions
Glucose meters will be supplied to all participants (if needed) and both the participant and 
legally acceptable representative will be instructed on the procedure for performing FSG 
measurements. At a minimum, the participant and legally acceptable representative will be 
instructed to monitor and document FSG values (1) once daily with at least 2 fasting (before 
breakfast) measurements each week, (2) whenever the participant has symptoms of 
hypoglycemia (Section 6.5.1), and (3) during intercurrent illnesses. For participants on 
insulin (as background therapy or as rescue/intensification during the study), the investigator 
will counsel the participant and legally acceptable representative on the recommended 
frequency of home glucose monitoring based on locally accepted clinical practice guidelines. 
The Blood Glucose Assessment Tools should also be completed when the participant is away 
from home. 
Note: The Blood Glucose Assessment Tools do not need to be dispensed during 
Discontinuation/Withdrawal from the Study Visit.  
Instruct on Hypoglycemia Symptoms and Management
The site will review the symptoms and management of hypoglycemia with the participant 
and legally acceptable representative. The site will counsel the participant and legally 
acceptable representative to immediately perform an FSG measurement if any symptoms 
occur that may be related to hypoglycemia (eg, weakness, dizziness, shakiness, increased 
sweating, palpitations, or confusion), but also to avoid delay in treating these symptoms. 
The participant and legally acceptable representative will be instructed to complete the 
provided blood glucose assessment tools provided for any symptomatic episodes he or she 
believes may represent hypoglycemia. If an FSG has been obtained before or shortly (ie, 
within a few minutes) after treating, the value will be recorded in the blood glucose 
assessment tools. In addition, participants and legally acceptable representatives will be 
instructed to record any FSG values ≤70 mg/dL (3.9 mmol/L) on the blood glucose 
assessment tools regardless of the presence of clinical symptoms.
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Participant and legally acceptable representatives will be instructed to contact the 
investigational site to report:

Any episode of possible hypoglycemia resulting in symptoms 

Any episode of hypoglycemia for which assistance was required (ie, severe 
hypoglycemia, details provided on the blood glucose assessment tools)

Any episode of FSG ≤70 mg/dL (3.9 mmol/L) with or without symptoms
Note:  As indicated, the participants will record symptoms and/or FSG measurements that 
they believe are related to hypoglycemia on the blood glucose assessment tools with the 
assistance of the legally acceptable representative. Each episode will be evaluated by the 
investigator and recorded on the appropriate eCRF. For episodes determined to be 
hypoglycemia (symptomatic or asymptomatic), and for all glucose values ≤70 mg/dL 
(3.9 mmol/L), regardless of whether they are considered an AE, the HA eCRF must also be 
completed. Each event of symptomatic hypoglycemia must be reported as an AE on the AE 
eCRF. Each episode of asymptomatic hypoglycemia considered by the investigator to be an 
AE will also be reported on the AE eCRF (refer to Appendix 3 for guidance on reporting).
Participants on Background Insulin Therapy
The dose of insulin will be down-titrated or interrupted if, in the opinion of the investigator, 
the hypoglycemia occurred in the absence of a readily apparent cause or precipitating factor. 
Further management of insulin doses will be at the investigator’s discretion.
Second Randomization
At Visit 5/Week 12, all participants will have an FS A1C measured at the site (Section 
8.3.8.1). Participants will undergo a second randomization as outlined in the SoA if their FS 
A1C is ≥7.0% (53 mmol/mol). At this second randomization, eligible participants on 
ertugliflozin 5 mg will be assigned to continue on the 5 mg dose or up-titrate to the 
ertugliflozin 15 mg dose in a 1:1 ratio. Eligible participants in the placebo group will 
participate in the second randomization, but all will remain on placebo and be mock-titrated
to preserve blinding. Note: The up-titration criteria for participants on insulin will include a 
FFSG ≥110 mg/dL (6.1 mmol/L) in addition to A1C ≥7.0% (53 mmol/mol) at 
Visit 5/Week 12. Participants who do not meet the threshold(s) for a second randomization 
will continue on ertugliflozin 5 mg/placebo. If a participant discontinues study medication 
before Visit 5/Week 12, the second randomization (and related assessments) should not be 
performed.  
At Visit 5/Week 12, a second allocation number will be randomly assigned by the IRT 
system for participants on ertugliflozin 5 mg who meet up-titration criteria. During the study, 
only the unblinded statistician will have access to this allocation number and its associated 
treatment assignment. Participants who undergo the second randomization will retain their 
initial randomization number assigned at Visit 3/Day 1/Randomization to uniquely identify 
them by blinded personnel during the study.
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The unblinded statistician who supports the DMC described in Section 9.7 will review the 
number of participants randomized to the ertugliflozin 5 mg and ertugliflozin 15 mg group at
the Visit 5/Week 12 second randomization and throughout the study. Based on the 
distribution of participants within the ertugliflozin 5 mg and 15 mg arms, the randomization 
ratio for the second randomization at Visit 5/Week 12 may be adjusted in order to achieve 
approximately 30 participants in the ertugliflozin 15 mg arm.
8.2
Efficacy Assessments
Body Weight
Body weight will be measured using a standardized digital scale. Details on measuring body 
weight are below. 

Weight will be measured in duplicate throughout the study, after voiding (ie, forced 
void), and while wearing only a gown and underwear (no street clothes, no shoes or 
socks). Investigator sites without access to gowns will weigh participants in light 
clothing. 

Participants will be instructed to step gently onto the scale, place both feet together in the 
center of the scale and stand straight with eyes directed ahead. Participants will be 
instructed to stand still and not sway. Measurements will be recorded after the weight has 
stabilized.

The 2 measurements will be recorded in the source documents. If the 2 measurements 
differ by more than 0.2 kg or by 0.4 lb, (1) check the participant to ensure proper 
positioning as indicated above (2) a different set of duplicate measurements must be 
obtained, and the 2 new measurements will be recorded in the source documents. The 
average of the 2 measurements will be recorded in the eCRF.  
Follow the manufacturer’s manual for accuracy checks of the scale as required. Contact the 
Sponsor if supplies are required to perform accuracy checks, or if calibration is required, or 
for a replacement if the scale is malfunctioning.
Waist Circumference
Tension-controlled measuring tapes will be used to measure waist circumference. The tape 
measure will be a non-stretching, non-metallic retractable tape.
The tape is placed around the participant’s trunk at the appropriate level for waist 
measurement. The tape’s “zero line” is aligned alongside of the tape graduations on the 
Metric side of the tape. The zero end of the tape is held in the left hand above the remaining 
part of the tape held by the right hand. The measurement is read next to the tape’s “zero line” 
and recorded in centimeters to the nearest millimeter.
Waist circumference will be measured according to the National Health and Nutrition 
Examination Survey (NHANES) III protocol. Measuring tapes may be provided by the 
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Sponsor. It is advisable that the participant’s waist be measured by the same study 
personnel at each visit to maintain consistency. Waist circumference will be measured 
after voiding, in gown, underwear and socks but without shoes. 
To define the level at which waist circumference is measured, a bony landmark is located and 
marked. The participant stands and the examiner, positioned at the right of the participant, 
palpates the upper hip bone to locate the right iliac crest. Just above the uppermost lateral 
border of the right iliac crest, a horizontal mark is drawn using a black pen, and then crossed 
with a vertical mark on the midaxillary line. The measuring tape is placed in a horizontal 
plane around the abdomen at the level of this marked point on the right side of the trunk. The 
plane of the tape is parallel to the floor and the tape is snug but does not compress the skin. 
The measurement is made at the end of normal minimal respiration (in duplicate). 
Measurements will be collected until 2 consecutive measurements do not differ by more 
than 1 cm. The average of these 2 measurements will be reported.   
Height
Height will be measured without shoes, using a stadiometer or other appropriate device. 
Standing height will be assessed through maximum vertical stature for persons who can stand 
unassisted. Hair ornaments, barrettes, braids, jewelry, or cornrows will be moved or removed 
from the top of the head before the measurement is taken.
A fixed stadiometer with vertical backboard, fixed floorboard and movable headboard will be 
used. Participants will stand with the heels of their feet against the vertical backboard with 
feet pointing outward at approximately a 60-degree angle. Body weight will be distributed 
evenly with both feet flat on the floor. The examiner will check several contact points with 
the vertical backboard, including heels, buttocks, shoulder blades, and the back of the head. 
This may be difficult for participants with certain body shapes. However, the head should be 
in the Frankfort plane (an imaginary line from the ear canal to just below the lower orbit of 
the eye will be parallel to the floor). Participants will be looking straight ahead and be asked 
to take a deep breath and stand tall. Once the participant is positioned, the headboard or a flat 
ruler will be placed on top of the head, with sufficient pressure to compress the hair. The 
measurement is recorded in centimeters (cm), to the nearest millimeter (mm). Measurements 
will be collected until 2 consecutive measurements do not differ by more than 2.5 cm from 
each other. The final height measurement must be recorded. Some participants may have 
physical conditions that may limit the ability to measure height accurately (eg, kyphosis). In 
such cases, height will be measured to the best of the examiner’s ability, and a note will be 
made of the condition.
BMI Percentile
The following equation will be used to calculate BMI:
Body weight in kilograms
BMI =      (height in meters)2
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Sites will follow their approved country-specific BMI-for–age percentile charts. If none are 
available, refer to Appendix 8. 
Vital Signs
Vital sign measurements include a triplicate measurement of sitting blood pressure and pulse 
rate. Blood pressure and pulse rate will be measured using an automated, oscillometric blood 
pressure measuring device. Site personnel will use the same blood pressure measuring device 
throughout the study for each participant. 
The following method will be used to record sitting blood pressure and pulse rate for 
participants in triplicate:

Participants will refrain from nicotine-containing products and/or ingesting caffeine 
for at least 30 minutes preceding the measurements.

Participants will be seated in a chair with their back supported, feet flat on the floor 
and arm bared (free of restrictions such as rolled up sleeves) and supported at heart 
level.

The appropriate cuff size must be used to ensure accurate measurement. Each 
participant’s cuff size will be noted in his/her source file to assure the same cuff size 
is used throughout the study.

Measurements will be taken on the same arm at each visit (preferably the non-
dominant arm).

Measurements will begin after at least 5 minutes of rest.

The 3 measurements of both the blood pressure and pulse rate must be taken 
approximately 2 minutes apart with the triplicate set recorded in the source document 
and the average of the 3 measurements recorded in the eCRFs.

Assessment of pulse rate can be manual (rather than using an automated device); 
however, when done manually, pulse rate must be measured in the brachial/radial 
artery for at least 30 seconds.
Other procedures will not be performed during the time of the blood pressure and pulse rate 
measurements.
Laboratory Measurements for Efficacy
Efficacy measurements include laboratory assessment for A1C and FPG. See Appendix 2 for 
additional details. 
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
A complete physical exam will be performed at the visits indicated in the SoA. 
Abnormalities considered clinically significant will be reported as AEs.
Diet and Exercise Counseling and Monitoring
Participants and legally acceptable representatives will be counseled to maintain a medically 
appropriate, routine exercise program; consistency and adherence to the recommended 
regimen of diet and exercise will be encouraged throughout the study, with monitoring of 
diet and exercise occurring at each scheduled study visit as outlined in Section 1.3. Detailed 
dietary and exercise information will not be captured in the study database. 
Tanner Staging
Tanner Staging will be performed in order to assess the physical measurements of sexual 
development (testicular volume and pubic hair in males and breast and pubic hair in 
females). Refer to Appendix 13.
Note: If at any of the evaluations, the participant’s sexual maturation (for testicular volume, 
pubic hair, or breast) is assessed as being Tanner Stage V, no further evaluations of that 
parameter are needed during the study. 
Abdominal Ultrasound
Abdominal ultrasounds will be performed at the visits indicated in the SoA. The abdominal 
baseline ultrasound is to be performed at Visit 2/Week -1 or between Visit 2/Week -1 and 
Visit 3/Day 1/Randomization. The abdominal baseline ultrasound must be successfully 
submitted to and pass a quality check by the central imaging vendor before Visit 3/Day 
1/Randomization. If necessary, the placebo run-in period can be extended by a week to 
ensure an acceptable abdominal ultrasound is on file before Visit 3/Day 1/ Randomization.
If the Visit 8/Week 54 or Discontinuation Visit abdominal ultrasound does not pass quality 
check, an acceptable abdominal ultrasound must be submitted within 2 weeks.
An independent reviewer will assess all ultrasounds for nephrocalcinosis.
If Discontinuation Visit procedures are not performed for a participant due to a site visit 
within 4 weeks (Section 8.1.9), an abdominal ultrasound will be performed if it was not 
performed at the site visit. 
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All ultrasounds will also be read locally to assess for any clinically relevant abnormalities. If 
any clinically relevant abnormality is detected, the site will be informed, and the participant 
will be followed up by the physician; the abnormality may be reported as an AE.  
Abdominal ultrasound will be performed on all participants and images will be submitted to a 
central imaging vendor. The central imaging vendor will conduct a blinded independent 
central review (BICR). The BICR will not be done in real time. Details will be provided in 
the site imaging manual. 
Electrocardiograms
A single supine 12-lead ECG will be obtained for screening purposes at the timepoint noted 
in the SoA. The ECG must be evaluated for study eligibility before Visit 3/Day 1/ 
Randomization.

Participants will refrain from nicotine-containing products and/or ingesting caffeine for at 
least 30 minutes preceding the procedure.

12-lead ECGs will be performed after the participant has rested quietly for at least 10 
minutes in a supine position.
12-lead ECGs will be obtained prior to the nominal time assessment of blood pressure, and 
pulse rate as well as prior to blood collection.
The ECG will be read and interpreted at the investigative site. The investigator is responsible 
for retaining all copies of ECG reports. ECGs with abnormalities that do not preclude 
exclusion of the participant should be entered into the appropriate eCRF. 
Review of SMBG Measurements and Blood Glucose Assessment Tools
SMBG measurements and the blood glucose assessment tools will be reviewed at the site
visits and telephone contacts outlined in the SoA. They will be used to determine the need for 
an Unscheduled Visit to evaluate criteria for glycemic rescue/intensification (Section 6.5.1), 
to assess for events of hypoglycemia, and to determine need for discontinuation from blinded 
study medication due to hypoglycemia.  
Review Rescue Criteria and Assess Need for Glycemic Intensification
The participant and legally acceptable representative will be informed of the FFSG 
rescue/intensification threshold that is applicable until the next visit (Table 3 and Table 4) 
and will be instructed to call the site if the FFSG value is greater than the threshold on 3 
consecutive days (see Section 6.5.1). 
Participants should not undergo glycemic rescue at an Unscheduled Visit between Week 10
and Visit 5/Week 12 (see Section 6.5.1).
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Additionally, at Visit 5/Week 12, participants who are eligible for the second randomization 
should NOT undergo glycemic rescue even if they meet the specified criteria. Instead, these 
participants should be advised to check FFSG measurements every day for the next 2 weeks 
and glycemic rescue therapy should be initiated 2 weeks after Visit 5/Week 12 if they
continue to meet the prespecified thresholds (Table 3). 
Note: The participant will be telephoned weekly in-between visits if insulin is initiated/up-
titrated until blood glucose and insulin doses are stable.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
All laboratory testing will be performed after an overnight fast ≥10 hours in duration, with 
the exception of Visit 4/Week 6. All laboratory tests outlined in the SoA will be performed 
by the central laboratory with the exception of the site FS A1C, site and participant FFSG, 
urine ketones (at Visits 1, 2, and 3 only), and urine pregnancy tests. At Visit 1, fasting C-
peptide will be collected in participants with diabetes for <2 years and all participants on 
insulin regardless of the duration of T2DM. At Visits 3, 6, and 8, fasting C-peptide will be 
collected in all participants.
Glycemic measurements will be masked during the double-blind treatment period for A1C 
and FPG. However, in order for the investigator to perform an evaluation for possible 
glycemic rescue/intensification and/or discontinuation, the central laboratory will report to 
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the investigator in an unmasked manner any FPG laboratory value meeting 
rescue/intensification and/or discontinuation criteria (Section 6.5.1 and Section 7.1).
Laboratory test results for chemistry (eg, ALT, AST, creatinine, eGFR) will not be masked, 
but will be flagged by the central laboratory if they meet protocol-specified exclusion and 
discontinuation criteria (Section 5.2 and Section 7.1).
At or after Visit 3/ Day 1/Randomization, ALT and AST elevations greater than or equal to 
3x ULN will be flagged by the central laboratory and participants will be retested, according 
to Appendix 10. 
8.3.8.1
Site FFSG and FS A1C Measurements
FFSG values performed at the study site will be used to assess exclusion criteria prior to 
randomization (Visit 3/Day 1/Randomization). The central laboratory A1C must be used to 
assess inclusion criteria. 
FS A1C will be measured at Visit 5/Week 12, Visit 6/Week 24, and Visit 7/Week 38.
Site FFSG and FS A1C will be used at Visit 5/Week 12, on participants on insulin, to 
determine eligibility for the second randomization.
During the double-blind treatment periods, FFSG values performed at home and/or at the site 
will be used to determine the need for glycemic rescue/intensification (Section 6.5.1). 
8.3.8.2
Site Measured Urine Ketones
Ketones will be checked by the site as outlined in the SoA and during intercurrent illnesses or 
if the participant’s fingerstick blood glucose is >400 mg/dL (22.2 mmol/L) at any time 
during the study. If urine ketones are "moderate” or “large,” or if ketonemia is positive at any 
time during the study, further assessment is required.
8.3.8.3
Urine Pregnancy Test
All females participating in the study will have a urine pregnancy test at visits indicated in
the SoA. If local regulations or guidelines for testing exist, they should be followed in 
addition to the protocol requirements (for exceptions, see Section 10.7, Appendix 7). If 
required by an investigational site’s Institutional Review Board/Ethics Review Committee 
(IRB/ERC), a serum pregnancy test can also be obtained in addition to the urine pregnancy 
test. A positive urine pregnancy test requires immediate interruption of study medication
until serum beta-hCG is performed and found to be negative. Participants must be 
discontinued from study medication and followed (Section 7.1) if pregnancy is confirmed by 
a positive serum pregnancy test. Contraception assessments and counseling will be 
performed and documented at every visit as outlined in the SoA (see Appendix 5). 
Note: For Visits 2/Week -1 or Rescue, the urine pregnancy test should only be performed if 
the prior visit is more than 4 weeks apart or if pregnancy is suspected.
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8.3.8.4
Archive Urine Sample
A urine sample to be archived will be collected at visits indicated in the SoA. Urine samples 
will be stored at the Sponsor-designated biorepository.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout, or run-in 
treatment
including placebo 
run-in)
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable. 
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance 
for assessment and follow-up of these criteria can be found in the Investigator Study 
File Binder (or equivalent).

An overdose of Sponsor’s product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.
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Other Safety Topics of Interest
The following have been identified as other safety topics of interest. Participants with events 
related to these safety topics of interest will be identified based on prespecified criteria.
Narratives will be written for events related to the terms listed below: 
1. Renal-related events
2. Hypersensitivity reactions
3. Pancreatitis
4. Bone fractures
5. Ketoacidosis
6. Volume depletion
7. Amputations
8. Diabetic foot syndrome
9. Nephrolithiasis
10. Fournier’s gangrene.
Monitor for Adverse Events
The investigator will evaluate all AEs with respect to the elements outlined in Appendix 3. 
Additionally, all potential ketoacidosis events will be assessed by the Internal Case Review 
Committee (Appendix 1).  
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 100 mg/day of ertugliflozin or matching 
placebo or any dose higher than 25 mg/day of ertugliflozin or matching placebo for more 
than 14 days. 
In the event of an overdose, employ the usual supportive measures (eg, remove unabsorbed
material from the gastrointestinal tract, employ clinical monitoring, and institute supportive 
treatment) as dictated by the participant’s clinical status. Removal of ertugliflozin by 
hemodialysis has not been studied.
Investigators/site personnel are to consult the local, approved metformin product label for 
guidance on the definition of an overdose and treatment for an overdose of metformin.
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
Note: Any overdose (ertugliflozin or metformin) meeting above criteria whether or not 
associated with an AE must be reported to Sponsor’s personnel within 5 calendar days of 
learning of the event.
8.6
Pharmacokinetics
To evaluate exposure of ertugliflozin 5 mg and 15 mg qd doses in pediatric T2DM 
participants, blood samples for PK analysis of ertugliflozin concentrations will be collected 
as shown in the SoA. The ertugliflozin plasma steady state exposure levels will be assessed 
using the predose PK samples collected at planned visits and times.
Blood Collection for Plasma Ertugliflozin
Blood samples (approximately 1 mL) to provide approximately 0.5 mL of plasma for PK
analysis will be collected at visits specified in the SoA. The exact date and time of the blood 
draw and the date and time of the last dose of investigational product (based on participant’s 
report) relative to that PK sample prior to the blood draw will be captured on the eCRF. The 
time of the observed dose taken after collection of the PK sample will also be captured on the 
eCRF. It is important to record the exact actual time of dose and PK sample draw. Site 
personnel will be trained to remind participants that the accuracy of the actual dose time is 
critical. Site personnel will also be asked to call on the evening 2 days prior to Visit 4/Week 
6, Visit 5/Week 12, and Visit 6/Week 24 and again text or call the morning prior to these
visits to remind participants to take the morning dose 1 day prior to the visit and record the 
actual time of the dose.   
Detailed instructions for the sample collection, processing, storage and shipment of plasma 
samples will be provided in the laboratory manual (supplied by the central laboratory).
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Serum for future research

Plasma for future research

DNA for future research
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8.9
Health Economics
Not applicable.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
General Information for Study Visits
Fasting Prior to Screening Visit/Visit 1, Visit 3/Day 1/Randomization, Visit 5/Week 12*, 
Visit 6/Week 24, Visit 7/Week 38, Visit 8/Week 54, Rescue and Discontinuation Visits
Participants will be counseled to fast (ie, no study medication, no food, no drink except 
water), for at least 10 hours prior to scheduled study visits that require fasting. Blinded study 
medication and background study medications (metformin and insulin) should not be taken 
the morning of the clinic visit; other medication(s) may be taken as directed by the 
prescribing physician.
*Fasting required only for participants on insulin. 
Scheduling Visits, Visit Windows, and Study Duration
At the end of each study visit, the next study visit should be scheduled. Every effort should 
be made to adhere to the visit schedule in the SoA, and generally, visits may be scheduled 
±1 week of the designated timepoint (Visit 7/Week 38 and Visit 8/Week 54 may be ± 
2 weeks). If unavoidable, a visit may be scheduled at a time outside of this recommended 
range, but the schedule for subsequent visits must be adjusted so that the total duration of the 
double-blind study period is as close as possible to 54 weeks. The minimum interval between 
Visit 2/ Week -1 and Visit 3/Day 1/Randomization should be 6 days. In this case, 100% 
compliance with single-blind placebo treatment will be required for randomization. The
maximum interval between Visit 2/ Week -1 and Visit 3/ Day 1/ Randomization should be
14 days, with ≥80% compliance with single-blind placebo treatment required for 
randomization. If a visit is scheduled at a time other than the protocol designated time,
careful consideration must be given to the amount of study treatment the participant 
has available. 
Visit Reminders – Telephone Contacts
Prior to each visit, participants will be contacted and reminded of:

The date and time of appointment.

The requirement to fast for at least 10 hours prior to Screening Visit/Visit 1, Visit 3/
Day 1/Randomization, Visit 5/Week 12, Visit 6/Week 24, Visit 7/ Week 38, Visit 
8/Week 54, Rescue/Intensification and Discontinuation Visits. 
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
The requirement to record the time investigational product was taken the day prior to 
Visit 4/Week 6, Visit 5/Week 12, and Visit 6/Week 24. 

The requirement not to take any blinded study medication or background study 
medications (metformin and insulin) at home the morning of all site visits (except at 
Visit 2/Week -1). Other medication(s) may be taken as directed by the prescribing 
physician.

The requirement to bring study medication (ie, double-blind treatment, background, 
and glycemic rescue/intensification medication), blood glucose meters, blood glucose 
assessment tools, and any collected SMBG information to the site visit.

Lifestyle restrictions outlined in Section 5.3.2 and Section 5.3.3.
Screening Visit / Visit 1
At Screening Visit/Visit 1, written informed consent from the participant’s legally 
acceptable representative and written assent from the participant must be obtained. Potential 
participants must be evaluated to determine that they fulfill the entry requirements as 
specified in protocol Section 5.1 and Section 5.2 and will receive a screening number. All 
procedures outlined in the SoA must be completed. 
At the site, the investigator may choose to prescreen participants with FS A1C measurements 
(prior to drawing blood samples for central laboratory screening measurements) to evaluate 
the likelihood of the participants subsequently meeting study glycemic inclusion criteria. 
Note:  Investigators should be aware that although FS A1C is generally predictive of values 
measured in the central laboratory, modest differences can occur in individual participants.  
Therefore, a FS A1C cannot substitute for a central laboratory measured A1C to 
determine if a participant meets study A1C inclusion criteria.
Screening procedures may be repeated (ie, rescreening) after consultation with the Sponsor.
Single-Blind Placebo Run-in - Visit 2/Week -1
Participants who are on a stable dose of metformin ± insulin who meet all other enrollment 
criteria will be eligible to enter the single-blind placebo run-in period. 
At Visit 2/Week -1 the site must perform all procedures for this visit as detailed in the SoA.
The first doses of single-blind placebo (ertugliflozin placebo) will be taken as witnessed 
doses at the site after completion of all Visit 2/Week -1 study procedures. It is essential 
that all procedures be performed before the participant takes the witnessed dose. Participants
will then take single-blind placebo as directed for 1 week prior to Randomization and will 
continue to take their background medication as before. 
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Double-Blind Treatment Period – Phase A - Visit 3/Day 1/ Randomization to 
Visit 6/Week 24
At Visit 3/Day 1/Randomization, participants who meet all study enrollment criteria will
have all baseline laboratory tests and study procedures performed (refer to the SoA).
Assignment of a randomization number occurs at Visit 3/Day 1/ Randomization.
The first dose of double-blind study treatment will be taken as a witnessed dose at the 
site after completion of all procedures for the study visit. It is essential that all procedures 
be performed before the participant takes the witnessed dose.
Participants will remain on a stable dose of double-blind study treatment for the duration of 
the study and will remain on the background medication of metformin ± insulin without 
changes in the doses (except for reductions in insulin dose if the participant experiences 
hypoglycemia, see Section 6.5.1). The double-blind study treatment must be taken orally in 
the morning with or without food at approximately the same time each day. For missed doses 
see Section 8.1.8.1. 
During Phase A, at Visit 5/Week 12, eligible participants will undergo a second 
randomization (see Section 8.1.14).  
Note: For Visit 4/Week 6, Visit 5/Week 12, and Visit 6/Week 24, collect the time at which 
study medication was taken the day before the site visit and the time the dose was taken the 
day of the site visit and report on the appropriate eCRF. 
If a participant discontinues study medication in Phase A but agrees to continue in the study, 
the participant’s diabetic care will be handled by the participant’s primary diabetes doctor or 
the investigator outside of this protocol. The study-site personnel will only collect 
assessments specified in the SoA. 
Telephone Call Week 18
The Week 18 Visit is a telephone call visit. The site will call the participant/participant’s 
legally acceptable representative and will complete all procedures indicated in the SoA. All
AEs, changes in concomitant medication, and any hypoglycemia events will be documented 
in the appropriate eCRFs. 
Double-Blind Treatment Period – Phase B - Visit 6/Week 24 Through Visit 
8/Week 54
The first dose of Phase B double-blind study treatment will be taken as a witnessed dose 
at the site after completion of all procedures for the Visit 6/Week 24 study visit. It is 
essential that all procedures be performed before the participant takes the witnessed dose.
Participants Who Have Not Been Rescued During Phase A will continue on their double –
blind study treatment and will initiate glycemic intensification as outlined in Table 2 if their 
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FFSG is >130 mg/dL (7.2 mmol/L) and their FS A1C is >7.5% (58 mmol/mol) (Table 4, 
Section 6.5.1).
Participants Who Have Been Rescued During Phase A will continue on their double –
blind study treatment and background medication of metformin + insulin (for rescue). Insulin 
doses will be titrated based on glycemic responses at the investigator’s discretion.
If a participant discontinues study medication in Phase B but agrees to continue in the study, 
the participant’s diabetic care will be handled by the participant’s primary diabetes doctor or 
the investigator outside of this protocol. The study site will only collect the assessments 
specified in the SoA. 
Telephone Call Week 30 and Week 44
Week 30 and Week 44 are telephone call visits. The site will call the participant/participant’s 
legally acceptable representative and will complete all procedures indicated in the SoA. All 
AEs, changes in concomitant medication, and any hypoglycemia events will be documented 
in the appropriate eCRFs. 
Study Visits Performed at Home
Visit 4/Week 6 and Visit 7/Week 38 may be performed, if approved by the country and local 
IRB/IEC, by a qualified health professional at the participant’s home or location other than 
the site. These visits may be performed according to the guidelines that may exist at the 
participating institution and will be consistent with the investigator’s usual clinical practice.  
Rescue/ Intensification Visit
Participants who require rescue therapy or intensification therapy per Section 6.5.1 must have 
glycemic rescue/intensification therapy initiated at either a scheduled or unscheduled site
visit and not by a telephone call. At the Rescue Visit, all laboratory testing will be performed 
after an overnight fast ≥10 hours in duration and all procedures outlined in the SoA are to be 
completed.
Participants should not undergo glycemic rescue at an Unscheduled Visit between Week 10
and the site visit at Visit 5/Week 12 (Section 6.5.1).
Discontinuation Visit
The Sponsor should be contacted when a participant discontinues study medication, 
withdraws from the study, or interrupts study medication because of an AE or a laboratory 
safety test abnormality. All participants will be followed up until resolution (ie, return to 
normal or participant’s baseline, diagnosis determined, or course of abnormalities 
established) for any laboratory safety test abnormality resulting in discontinuation.
All participants who discontinue study medication prior to completion of the protocol-
specified treatment period will be encouraged to continue their participation in the study off 
study medication and be followed for all remaining study visits as outlined in the SoA. 
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At a Discontinuation Visit, all laboratory testing will be performed after an overnight fast 
≥10 hours in duration and all procedures outlined in the SoA are to be completed.
Discontinuation Visit procedures will be performed on participants who discontinue study 
medication or discontinue the study as soon as possible after discontinuing study medication
(within 4 weeks).
If a participant discontinues study medication before Visit 5/Week 12, the second 
randomization (and related assessments) should not be performed.  
Mandatory Poststudy Telephone Follow-up
For all participants (except for those who withdraw consent), a poststudy telephone follow-
up call will be performed 14 days after the last dose of study medication (whether due to 
study completion or premature discontinuation from the study) to assess and collect 
information on AEs, SAEs, and any other reportable safety events that occurred after the 
administration of the last dose of study medication. The date of the telephone contact will be 
recorded and any events that have occurred will be recorded in the AE eCRF. 
If any event requires supplemental procedures, they will be performed as medically 
necessary and recorded in the applicable eCRF.
Follow Up of Participants Who Have Discontinued Study Medication Prior to 
Study Completion
After the 14-day post-study medication discontinuation telephone contact is made, activities 
scheduled in the SoA will be performed for participants who discontinued study medication,
but agreed to remain in the study. No follow-up telephone call is needed after Week 54.  
Note: Study-site personnel should make all reasonable efforts to counsel the participant to 
stay in the study even if they discontinued the study medication.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in 
the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
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Statistical Analysis Plan Summary
Study Design Overview
Ertugliflozin T2DM Pediatric Study
Treatment Assignment
Participants will be randomized in a 2:1 ratio to the ertugliflozin 5 mg 
group or placebo group. Randomization will be stratified by age (10 to 
14 years of age, 15 to 17 years of age) and insulin use (No, Yes). A 
second randomization at Visit 5/Week 12 will randomize eligible 
participants (Section 6.1) in the ertugliflozin 5 mg group in a 1:1 ratio to 
continue on ertugliflozin 5 mg or up-titrate to ertugliflozin 15 mg. The 
second randomization will be stratified by insulin use (No, Yes). An IA
to assess PK may result in dropping the 15 mg dose group. If this occurs, 
the second randomization will be discontinued and the participants in the 
15 mg group will be down-titrated to the 5 mg dose for the remainder of 
the study.
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
Primary Endpoint
A1C: Change from baseline at Week 24
Secondary Endpoints
A1C: Change from baseline at Week 54
FPG: Change from baseline at Week 24 and at Week 54
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypothesis will be evaluated by comparing ertugliflozin 
(combined 5 mg and 15 mg doses) to placebo with respect to A1C 
change from baseline at Week 24. The treatment policy (TP) estimand is 
expected to be considered primary in some regions. In all other regions, 
the Treatment Effect (TE) estimand will be primary. The TP estimand 
will estimate the difference in change from baseline means comparing 
the effect of being randomized to ertugliflozin versus placebo whereas 
the TE estimand will estimate the effect of being treated with 
ertugliflozin versus placebo. The primary analysis approach for the TP 
estimand will evaluate the treatment difference via a Bayesian 
borrowing approach using an informative prior distribution derived from 
a completed adult study of ertugliflozin (MK-8835 P007) and with 
missing Week 24 A1C data imputed using a Retrieved Dropout (RD) or 
Washout Imputation (WI) approach. The weight given to the adult prior 
distribution for the primary hypothesis test will be 0.134. The primary 
analysis approach for the TE estimand will evaluate the treatment 
difference via a frequentist analysis using a constrained longitudinal 
analysis model (cLDA). 
The key secondary hypotheses will be assessed using an ANCOVA 
model after imputing missing data using RD or WI. These hypotheses 
will be tested under only the TP estimand and will apply weights to the 
treatments as follows:

Participants on placebo have a weight of 1

Participants on ertugliflozin 5 mg who were not re-randomized at 
Visit 5/Week 12 have a weight of 1
For the hypothesis comparing the addition of ertugliflozin, with 
dosing optimized according to A1C response, to the addition of
placebo, the weights for the re-randomized participants will be 
defined as follows:

Participants who were re-randomized to 15 mg at 
Visit 5/Week 12 have a weight of 2
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
Participants who were re-randomized to 5 mg at 
Visit 5/Week 12 have a weight of 0.
For the hypothesis comparing ertugliflozin 5 mg with placebo the 
weights for the re-randomized participants will be defined as follows:

Participants who were re-randomized to 5 mg at 
Visit 5/Week 12 have a weight of 2. 

Participants who were re-randomized to 15 mg at
Visit 5/Week 12 have a weight of 0.
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 AEs) and 95% confidence intervals (CI) (Tier 1 and 
Tier 2 AEs) will be provided for between-treatment differences in the 
percentage of participants with events; these analyses will be performed 
using the Miettinen and Nurminen (M&N) method [Miettinen, O. and 
Nurminen, M. 1985].
Interim Analyses
When ~30 participants on study medication (~20 participants on 
ertugliflozin) complete Visit 4/Week 6, the PK IA will be conducted to 
confirm ertugliflozin exposure. Details are provided in Section 9.7.
Multiplicity
The type 1 error rate for the Bayesian methodology addressing the 
primary hypothesis under the TP estimand was estimated via simulation 
to be 0.10. If the success criterion for the primary hypothesis (H1) is met 
under the TP estimand, then hypotheses H2 will be tested at 
alpha = 0.05. If H2 is successful then H3 will be tested at alpha = 0.05. 
The overall study wise type 1 error rate will be greater than 0.05
[Maurer, W. and Bretz, F. 2013].
Sample Size and Power 
The planned sample size is approximately 165 participants with 
55 participants in the placebo group and 110 participants in the 
ertugliflozin group (ertugliflozin 5 mg and 15 mg groups combined). 
Assuming that approximately 96.1% of participants will have data at 
Week 24 on study medication, this sample size will provide 
approximately 80% power (percent of posterior credible intervals <0) to 
detect a between-group difference in A1C change from baseline at 
Week 24 of -0.6% given a standard deviation of 1.5% under the TP 
estimand with RD imputation. 
Under the TE estimand using the cLDA method, the planned sample size 
provides 80% power assuming the difference in A1C change from 
baseline at Week 24 is -0.75% using a standard deviation of 1.5% and 
missing data due to discontinuation from study medication or censoring 
due to initiation of glycemic rescue or intensification is at most 14%.  
The power for each secondary hypothesis is approximately 74% for the
TP estimand.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
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The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented by the IRT vendor.
Blinding issues related to the planned IA are described in Section 9.7. 
9.3
Hypotheses/Estimation
Objectives and hypotheses are stated in Section 3. 
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
The baseline value will be defined as the Visit 3/Day 1/Randomization measurement. If this 
measurement is not available, the last available pre-treatment value will be used. If no pre-
treatment measurement is available, the baseline value will be treated as missing. 
Efficacy Endpoints
The descriptions of the efficacy measurements and timepoints at which they are measured are 
described in Section 8.2 and Section 1.3. The efficacy endpoints to be analyzed are listed in 
Table 6. 
The mapping of relative day ranges to Week is provided in Appendix 11.
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Table 6
Efficacy Variables/Endpoints
Primary 
Change from Baseline in A1C at Week 24 (pooled ertugliflozin 5 mg and 15 mg versus placebo)
Key Secondary
Change from Baseline in A1C at Week 24 (dose-optimized ertugliflozin versus placebo, and ertugliflozin 5 
mg versus placebo)
Secondary 
Change from Baseline in A1C at Week 54
Change from Baseline in FPG at Week 24 and at Week 54
Exploratory 
Change from Baseline in A1C at Week 12
Proportion of participants initiating glycemic rescue therapy by Week 24
Proportion of participants initiating glycemic rescue or intensification therapy by Week 54
Proportion of participants with A1C <7.0% (53 mmol/mol) at Week 54 among those who up-titrated from 
ertugliflozin 5 mg/day to 15 mg/day
At Week 24 and Week 54:
Proportion of participants with A1C <7.0% (53 mmol/mol) 
Proportion of participants with A1C <6.5% (48 mmol/mol) 
Proportion of participants with A1C <7.0% (53 mmol/mol) among those with a baseline A1C ≥7.0% 
(53 mmol/mol) 
Change from Baseline in:

Body weight

BMI percentile

A1C among participants who up-titrated from ertugliflozin 5 mg/day to 15 mg/day 

Systolic blood pressure 

Diastolic blood pressure 

Waist circumference 

Waist circumference to height ratio  
A1C = glycosylated hemoglobin; BMI = body mass index; FPG = fasting plasma glucose.
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Safety Endpoints
The descriptions of the safety measurements and timepoints at which they are measured are 
described in Section 8.3 and Section 1.3. The safety endpoints to be analyzed are listed in 
Table 9. Safety analyses will be conducted across Week 0 to Week 54 (Phase A+B) with 
selected analyses also done across Week 0 to Week 24 (Phase A).
Events of symptomatic hypoglycemia, AEs associated with genital mycotic infection (gender 
specific), hypovolemia, and UTI are considered Tier 1 events.
Hypoglycemia will be described using the following definitions:

Symptomatic hypoglycemia: Episodes with clinical symptoms reported by the
investigator as hypoglycemia (biochemical documentation not required).

Severe hypoglycemia: Episodes that required assistance, either medical or non-
medical. Episodes with a markedly depressed level of consciousness, a loss of
consciousness, or seizure will be classified as having required medical assistance,
whether or not medical assistance was obtained.

Documented symptomatic hypoglycemia: Episodes with clinical symptoms attributed
to hypoglycemia with a glucose level ≤70 mg/dL (3.9 mmol/L) or <54 mg/dL 
(3.0 mmol/L).

Asymptomatic hypoglycemia: Episodes without symptoms attributed to
hypoglycemia, but with a documented glucose level ≤70 mg/dL (3.9 mmol/L) or
<54 mg/dL (3.0 mmol/L).

Documented hypoglycemia (symptomatic and asymptomatic): Episodes with a 
glucose level ≤70 mg/dL (3.9 mmol/L) or <54 mg/dL (3.0 mmol/L), with or without 
symptoms.
9.5
Analysis Populations
Efficacy Analysis Populations
The FAS population will serve as the primary population for efficacy analyses. The FAS 
population will include all randomized participants who took at least one dose of study 
treatment. 
For exploratory analyses in those who up-titrated from ertugliflozin 5 mg/day to 15 mg/day, 
participants will be counted only if they received at least one tablet of ertugliflozin 
15 mg/day after the second randomization at Visit 5/Week 12.
For analyses that require a baseline value, participants with a missing baseline value will be 
excluded. All participants randomized within the incorrect stratum for insulin use will be 
classified according to their intended stratum (ie, the stratum to which they should have been 
randomized) in all analyses that include the stratification factor. The intended stratum will be
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derived based on insulin use at Visit 1/Screening. An accounting of incorrectly stratified 
patients will be provided in the CSR.
Safety Analysis Populations
Safety analyses will be performed in the APaT population consisting of all randomized 
participants who received at least one dose of study treatment and will include participants in 
the ertugliflozin 15 mg dose group, regardless of the outcome of the PK IA. 
At least 1 laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Safety analysis will be based on observed data only. No imputation will be performed for 
missing data.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values (ie, unadjusted for 
multiplicity) may be computed for other efficacy analyses for descriptive purposes rather 
than for assessing statistical significance. 
The primary approach for all efficacy and safety analyses will pool participants from both 
ertugliflozin dose groups (5 mg and 15 mg) for comparison with placebo. In addition, A1C 
change from Baseline at Week 24 will be compared for 2 treatment strategies, (1) dose-
optimized ertugliflozin versus placebo and (2) ertugliflozin 5 mg versus placebo. Dose-
optimized ertugliflozin consists of participants who were randomized to ertugliflozin and 
either did not meet the re-randomization criterion at Week 12 or who met the re-
randomization criterion and were re-randomized to ertugliflozin 15 mg. Descriptive statistics 
will be used for efficacy and safety endpoints to summarize ertugliflozin data by dose group 
and by combined doses. Descriptive statistics will also be used to summarize the individual 
ertugliflozin dose arms in the subset of participants who were re-randomized at Visit 5/Week 
12.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
There will be 2 estimands for the analysis of continuous efficacy endpoints, TP and TE. The 
primary hypothesis will be tested using both estimands. Based on local regulatory 
requirements, one of the estimands will be considered primary and the other supplementary. 
The key secondary endpoints and hypotheses associated with them (H2 and H3) will be 
analyzed under only the TP estimand.
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The TP estimand consists of the following elements:

Target population: Pediatric patients (age 10 to 17 years, inclusive) with T2DM who 
meet the glycemic criteria defined in this protocol

Variable: Change from baseline in A1C at Week 24

Intercurrent events: Regardless of whether study treatment or rescue medication was 
taken 

Population level-summary: Difference in means at Week 24

Treatment Comparison of Interest: The effect of being randomized to ertugliflozin 
(combined doses) versus placebo.
Analyses corresponding to the TP estimand will include all available data at the Week 24 
timepoint, including data after rescue or after the last dose of study treatment in any 
participants who remain in the study after discontinuing study treatment.
Analyses corresponding to the TP estimand will include all available data at the Week 24 
timepoint, including data after rescue or after the last dose of study treatment in any 
participants who remain in the study after discontinuing study treatment.
The TE estimand consists of the following elements:

Target population: Pediatric patients (age 10 to 17 years, inclusive) with T2DM who 
meet the glycemic criteria defined in this protocol 

Variable: Change from baseline in A1C at Week 24 as if all participants remained on 
treatment

Intercurrent events: Data obtained after discontinuation of treatment or after taking 
rescue treatment are not relevant to this estimand

Population level-summary: Difference in means at Week 24

Treatment comparison of interest: The effect of taking the randomized treatments 
(ertugliflozin [combined doses] versus placebo).
The TE estimand will exclude measurements collected more than 5 days after the last dose of 
study treatment or after other AHA treatments, such as rescue/intensification treatment, are 
added.
For all efficacy analyses with the exception of exploratory analyses for participants who up-
titrated from ertugliflozin 5 mg/day to 15 mg/day, participants will be classified as belonging 
to the ertugliflozin or placebo group according to their randomized treatment assignment at 
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Visit 3/Day 1/Randomization regardless of the treatment received during the course of the 
study. 
Any participant randomized at the first or second randomization within the incorrect stratum 
will be classified according to the intended stratum in all analyses that include stratum. The 
intended stratum will be derived based on the participant’s age and insulin use at Screening 
Visit/Visit 1 or insulin use at Visit 5/Week 12 as captured in the study database. An 
accounting of any incorrectly stratified participants will be provided in the CSR.
Week 24
For the primary analysis using the TP estimand, treatment group comparisons for the A1C 
mean change from baseline at Week 24 will be done using a Bayesian borrowing approach. 
The Bayesian borrowing approach will be done using an ANCOVA model with treatment, 
the age and insulin use strata as fixed effects, and the baseline A1C measurement as a 
covariate with normal priors on the model parameters and a mixture prior distribution on the 
treatment model effect, δp:
YWeek24~N(β0 + β1 * Age + β2 * Insulin Use + β3 * Baseline A1C + δp * Treatment, σ2).
The model parameters for intercept, age, insulin use and baseline A1C will have wide normal 
prior distributions as follows:
βi~N(0, 1002 ), i = 0,1,2,3
The treatment effect parameter will have a mixture normal prior with 2 components: an 
informative prior mean and variance based on the full ITT population from the 8835-007 
study and a general skeptical prior. The prior distribution of δp is as follows:
δp |z = 0 ~ Ngeneral (0, (1.5*1.52 ))
δp |z = 1 ~Nadult (-0.598, 0.0662 )
where the weight z has a prior Bernoulli distribution with a parameter, p.
For the primary analysis, a Bernoulli parameter of 0.134 will be used. The skeptical prior 
variance as well as the mixture prior parameter of 0.134 were selected based on the Effective 
Sample Size (ESS) metric as defined in Neuenschwander et al. [Neuenschwander, B., et al 
2020]. For the variance of the general normal distribution in the mixture prior, an ESS of 3 
pediatric participants (2 in ertugliflozin arm and 1 in placebo arm) will be used to ensure the 
prior is skeptical without being non-informative. A prior parameter with a value of 0.134 was 
selected to ensure the mixture distribution has an ESS equal to a total of 165 pediatric 
participants (110 in ertugliflozin arm and 55 in placebo arm). This will ensure that the 
information borrowed from the mixture prior does not exceed the planned sample size of 165
pediatric participants in the P059 study.
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The success criterion for declaring that ertugliflozin (pooled doses) is superior to placebo in 
reducing A1C at Week 24 is having the upper bound of the posterior 95% credible interval 
for δp < 0.
As a sensitivity analysis, a tipping point-like approach will be used in which the prior weight 
parameter, p, will be varied from 0 to 1 in increments of 0.05. The point at which the analysis 
shifts from not significant to significant will be noted.
Data permitting (discussed below), missing data will be imputed using an RD approach 
which assumes that all missing Week 24 data can be represented by the observed Week 24
data for participants in the same group who discontinued study treatment but remained in the 
study. 
A “retrieved dropout” value is defined as an observed Week 24 value in a participant who 
discontinued study medication prior to Week 24 but remained in the study. For the RD 
approach, missing Week 24 values will be imputed as follows:
RD imputation will be done within each treatment arm (placebo or combined ertugliflozin for 
H1, placebo or dose-optimized ertugliflozin for H2, or placebo or ertugliflozin 5 mg for H3).
All Week 24 RD values will be used for imputation, regardless of when a participant 
discontinued from study medication. CCI
CCI
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The RD analysis may not be feasible due to insufficient observed Week 24 data post
discontinuation of study medication. If the number of RD participants per group is at least 
50% of participants who discontinue from study medication per arm, then RD will be the 
primary approach to impute missing data for the TP estimand. If at least one group has either
less than 50% RD participants or fewer than 5 total RD participants, then RD will not be 
performed, and WI will become the primary analysis method. If the minimum data 
requirement for the RD method is met, then WI will be implemented as a sensitivity 
approach for the TP estimand. The WI analysis assumes participants who prematurely 
discontinued from the study or who have an intermittent missing Week 24 value would have 
a ‘washout’ of any potential effect of the assigned study medication.
For all analyses involving simulated data, a seed of 8835059 will be used for random number 
generation.
CCI
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A constrained longitudinal data analysis (cLDA) model, based on Liang and Zeger [Liang, 
K.-Y. and Zeger, S. L. 2000], will be used for analyses addressing the TE estimand for A1C 
mean change from baseline and FPG mean change from baseline. Time will be treated as a 
categorical variable so that no restriction is imposed on the trajectory of the means over time.
The cLDA model will also adjust for treatment, the age stratum, the insulin use stratum, and 
the interaction of time by treatment. The cLDA model assumes a common mean across 
treatment groups at baseline within each age and insulin use category (due to randomization) 
but different means between categories, and a different mean for each treatment at each of 
the post-baseline timepoints. In the cLDA model, the response vector consists of baseline and 
the values observed at each post-baseline timepoint. The treatment difference in terms of 
mean change from baseline to a given timepoint will be estimated and tested from this model. 
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements.
For the cLDA model, the Kenward-Roger adjustment will be used with restricted (or 
residual) maximum likelihood (REML) to make proper statistical inference. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements and 
hence avoids the potential bias that could result from the use of specific structured covariance 
models. If the unstructured covariance model fails to converge with the default Newton-
Raphson algorithm, the Fisher scoring algorithm or other appropriate methods can be used to 
provide initial values of the covariance parameters. In the rare event that none of the above 
methods yield convergence, a structured covariance such as Toeplitz can be used to model 
the correlation among repeated measurements. In this case, the empirical option will be used 
because the sandwich variance estimator is asymptotically unbiased while the model-based 
variance estimator can substantially overestimate or underestimate the true variance. The 
cLDA model uses the maximum likelihood principle to estimate the parameters and account 
for missing data in an implicit fashion.
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups within the same age and insulin use categories. Of note, in the event that 
there are no missing data, the estimated treatment difference from the above cLDA model 
will be identical to that from a traditional longitudinal ANCOVA model, which uses the 
baseline value as a covariate. However, unlike longitudinal ANCOVA, the cLDA model 
accounts for variability in the baseline values, thus providing more accurate standard errors 
and CIs for individual treatment effects. Moreover, this model allows the inclusion of 
participants who are missing either the baseline or post-baseline measurements, thereby 
increasing efficiency.
The cLDA method assumes that the mechanism for missing data is missing at random 
(MAR).
Assessment of the Key Secondary Endpoints
The key secondary endpoints will be evaluated under only the TP estimand analysis 
approach.
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All elements of the TP estimands below are the same as the primary TP estimand except for 
the treatment comparisons:
Treatment comparison of interest:
For H2 - The effect of being randomized to dose-optimized ertugliflozin versus 
placebo.
For H3 - The effect of being randomized to ertugliflozin 5 mg versus placebo.
Specific weighting schemes will be used to test H2 and H3. The weighting schemes are 
defined as follows:  

All participants on placebo have a weight of 1

All participants on ertugliflozin who were not re-randomized at Visit 5/Week 12 have 
a weight of 1

For H2 - the hypothesis comparing dose-optimized ertugliflozin to placebo 
(weighting scheme A):
o
All participants on ertugliflozin who were re-randomized to 5 mg at 
Visit 5/Week 12 have a weight of 0
o
All participants on ertugliflozin who were re-randomized to 15 mg at 
Visit 5/Week 12 have a weight of 2

For H3 - the hypothesis comparing ertugliflozin 5 mg with placebo (weighting 
scheme B):
o
Participants who were re-randomized to 5 mg at Visit 5/Week 12 have a weight 
of 2
o
Participants who were re-randomized to 15 mg at Visit 5/Week 12 have a weight 
of 0
For the key secondary endpoints, treatment group comparisons for the A1C mean change 
from baseline at Week 24 will be done using an ANCOVA model with treatment, the age and 
insulin use strata as fixed effects, and baseline measurement as a covariate. Hypotheses H2 
and H3 analyses for RD and WI are shown below. 
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The RD imputation and analysis steps are as follows for H2 and H3 using Rubin’s rule for 
100 total imputed datasets:
1. Within each imputation sample, do the following:
a.
Impute missing Week 24 values using a normal distribution where the expected 
change from baseline value is set to the estimated mean change from baseline value 
from the RD participants in the same treatment group. The standard deviation will be 
the RMSE derived from the ANCOVA model described above and estimated based 
on all participants with Week 24 data. 
b. After step a, each of the 100 resulting datasets will contain the original non-missing 
data and the imputed data for those with missing Week 24 values.
2. The 100 datasets will be analyzed using a weighted ANCOVA model with Baseline A1C 
and the two stratification factors as covariates. The weights will be defined as listed 
above and included in the model using the weight option from SAS PROC MIXED. The 
100 weighted ANCOVA-based estimates of the treatment difference will be combined 
using PROC MIANALYZE based on Rubin’s rule, which accounts for between and 
within imputation variability.
The WI imputation and analysis steps are as follows for H2 and H3: 
For participants in the ertugliflozin group:
1) Fit a regression model as Y24 = β0 + β1*Y0 + γ*X + error, where Y0 and Y24 are the 
placebo group A1C values at Baseline and Week 24, respectively, and X is a matrix for 
the age and insulin stratum fixed covariates.
2) Impute missing Week 24 A1C values for ertugliflozin using the estimated mean from the 
above model and standard deviation equal to the RMSE from the model.
For participants in the placebo group:
1) Fit models according to the intermittent missing data pattern with A1C values from the 
placebo group only:
a.
For participants with only Baseline data: Y24 = β0 + β1*Y0 + γ*X + error
b. For participants with only Baseline and Week 6 data: Y24 = β0 + β1*Y0 + β2*Y6 + γ*X 
+ error
c.
For participants with only Baseline, Week 6 and Week 12 data: Y24 = β0 + β1*Y0 + 
β2*Y6 + β2*Y12 + γ*X + error
2) Impute missing Week 24 A1C values for placebo using one of the 3 models above based 
on the missing data pattern with a mean equal to the mean from the regression model and 
a standard deviation equal to the RMSE from the model.
Descriptive statistics will be used to summarize the A1C mean change from baseline at 
Week 24 for the individual ertugliflozin dose arms in the subset of participants who were re-
randomized at Visit 5/Week 12. All other continuous efficacy endpoints with the exception 
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of the 2 key secondary endpoints associated with hypotheses H2 and H3, including the 
Week 12 A1C change from baseline, will be analyzed following the same cLDA method 
used for the A1C TE estimand under H1 (combined ertugliflozin doses vs. placebo) and will 
not be analyzed under the TP estimand.
Week 54
The Week 54 analyses will be based on the same FAS population used for the Week 24
analyses. The statistical models for the analyses at Week 54 will be analogous to those at 
Week 24, except that no between-group comparisons will be provided for Week 54. The 
efficacy endpoints will be summarized for within-group mean change from baseline with 
estimates and 95% CIs calculated from the analysis model.
Table 7 summarizes the analysis strategy for primary and secondary efficacy endpoints at 
Week 24 and at Week 54.
Table 7
Analysis Strategy for Efficacy Variables at Week 24 and at Week 54
Variable
Estimand/Approach
Statistical Method
Missing Data 
Approach
Primary
Change from baseline in 
A1C - pooled 
ertugliflozin vs placebo
TP/Primary
Bayesian Borrowing
RD†
TE/Primary
cLDA
Model-based
Key Secondary 
Change from baseline in 
A1C - dose-optimized
ertugliflozin vs placebo
TP/Primary
ANCOVA (weighting scheme A)
RD†
Change from baseline in 
A1C - ertugliflozin 5 mg 
vs placebo
TP/Primary
ANCOVA (weighting scheme B)
RD†
Secondary
Change from baseline in 
FPG
TE/Primary
cLDA
Model-based
A1C = glycosylated hemoglobin; ANCOVA = analysis of covariance; cLDA = constrained longitudinal data 
analysis; FPG = fasting plasma glucose; RD = Retrieved Dropout; TE = Treatment Effect; TP = Treatment 
Policy; WI = Washout Imputation.
† The primary analysis for the TP estimand will use RD to impute missing data if RD is feasible. If RD is not 
feasible, WI will be used.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs measurements. Safety analyses will be conducted across 
Week 0 to Week 54 (Phase A+B) with selected analyses also done across Week 0 to 
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Week 24 (Phase A). For safety and tolerability analyses, the pooled ertugliflozin group (5 mg 
and 15 mg) will be compared with the placebo group.
Participants will be included in the treatment group corresponding to the study treatment they 
actually received for the analysis of safety data using the APaT population. This will be the 
treatment group to which they are randomized, except for any participants who take incorrect 
study treatment for the entire treatment period. Such participants will be included in the 
treatment group corresponding to the study treatment actually received. 
The following analysis approaches will be used:
All safety endpoints except hypoglycemia will be summarized regardless of the initiation of 
rescue or intensification therapy. This approach is referred to as the “including rescue” 
approach (IR). The Treatment Period will include all data from randomization up to 14 days 
after the last dose of study treatment for AEs, Tanner Staging and abdominal ultrasounds, up 
to 2 days after the last dose of study treatment for laboratory endpoints, and up to 5 days after 
the last dose for growth velocity and vital signs with the exception of analyses of Phase A 
alone, for which the additional follow-up days will not be included for participants who 
continue into Phase B (ie, Phase B data will be excluded from analyses of Phase A only).
SAEs and deaths will also be summarized inclusive of all post-randomization follow-up 
(APRFU), regardless of study treatment adherence and without an upper day limit.
AE summary measures will be tabulated by ertugliflozin dose in the subset of participants 
who were re-randomized at Visit 5/Week 12.
Hypoglycemia endpoints will be summarized excluding data collected following the 
initiation of rescue therapy or intensification therapy. This approach is referred to as the 
“excluding rescue” approach (ER). 
Table 8 summarizes the analysis strategy by study phase and analysis approach.
Table 8
Analysis Strategy for Safety Endpoints by Study Phase
Phase
Analysis Approach
Endpoints
Phase A
Treatment period, IR
all AE endpoints and PDLCs
Treatment period, ER
hypoglycemia endpoints
A + B
Treatment period, IR
all safety endpoints except for 
hypoglycemia endpoints
Treatment period, ER
hypoglycemia endpoints
Treatment period + APRFU, IR
SAEs and deaths
AE = adverse event; APRFU = all post-randomization follow-up; ER = excluding data after initiation of 
glycemic rescue/intensification therapy; IR = including data after initiation of glycemic rescue/intensification 
therapy; PDLC = predefined limits of change; SAE = serious adverse event(s).
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The analysis of safety results will follow a tiered approach (Table 9). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) are either prespecified as “Tier 1” endpoints or will be classified as 
belonging to “Tier 2” or “Tier 3” based on the number of events observed. 
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be tested for statistical significance with p-values and 95% CIs to 
be provided for between-treatment differences in the proportion of participants with events; 
these analyses will be performed using the M&N method [Miettinen, O. and Nurminen, M. 
1985], an unconditional, asymptotic method. For this protocol, events of symptomatic 
hypoglycemia, and AEs associated with genital mycotic infection (gender specific), 
hypovolemia, and UTI are considered Tier 1 events. AEs associated with UTI, hypovolemia, 
and genital mycotic infection will be identified by Custom MedDRA queries (CMQ), which 
will be defined in the sSAP.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the M&N method [Miettinen, O. and 
Nurminen, M. 1985]).
Membership in Tier 2 requires that at least 8 participants in the combined ertugliflozin group 
or 2 participants in the placebo group exhibit the event; all other adverse events and 
predefined limits of change will belong to Tier 3.
The thresholds of events were chosen because the 95% confidence interval for the between-
group difference in percent incidence will always include zero when fewer participants per 
group, respectively, experience events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% confidence intervals may be provided 
without adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse events and safety parameters that 
meet predefined limits of change.
In addition to individual events that occur in at least 8 participants in the combined 
ertugliflozin group or 2 participants in the placebo group, the summary measures of AEs
consisting of the proportion of participants with any AE, a drug-related AE, an SAE, an AE 
that is both drug-related and serious, and discontinuation due to an AE, will be considered 
Tier 2 endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
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Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory and vital signs, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format. In addition, for continuous Tier 3 safety 
endpoints, graphical representations of mean ± SE values over time may be provided for 
selected endpoints. 
For safety endpoints, all analyses will be based on the observed data (ie, with no imputation 
of missing data). Table 9 summarizes the analysis strategy for safety endpoints. 
Table 9
Analysis Strategy for Safety
Tier
Safety Variable/Endpoint
p-Value
95% CI for 
Treatment 
Comparisons
Descriptive 
Statistics
Tier 1
AEs of genital mycotic infection (gender 
specific)
AEs of hypovolemia
X
X
X
X
X
X
Events of symptomatic hypoglycemia
X
X
X
AEs of UTI
X
X
X
Tier 2†
Episodes of severe hypoglycemia
X
X
   Any
X
X
   Requiring medical assistance
X
X
    Not requiring medical assistance
Episodes of documented hypoglycemia
AE summary measures
Specific AEs‡ or PDLCs (incidence ≥8
participants in the combined ertugliflozin 
group or ≥2 participants in the placebo group)
X
X
X
X
X
X
X
X
Tier 3
Specific AEs‡ or PDLCs (incidence <8
participants in combined ertugliflozin group 
or <2 participants in the placebo group)
X
Additional hypoglycemia endpoints
X
Change from baseline results (labs [including 
bone biomarkers], vital signs, and abdominal
ultrasounds)
X
Growth velocity and Tanner Staging
X
AE = adverse event; CI = confidence interval; PDLC = predefined limits of change; UTI = urinary tract 
infection; X = results will be provided.
† Endpoints listed here will qualify for Tier 2 only if the incidence is ≥8 participants in the combined 
ertugliflozin group or ≥2 participants in the placebo group.
‡ Includes only those endpoints not prespecified as Tier 1 or not already prespecified as Tier 2 endpoints.
Analysis of Hypoglycemia
For the hypoglycemia endpoints described in Section 9.4.2, the analyses of hypoglycemia 
will be performed separately for participants on a background of insulin and for participants 
not on a background of insulin at screening. Analyses of hypoglycemia combining 
participants on and not on a background of insulin are not planned.
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Tier 1 endpoints for hypoglycemia are the percentages of participants experiencing 1 or more 
episodes of symptomatic hypoglycemia.
Tier 2 endpoints for hypoglycemia are the percentages of participants experiencing 1 or more 
episodes of documented or severe hypoglycemia defined above. Summaries will be provided 
for all episodes.
Tier 3 endpoints for hypoglycemia are the percentages of participants with documented
hypoglycemia as defined above:

by lowest reported glucose category (<54 mg/dL [3.0 mmol/L], ≤70 mg/dL 
[3.9 mmol/L]); and

by number of episodes.
Glucose categorization will be performed based on the units (mg/dL or mmol/L) in which the 
glucose measurements were reported. A participant’s lowest glucose category will be 
classified as unknown only if no glucose measurements are available for that participant.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables. 
9.7
Interim Analyses
Periodic review of data to include safety and study conduct will be performed by an external 
Data Monitoring Committee (DMC). An internal unblinded statistician and unblinded 
programmer who otherwise have no other responsibilities associated with the study or the 
ertugliflozin program will support the DMC.  
Additionally, one PK IA will be performed to estimate ertugliflozin exposure in pediatric 
T2DM participants. The PK IA will be conducted when ~30 participants on study medication 
have completed Visit 4/Week 6 (with the expectation that ~20 of those participants would be 
on ertugliflozin). An unblinded PK analyst, external to the Sponsor, will perform the PK IA 
and present the results to the DMC. The unblinded PK analyst will have no other 
responsibilities associated with the study or the ertugliflozin program. 
The DMC will serve as the primary reviewer of the results of the PK IA and will make 
recommendations regarding the continuation of the second randomization to the Executive 
Oversight Committee (EOC). The PK IA will compare the median dose-normalized trough 
concentration to a 2.0 ng/mL/mg cutoff. This cutoff was determined by simulations based on 
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adult PK data with details provided in Appendix 12. If the median dose-normalized trough 
concentration at the time of the IA is >2.0 ng/mL/mg, the DMC may recommend the 15 mg 
dose be down-titrated to 5 mg, and the second randomization discontinued. If the median 
trough concentration is ≤2.0 ng/mL/mg, then the study will continue with the second 
randomization, and up-titrate to ertugliflozin 15 mg if they meet eligibility criteria. With a 
sample of ~20 ertugliflozin participants, the PK IA is expected to result in a decision to 
down-titrate the 15 mg dose and discontinue the second randomization 90.9% of the time if 
the mean pediatric clearance is ≤60% of the adult clearance. 
If the second randomization is discontinued, ongoing participants who have up-titrated to 
ertugliflozin 15 mg/day will have an Unscheduled Visit as soon as possible to be down-
titrated to ertugliflozin 5 mg/day in a blinded manner, participants in the placebo group who 
have been mock up-titrated will also be mock down-titrated. If the 15 mg arm is dropped 
then hypotheses H2 and H3 will not be tested.
Study enrollment will be ongoing at the time of the PK IA. Blinding to treatment assignment 
will be maintained at all investigational sites. Results of the PK IA will not be shared with 
the investigators prior to the completion of the study. Study monitors will remain blinded. 
The EOC may be unblinded to results at the treatment level in order to act on these 
recommendations. The extent to which individuals are unblinded with respect to results of 
the PK IA will be documented by the internal unblinded statistician, who will be different 
from the unblinded PK analyst. 
Additional details such as DMC meeting frequency and conduct, governance, and 
communication with the EOC will be provided in the DMC Charter. 
9.8
Multiplicity
The type 1 error rate for the Bayesian methodology addressing the primary hypothesis under 
the TP estimand was estimated via simulation to be 0.10. If the success criterion for the 
primary hypothesis (H1) is met under the TP estimand, then hypotheses H2 will be tested at 
alpha = 0.05. If H2 is successful then H3 will be tested at alpha = 0.05. The overall study 
wise type 1 error rate will be greater than 0.05.
If the 15 mg arm is dropped then hypotheses H2 and H3 will not be tested.
9.9
Sample Size and Power Calculations
This study will randomize approximately 165 participants using a 2:1 randomization ratio at 
Visit 3/Day 1/Randomization for ertugliflozin and placebo resulting in approximately 110
participants in the ertugliflozin group (combined doses) and 55 participants in the placebo 
group.
TP Estimand Power
The type 1 error and power (percent of 95% posterior credible intervals <0) were simulated 
(10,000 simulations) using the rjags and coda packages in R and the credible intervals were 
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computed using the HDInterval package. With an informative prior, the type 1 error will 
exceed 0.05. Using the adult data from 8835-007 and a weight parameter of 0.134, a sample 
size of 165 will provide approximately 80% power to detect a true difference of -0.6% in the 
mean change from baseline in A1C between ertugliflozin and placebo, given the SD=1.5% 
and discontinuations from study medication as of the primary timepoint are approximately 
3.9%. The type 1 error and power were estimated based on the WI approach instead of the 
RD approach given all randomized participants have either completed on or off study 
medication or have discontinued from the study in Phase A.
Regarding the secondary hypotheses, the assumptions for the efficacy of the dose-optimized
ertugliflozin regimen and of the 5 mg ertugliflozin dose are the same as for the pooled 
ertugliflozin doses. However, the power for the secondary hypotheses will be lower than that 
of the primary hypothesis on account of the weighting scheme. Based on simulations, the 
percent reduction in power is 13% of the primary hypothesis power. Thus, the estimated 
power for each secondary hypothesis is 70%. 
TE Estimand Power
Assuming 86% of the participants will have data at Week 24 (14% with missing data due to 
discontinuation from study medication or censoring after initiation of rescue), 95 participants 
in the combined ertugliflozin arm and 47 in the placebo arm will provide at least 80% power
for the primary hypothesis test assuming that the between-group difference in A1C change 
from baseline at Week 24 is -0.75% and using a SD of 1.5%. Assumptions of cumulative 
attrition rates and covariance matrix at Week 6, Week 12 and Week 24 are listed below:
1. The cumulative attrition rates (due to dropout and/or censoring due to 
discontinuation of study medication or initiation of rescue) at Week 6, Week 12, 
and Week 24 are 4%, 8% and 14%.
2. The conditional covariance matrix is  
1.11
0.8
0.6
0.8
1.17
0.8
0.6
0.8
2.25
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for the primary variable will be summarized and plotted 
within each category of each subgroup. Treatment groups will be consistent with the primary 
analysis: ertugliflozin (combined doses) and placebo. Subgroups analyses will be performed 
only for the primary analysis and treatment comparison. The following subgroups will be 
analyzed: 

Baseline A1C by categories: ≥ or <median A1C 
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
Sex (Male, Female)

Race (White, Black, Asian, American Indian or Alaska Native)
Participants who report belonging to more than one racial group will each be assigned 
to the racial group that has the highest risk for Type 2 diabetes in the order of 
American Indian or Alaska Native, Asian, Black, White [Copeland, K. C., et al 2011].

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Age at Screening (10 to 14 years of age, 15 to 17 years of age)

Insulin use at Screening (No, Yes)

Geographic region (EU, North America, Other)
Under the TP estimand, summary statistics will be provided for each subgroup analysis to 
include sample sizes, means, medians, standard deviations, and 95% confidence intervals on 
the differences in means based on a normal distribution.
Under the TE estimand, the subgroup analyses will be based on a repeated measures 
ANCOVA model including terms for treatment, insulin use, the subgroup, time as a 
categorical factor, baseline A1C, and the treatment-by-subgroup interaction. Treatment 
effects and nominal 95% CIs by category for the classification variables listed above will be 
reported. Formal statistical testing of treatment-by-subgroup interactions will not be 
performed. Forest plots will be produced for each estimand, which provide the point 
estimates and 95% CIs for the estimated treatment effect across the categories of subgroups 
listed above.
Results from the subgroup analyses should be reviewed cautiously. Because sample sizes 
within subgroups will be smaller than the overall study sample size, estimation may not be 
precise, and 95% CIs will usually be wide in the subgroup analyses. 
9.11
Compliance (Medication Adherence)
A day within the Double-blind Treatment Period will be considered a compliant day if the 
participant takes 1 tablet of ertugliflozin 5 mg/placebo and 1 tablet of ertugliflozin 
15 mg/placebo.
If the study treatment eCRF indicates general compliance problems with any double-blinded 
therapy, the participant will be considered non-compliant for that day regardless of the 
number of tablets for the assigned treatment(s) and any matching placebo reported.
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For each participant, the compliance rate, based on time until study treatment 
discontinuation, and the adherence rate, based on time until study discontinuation, will be 
calculated, using the following formulas:
Compliance rate (%) =
Number of Compliant Days
× 100%.
Number of Days in the Double-blind Treatment Period
Adherence rate (%) =
Number of Compliant Days
× 100%.
Number of Days in the Study
For each participant the “Number of Days in Double-blind Treatment Period” is the total 
number of days from the first dose of double-blind study treatment to the date of the last dose 
of study treatment. The “Number of Days in the Study” is the total number of days from 
Day 1 to the day of study completion or withdrawal from the study.
9.12
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics and 
frequencies for the “Number of Days on Therapy” by treatment group (ertugliflozin and 
placebo).
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I. Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), Regulation 
(EU) 536/2014, the International Council for Harmonisation Good Clinical Practice 
(ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, and in 
accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
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The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease-related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
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according to the prespecified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific standards.
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Pursuant to Union law (Clinical Trials Directive 2001/20/EC and Clinical Trials Regulation 
536/2014), the Investigator is responsible for pseudonymizing and assigning a key-
code/patient ID to each study subject. In addition, the Investigator is required by Union law 
to store the Key (linking the Patient ID to the full name of the study subject) at the site in the 
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EU/EEA throughout the course of the study and for a designated period of time thereafter. 
Finally, the study site is only permitted to share pseudonymized study subject personal data 
with the Sponsor.
The European Data protection Board, in its Recommendations 01/2020 on measures that 
supplement transfer tools to ensure compliance with the EU level of protection of personal 
data (“Recommendations”), states in Paragraph 85 that pseudonymization (of study subject) 
personal data under the conditions described above constitutes effective supplemental 
measure. 
Organizational measures are contractually imposed on third party vendors whenever 
possible, to ensure that Personal Data are protected by industry-best practices against 
accidental destruction or loss (physical/logical) which include regular backup procedures, 
Firewalls, and disaster recovery plans.
In support of Corporate Policy 1 Information Risk Management, on a Sponsor-wide basis all 
supplier relationships, both IT and non-IT related, are strongly encouraged to meet the 
Sponsor’s Supplier Information Risk Management Standard.  To protect the confidentiality, 
availability and integrity of Sponsor information, conformity to information risk 
requirements by supplier personnel, hardware and software may be measured, analyzed and 
appropriate corrective/preventative actions taken as necessary. Based on the supplier 
criticality, additional activities (e.g., on-site reviews, integrated business continuity exercises) 
may be required to ensure the cyber-resiliency of the supplier on an ongoing basis.
The Sponsor has implemented (Corporate Policy 13.1 Information Security Standards 
Handbook) an organization-wide process to assign user access rights based on the whether 
the employee/contractor has a legitimate need to utilize a database in order to carry out 
his/her job; manager approval is required when granting user access rights (beyond those 
sites or databases intended for all employees/contractors); and a process is in place for an 
annual review by each manager of the user access rights currently in place.  Organizational 
measures, also contractually imposed on third party vendors, to prevent data processing 
systems from being used by unauthorized persons include i) user identification and 
authentication procedures (e.g., special characters, minimum length, regular change of 
password), and ii) automatic blocking (e.g., password or timeout).
The Sponsor utilizes a database called “InForm”, operated by Oracle, for the storage of its 
study subject clinical trial data. InForm is a role-based system and only authorized users can 
see the data. Sites may only see the data they have entered.  Access by Sponsor users is 
restricted to only those associated with a specific clinical trial. 
Study sites are provided with a password to access the database.  Access to InForm requires 
https (Secure Socket Layer) with a FIPS 140-2 compliant algorithm to connect to the 
application via the study site’s web browser.  Once logged into the system, the connection 
between the database, located in Ashburn, Virginia, USA, and the site, is encrypted.  The 
Sponsor also stores the name and access credentials of the Investigators and other site staff 
(Study Coordinators) who record patient data into InForm.  Such study staff personal data is 
not pseudonymized.  Note, such encryption during transmission may not meet all conditions 
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imposed by the EDPB in its Recommendations for this encryption, on its own, to constitute 
an effective supplemental measure.
Data, whether concerning a study subject or site staff, stored in the InForm database is 
encrypted.  Note, such encryption may not meet all conditions imposed by the EDPB in its 
Recommendations for this encryption, on its own, to constitute an effective supplemental 
measure.  
Whenever possible, organization-wide measures are imposed on third party vendors to 
prevent unauthorized persons from gaining access to the data processing systems available on 
premises and in facilities (including databases, application servers and related hardware), 
where Personal Data are processed, include i) Access control system (ID reader, chip), ii) key 
management, card-keys procedures, and iii) on-site security personnel and alarm system.
InForm is a HIPAA Part 11 capable system.  Any data entered/changed or deleted will be 
associated with a viewable audit trail.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20).  Pursuant to organization-wide 
requirements, the Sponsor periodically conducts audits of the vendors providing IT services, 
including Oracle, the vendor supporting the InForm database.  The most recent audit of 
Oracle and its operations of InForm occurred in May 2020.  Finally, Oracle has obtained ISO 
27001 certification for the various databases it offers to third parties as a service, including 
the InForm database.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
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10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC is comprised of both Sponsor and non-Sponsor scientific experts who provide input 
with respect to study design, interpretation of study results, and subsequent peer-reviewed 
scientific publications.
10.1.4.2
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
DMC regarding the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.4
Internal Case Review Committee for Ketoacidosis
An internal case review committee will be set-up to review potential ketoacidosis events 
identified in the ertugliflozin pediatric study. The committee will assess whether the cases 
meet a prespecified case definition of ketoacidosis. Further details will be provided in the 
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charter for clinical case review of ketoacidosis. All personnel involved in the Internal Case 
Review Committee will remain blinded to study treatment allocation throughout the study.
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
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requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participant’s documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Participants should not engage in physically strenuous exercise (eg, heavy lifting, weight 
training, calisthenics, and aerobics) within 48 hours before each blood sample collection for 
clinical laboratory tests for the duration of participation in the study. 
Laboratory safety tests will be performed after at least a 10-hour fast (ie, no food, no study 
treatment, no AHA medication, and no drink except for water and non-AHA prescribed 
medication), except at Visit 4/Week 6.
List of Laboratory Evaluations:

FPG test 

Whole blood A1C test 
Do not collect A1C at Rescue/Intensification or Discontinuation Visits if the visit 
occurs before Week 8.
The Visit 5/Week 12, Visit 6/Week 24, and Visit 7/Week 38 samples must be 
measured both at the site and by the Central lab.

Fasting serum C-peptide test
Fasting C-peptide will be collected at Visit 1/Screening only in participants with 
diabetes for <2 years and in all participants on background insulin regardless of the 
duration of T2DM. At Visits 3, 6, and 8, it will be collected in all participants.

Lipid analyses: total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol-
calculated, non-HDL cholesterol – calculated.

Hematology (CBC differential): hemoglobin, hematocrit, red blood cell count, mean 
corpuscular hemoglobin concentration and mean corpuscular volume, white blood 
cell count and differential, platelet count, absolute neutrophil count, eosinophils, 
monocytes, basophils, lymphocytes. 

Serum blood chemistry: sodium, potassium, chloride, bicarbonate, calcium, 
phosphate, albumin, ALP, uric acid, total serum protein, ALT, AST, creatine 
phosphokinase, total bilirubin (direct conjugated bilirubin and indirect unconjugated 
bilirubin will be measured when total bilirubin is greater than ULN), BUN,
creatinine, magnesium. 
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
Urine pregnancy test performed for all females at the investigator’s site (for 
exceptions, see Section 10.7).
Serum beta-human chorionic gonadotropin (hCG) test in all randomized participants
with a positive urine pregnancy test.

Eligibility serum hCG test performed for female participants from countries where it 
is required by Health Authorities and/or IRBs/ECs (see Section 10.7.2). 

Urine collection for dipstick urinalysis (pH, protein, blood, ketones, leukocyte, 
esterase, nitrites) and urine albumin/creatinine ratio should be performed on a mid-
stream sample collected after adequately cleaning the genital area using appropriate 
wipes (“clean catch”).
Notes: 
(1) If dipstick urinalysis is positive for blood, leukocyte esterase, nitrites, or protein, 
then microscopy will be done. 
(2) Participants found to have microscopic hematuria (defined as the presence of 3 or 
more red blood cells per high powered field on microscopic examination) from a 
properly collected, non-contaminated urinalysis with no evidence of infection, will be 
referred to an urologist for appropriate work-up.
(3) Urine collection should not be performed if participant is menstruating, has 
vigorously exercised within 24 hours, or had fever or an active infection within 
2 days of the visit. Under such circumstances, the participant should provide a urine 
sample at an Unscheduled Visit. 

Thyroid function test: serum TSH test

Biomarkers of bone turnover: 
-urine (second AM void) N-terminal cross-linking telopeptide of bone collagen 
(NTX) and creatinine
-serum bone-specific alkaline phosphatase (Ostace assay). 

Cystatin C
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Note: At the indicated times in the SoA, samples for ertugliflozin PK will be collected and 
sent to the Central Lab prior to transfer to the vendor for analyses. 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:

Results in death

Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.

Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.

Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.

Is a cancer

Is associated with an overdose
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Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is 
wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric studies, extremely distressed or unable to do usual activities).
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Assessment of causality

Did the Sponsor’s product intervention cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was 
done. This initialed document must be retained for the required regulatory time frame. 
The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test product and the AE based 
upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components
and their respective elements (in number and/or intensity), the more likely the 
Sponsor’s product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies with investigational 
medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors.
-
Dechallenge: Was the Sponsor’s product discontinued or 
dose/exposure/frequency reduced?
o
If yes, did the AE resolve or improve?
o
If yes, this is a positive dechallenge.
o
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; (3) the study is a single-dose drug study; or (4) Sponsor’s 
product (s) is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the Sponsor’s product in this 
study?
o
If yes, did the AE recur or worsen?
o
If yes, this is a positive rechallenge.
o
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
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NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF REEXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
o
There is evidence of exposure to the Sponsor’s product. The temporal 
sequence of the AE onset relative to the administration of the Sponsor’s 
product is reasonable. The AE is more likely explained by the Sponsor’s 
product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
o
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)

The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements.
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next 
section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collections, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Contraception Requirements
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 10 consistently and correctly during the 
protocol-defined time frame.
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Table 10
Contraceptive Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantc,d

IUSc,e

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days. 

Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
Methods That Are Not Considered Highly Effective 
Failure rate of >1% per year when used consistently and correctly.

Progestogen-only hormonal contraception where inhibition of ovulation is not the primary mode of action

Penile/external or vaginal/internal condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
b) Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c) Male condoms must be used in addition to hormonal contraception.
d) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive implants are 
limited to those which inhibit ovulation.
e) IUS is a progestin releasing IUD
Note: The following are not acceptable methods of contraception:
-Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM.
-Male condom with cap, diaphragm, or sponge with spermicide.
-Male and female condom should not be used together (due to risk of failure with friction). 
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Pregnancy Testing
All females participating in the study will have a urine pregnancy test at visits indicated in 
the SoA (for exceptions, see Section 10.7) (if required by an investigational site’s IRB/ERC, 
a serum pregnancy test can also be obtained in addition to the urine pregnancy test). A 
positive urine pregnancy test requires immediate interruption of study treatment until serum 
beta-hCG is performed and found to be negative. Participants must be discontinued from 
study treatment and followed (Section 7.1) if pregnancy is confirmed by a positive serum 
pregnancy test.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant's clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the study investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed before to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council for Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Saudi Arabia and United Arab Emirates Requirements
The protocol change outlined in this section is being made to align with legal and cultural 
mores in Saudi Arabia and United Arab Emirates: 
Pregnancy Testing
All married female participants (or female participants who in the clinical opinion of the 
investigator could be pregnant) will have a urine pregnancy test at the visits indicated in the 
SoA.
Serum Pregnancy Requirements
Pregnancy Testing
If required by the Health Authorities and/or IRBs/ECs, female participants from those 
countries/sites (eg, United Kingdom, Guatemala) will have a serum pregnancy test performed 
to determine eligibility instead of a urine pregnancy test.
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10.8
Appendix 8: BMI for Age Charts
Sites should follow their approved country-specific BMI-for-age percentile charts, if 
available (eg, sites within the US will refer to the Centers for Disease Control charts). If an 
approved country-specific BMI-for-age percentile chart is not available, refer to the WHO 
charts shown in Figure 2 and Figure 3.
Instructions for obtaining the body mass index-for-age percentile:

Find the child’s age on the horizontal axis 

Find the BMI measurement on the vertical axis (to determine BMI, refer to Section 
8.2.4).

The body mass index-for-age percentile will be at the intersection of the child’s age and 
BMI measurement.
Figure 2
BMI for Age Girls, 5 to 19 Years (Percentiles)
Ref: [deOnis, M. 2007]
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Figure 3
BMI for Age Boys, 5 to 19 Years (Percentiles)
Ref: [deOnis, M. 2007]
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10.9
Appendix 9: Blood Pressure Tables
Table 11
Blood Pressure Table for Gender/Age/Height for Boys Age 10 to 17
Years 
of Age
Blood 
Pressure
Systolic Blood Pressure by Percentile of 
Height (mmHg)
Diastolic Blood Pressure by Percentile of 
Height (mmHg)
(Years)
Percentile
5%
10% 25% 50% 75% 90% 95%
5%
10% 25% 50% 75% 90% 95%
10
90th
111
112
114
115
117
119
119
73
73
74
75
76
77
78
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
99th
122
123
125
127
128
130
130
85
86
86
88
88
89
90
11
90th
113
114
115
117
119
120
121
74
74
75
76
77
78
78
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
99th
124
125
127
129
130
132
132
86
86
87
88
89
90
90
12
90th
115
116
118
120
121
123
123
74
75
75
76
77
78
79
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
99th
126
127
129
131
133
134
135
86
87
88
89
90
90
91
13
90th
117
118
120
122
124
125
126
75
75
76
77
78
79
79
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
99th
128
130
131
133
135
136
137
87
87
88
89
90
91
91
14
90th
120
121
123
125
126
128
128
75
76
77
78
79
79
80
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
99th
131
132
134
136
138
139
140
87
88
89
90
91
92
92
15
90th
122
124
125
127
129
130
131
76
77
78
79
80
80
81
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
99th
134
135
136
138
140
142
142
88
89
90
91
92
93
93
16
90th
125
126
128
130
131
133
134
78
78
79
80
81
82
82
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
99th
136
137
139
141
143
144
145
90
90
91
92
93
94
94
17
90th
127
128
130
132
134
135
136
80
80
81
82
83
84
84
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
99th
139
140
141
143
145
146
147
92
93
93
94
95
96
97
Note:  country-specific Blood Pressure norms may be used; otherwise, these guidelines should be used. 
Ref: [National High Blood Pressure Education Program Working Group on 2004]
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Table 12
Blood Pressure Table for Gender/Age/Height for Girls Age 10 to 17
Years of 
Age
Blood 
Pressure
Systolic Blood Pressure by Percentile of 
Height (mmHg)
Diastolic Blood Pressure by Percentile of 
Height (mmHg)
(Years)
Percentile
5%
10% 25% 50% 75% 90% 95%
5%
10% 25% 50% 75% 90% 95%
10
90th
112
112
114
115
116
118
118
73
73
73
74
75
76
76
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
99th
123
123
125
126
127
129
129
84
84
85
86
86
87
88
11
90th
114
114
116
117
118
119
120
74
74
74
75
76
77
77
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
99th
125
125
126
128
129
130
131
85
85
86
87
87
88
89
12
90th
116
116
117
119
120
121
122
75
75
75
76
77
78
78
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
99th
127
127
128
130
131
132
133
86
86
87
88
88
89
90
13
90th
117
118
119
121
122
123
124
76
76
76
77
78
79
79
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
99th
128
129
130
132
133
134
135
87
87
88
89
89
90
91
14
90th
119
120
121
122
124
125
125
77
77
77
78
79
80
80
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
99th
130
131
132
133
135
136
136
88
88
89
90
90
91
92
+15
90th
120
121
122
123
125
126
127
78
78
78
79
80
81
81
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
99th
131
132
133
134
136
137
138
89
89
90
91
91
92
93
16
90th
121
122
123
124
126
127
128
78
78
79
80
81
81
82
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
99th
132
133
134
135
137
138
139
90
90
90
91
92
93
93
17
90th
122
122
123
125
126
127
128
78
79
79
80
81
81
82
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
99th
133
133
134
136
137
138
139
90
90
91
91
92
93
93
Note:  country-specific Blood Pressure norms may be used; otherwise, these guidelines should be used. 
Ref: [National High Blood Pressure Education Program Working Group on 2004]
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10.10 Appendix 10: Management of Participants with Elevated Liver Enzymes (ALT 
or AST ≥3x ULN)
Section I: Identification and Management of Participants with ALT or AST Results ≥3X ULN
Increases in ALT or AST ≥3X the ULN are defined as clinically significant for this study. 
The central laboratory report will alert the investigator if a participant meets this threshold. 
When a randomized participant who is receiving blinded investigational product has an ALT 
or AST elevation beyond the clinical significant margin above, the investigator should 
monitor the participant according to the instructions below and discontinue the participant 
from blinded investigational product if a prespecified criterion is met. 
The investigator should select the appropriate set of instructions (either A, B, or C below) for 
managing a participant with elevated liver enzymes based upon the following factors: (1) the 
magnitude of a participant’s ALT or AST elevation, (2) the presence or absence of 
symptoms, (3) whether there is a corresponding increase in total bilirubin ≥2X ULN. 
Investigator Instructions for Management of Participants with ALT or AST ≥3X ULN
A) Participant has: 

ALT or AST ≥3X ULN with total bilirubin ≥2X ULN and ALP <2X ULN
1. The participant should interrupt blinded investigational product. 
2. Refer to the “Event of Clinical Interest (ECI) Guidance for Potential DILI 
(Drug-Induced Liver Injury) in Clinical Trials” (located in the Investigator 
Trial File Binder or equivalent) and perform procedures accordingly. 
3. If an etiology for the elevated ALT or AST and total bilirubin levels is 
established and the abnormalities resolve, blinded investigational product may 
be restarted with approval by the Sponsor. Otherwise, the participant should 
discontinue treatment with blinded investigational product.
Note: Laboratory assessments prescribed in the Event of Clinical Interest (ECI) Guidance 
for Potential DILI (Drug-Induced Liver Injury) in Clinical Trials may be sent locally in 
emergent cases and to support participant compliance with the necessary evaluations. 
Participants unwilling or unable to undergo the prescribed testing should be discontinued 
from treatment with blinded investigational product. 
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B) Participant has: 

ALT or AST ≥8X ULN OR

ALT or AST ≥3X ULN and signs or symptoms of a drug reaction consistent 
with liver injury (eg, fever, eosinophilia, right upper quadrant pain, dark 
urine, fatigue, etc.)
1. The participant should interrupt blinded investigational product. 
2. Perform repeat ALT and AST within 3 days of receipt of the laboratory report.
3. Initiate evaluation for potential causes. See Section II below. 
4. Repeat ALT and AST tests at appropriate intervals, initially approximately 2-
times per week, until resolution or return to baseline. 
5. If an etiology for the elevated liver enzymes is established (eg, active hepatitis 
with specific etiology demonstrated, cholecystitis, biliary obstruction), blinded 
investigational product may be restarted with approval by the Sponsor. 
Otherwise, the participant should discontinue treatment with blinded 
investigational product.
Note: Local laboratory assessments can be used to support compliance with the repeat 
testing procedure described above if required. Participants unwilling or unable to undergo 
repeat ALT and AST testing at the frequency recommended above should be discontinued 
from treatment with blinded investigational product. 
C) Participant has:

ALT or AST ≥3X and <8X ULN
1. For participants with: 
ALT or AST ≥3X and <5X ULN:

Perform repeat ALT and AST within 3-5 days of receipt of the laboratory 
report. 
OR
ALT or AST ≥5X ULN and <8X ULN:

Perform repeat ALT and AST within 3 days of receipt of the laboratory 
report. Participants unable to undergo repeat measurements within 3 days 
must interrupt blinded investigational product. 
2. Initiate evaluation for potential causes. See Section II below. 
3. Actions based upon initial repeat testing:

If ALT or AST ≥3X ULN with total bilirubin ≥2X ULN, then interrupt 
blinded investigational product and monitor as described in the Section A
Instructions above and also per the “Event of Clinical Interest (ECI) 
Guidance for Potential DILI (Drug-Induced Liver Injury) in Clinical 
Trials” (located in the Investigator Trial File Binder or equivalent) and 
perform procedures accordingly.
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
If ALT or AST ≥8X ULN or ALT or AST ≥3X ULN with symptoms 
present (eg, fever, eosinophilia, right upper quadrant pain, dark urine, 
fatigue, etc.), then interrupt blinded investigational product and monitor as 
described in the Section B Instructions above. 

If ALT or AST ≥3X ULN and <8X ULN (without above criteria met), 
continue to measure ALT and AST 1- to 2-times per week (2-times per 
week if ALT or AST ≥5X ULN or if an increase >20% occurred since the 
first elevated value[s]). 

If ALT and AST > ULN and <3X ULN, perform repeat determination in 
5-7 days, and then at appropriate intervals (eg, every other week) until the 
participant’s ALT and AST levels are within normal limits or are similar to 
baseline. 
4. Actions based upon follow-up repeat testing:

If ALT or AST ≥5X ULN after 2 weeks, discontinue blinded 
investigational product.

If ALT or AST remain elevated (≥3X and <5X ULN) but stable, the 
frequency of retesting can decrease (eg, every other week) with approval 
from the Sponsor. 

If ALT and AST >ULN and <3X ULN, perform repeat determination in 
5-7 days, and then at appropriate intervals (eg, every other week) until the 
participant’s ALT and AST levels are within normal limits or are similar to 
baseline. 
Note: Local laboratory assessments can be used to support compliance with the repeat 
testing procedures described above if required. Participants unwilling or unable to undergo 
repeat ALT and AST testing at the frequency defined above should be discontinued from 
treatment with blinded investigational product. 
In summary, participants should be discontinued from blinded investigational product for any 
of the following reasons:

ALT or AST ≥3X ULN with total bilirubin ≥2X ULN and ALP <2X ULN and without an 
established etiology

ALT or AST ≥8X ULN or ≥3X ULN with symptoms consistent with liver injury and 
without an established etiology

ALT or AST ≥5X ULN for 2 weeks or longer
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Section II: Guidance for Assessment of Potential Etiology
Questions to Assess Etiology
Investigate potential causes for the participant’s elevated liver enzymes using the questions 
below. Answers to the questions should be recorded in the participant’s source documents 
and appropriate eCRFs. 
1. Has the participant recently:

Had a change in his/her pattern of alcohol use? Investigate historic pattern of 
alcohol use as well.

Administered an illegal drug(s) (including intravenous drugs)?

Been exposed to a chemical agent or other environmental toxin?

Consumed any unusual foods (eg, mushrooms), seasonal foods, or initiated 
treatment with new herbal/nutritional supplements?

Initiated a new diet regimen, started a rigorous exercise program, or 
experienced any form of severe physical exertion? 

Traveled to another country or region?
2. Does the participant have a relevant concomitant illness (eg, cholelithiasis, hepatitis, 
etc.) or has the participant had potential exposure to viral hepatitis (transfusion, 
tattoo, new sexual partner)?
3. Does the participant have a relevant medical history (eg, autoimmune disorder, 
cancer, Gilbert’s syndrome, obesity, Wilson’s disease, NASH, alcoholic or 
infectious hepatitis, biliary tract disease, hypoxic/ischemic hepatopathy, etc.)?
4. Has the participant recently been treated with a concomitant medication(s) with 
demonstrated or suspected effects on the liver (eg, acetaminophen; amiodarone; 
aspirin; chlorpromazine; dantrolene; erythromycin; halothane; isoniazid; 
methyldopa; nitrofurantoin; oxyphenisatin; perhexiline maleate; phenytoin; 
propylthiouracil; rifampin; sulfonamides; tetracyclines) or initiated treatment with 
another new medication(s)?
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Additional Laboratory/Imaging Evaluations
In participants for whom an etiology for the abnormal liver enzymes is unknown or whose 
elevated liver enzymes persist for more than 1-week:
1. Consider performing serologic tests including: (a) Hepatitis A (IgM); (b) Hepatitis B 
(surface antigen and core IgM); (c) Hepatitis C (antibody); (d) Hepatitis E (IgG and 
IgM). Obtain consent prior to testing, if required locally. Additional evaluations may 
be performed at the discretion of the investigator. 
2. Consider an ultrasound of the participant’s right upper quadrant and additional scans 
(endoscopic retrograde cholangiopancreatography [ERCP] or magnetic resonance 
cholangiopancreatography [MRCP]) if needed. 
Note: Participants may also be referred to a gastroenterologist or hepatologist for an 
additional work-up if considered necessary by the investigator.
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10.11 Appendix 11: Mapping of Relative Day Ranges to Weeks
The rules outlined in Table 13 will be used to map the relative day ranges to weeks for A1C. 
Table 13
Relative Day Ranges to Weeks for A1C
Week
Required Phase
Relative Day Range 
Day Relative to Start of Trial†
Min (Day/7, -1)
--
Visit < 2 and Day < 1
-1
Placebo Run-In
Visit 2 and Day <1
0
Placebo Run-In
Visit 3 and Day ≤1
6
A
2≤ Day ≤63
12
A
64≤ Day ≤126
24
A
Day 127
Day Relative to Start of Phase B‡
38
B
1≤ Day ≤154
54
B
Day 155
A1C=glycosylated hemoglobin
†Start of Phase A is defined as first dose of Phase A study treatment for all treated participants and the 
randomization day for participants who did not take any dose of study treatment.
‡Start of Phase B is defined as first dose day of Phase B study treatment or Week 24 for participants who 
entered Phase B off study treatment.
The rules outlined in Table 14 will be used to map the relative day ranges for FPG, lab, and 
lipid endpoints. 
Table 14
Relative Day Ranges to Weeks for FPG, Lab, and Lipid Endpoints
Week
Required Phase
Relative Day Range 
Day Relative to Start of Trial†
Min (Day/7, -1)
--
Visit < 2 and Day < 1
-1
Placebo Run-In
Visit 2 and Day <1
0
Placebo Run-In
Visit 3 and Day ≤1
24
A
Day 2
Day Relative to Start of Phase B‡
54
B
Day 1
†Start of Phase A is defined as first dose of Phase A study treatment for all treated participants and the 
randomization day for participants who did not take any dose of study treatment.
‡Start of Phase B is defined as first dose day of Phase B study treatment or Week 24 for participants who 
entered Phase B off study treatment.
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10.12 Appendix 12: Interim PK Analysis
Background 
In Phase 1 dose-escalation studies, oral doses of ertugliflozin as high as 300 mg (single dose) 
and 100 mg qd (up to 14 days) were safe and well tolerated in healthy adult participants. The 
maximum dose given long term (12 weeks) to adult T2DM participants was 25 mg qd; this 
dose was generally safe and well tolerated. Based on the known linear PK of ertugliflozin, 
this provides a conservative 1.67-fold margin over the highest dose studied in the adult 
Phase 3 program (15 mg qd). The PK IA will be performed to confirm ertugliflozin exposure 
in pediatric T2DM participants in order to limit potentially exceeding the exposures observed 
with the highest dose used in adult Phase 2 clinical trials. 
Due to challenges of collecting post-dose PK samples in the T2DM pediatric population, 
only trough samples will be collected to evaluate exposure in this population. With the sparse 
PK sampling, AUC24 can only be calculated using post hoc individual CL/F estimates from a 
population PK analysis. Shrinkage (a reduction in inter-individual variability) with 
estimating post hoc individual CL/F would be expected; this is an artifact of PK sampling 
that is too sparse. Therefore, the PK interim assessment will be based on observed trough 
concentrations collected in this study rather than model-based estimates of AUC24. 
Objective
Define criterion for the IA where: 
1) If the mean AUC24 in the pediatric participants is 1.67 times higher than adults, the 
criterion would have >90% probability of leading to a recommendation to drop the 15 mg qd
dose and discontinue the second randomization; 
2) If the mean AUC24 in the pediatric participants is the same as adults, the criterion would 
have a <10% probability of incorrectly leading to a recommendation to drop the 15 mg qd 
dose and discontinue the second randomization. 
Data 
The adult population PK model and the input dataset for the final model were used for the 
simulation. Observed trough PK concentrations from 3 Phase 3 studies (P003/1022, 
P005/1019, and P007/1017) were included in the simulation. A PK sample was defined as
“trough” if it was collected 20 to 28 hours post dose based on the actual PK sample 
collection time, and the time of the dose preceding PK sample collection. If a participant has 
multiple trough samples, only the first 3 were included to mimic the expected PK sampling in 
the pediatric study. A total of 3387 trough samples from 1335 adult participants were 
included in the dataset used for the simulation. 
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Methods
The PK IA will be conducted by comparing the median of the dose-normalized trough 
concentrations to a cutoff. The median value had the lowest variability among the various 
percentiles considered (eg, 90th or 95th percentiles) based on observed adult data in the 
Phase 3 studies and was therefore selected for IA decision-making. Dose normalization is 
appropriate given that the PK of ertugliflozin is linear from 0.5 mg to 300 mg. Dose 
normalization allows for the IA to be conducted with a smaller sample size for earlier 
decision-making because data from both the 5 mg and 15 mg doses can be combined. In this 
study, a PK sample will be defined as “trough” and included in the PK IA if it is collected 20 
to 28 hours post dose based on the actual PK sample collection time, and the time of the dose 
preceding PK sample collection.
A population PK simulation was conducted to determine the sample size (number of 
participants) required for the IA and to select a cutoff value for the median of the dose 
normalized observed trough concentrations that would ensure: 1) if the model based mean 
AUC24 in the pediatric participants were 1.67 times higher than adult participants, the 
criterion would have >90% probability of leading to a recommendation to drop the 15 mg 
dose; 2) if the model based mean AUC24 in the pediatric participants is the same as adults 
participants, the criterion would have a <10% probability of incorrectly leading to a 
recommendation to drop the 15 mg qd dose. Three different samples sizes were simulated: 
N=15, N=20, and N=25. 
Two different scenarios were simulated: 1) the pediatric PK (mean apparent CL/F) is the 
same as adults; and 2) the mean (typical value) CL/F in pediatrics is 7.2 L/hr, which is 60% 
of the typical value of adult CL/F (12.0 L/hr) and represents 1.67 times exposure (as if the 
15 mg steady state AUC24 in pediatrics were the same as the 25 mg steady state AUC24 in 
adults). Under both scenarios, it was assumed 1 to 3 steady state trough samples per 
participant will be available for analysis.
Scenario 1) Pediatric PK is the same as adult PK: 
The following assumptions were made: the PK in the pediatric population is the same as 
adults; the distribution of the trough concentrations is the same as the 3 adult Phase 3 studies 
where PK was collected (P003/1022, P005/1019, and P007/1017). Therefore, the observed 
trough concentrations from the 3 adult Phase 3 studies were used for this simulation. 
The simulations were conducted by randomly sampling N=15, N=20, or N= 25 participants 
from the 1335 phase 3 participants. For each simulation, the observed trough concentrations 
from the sampled participants (N=15, N=20, or N=25) were dose normalized and the median 
was compared to a cutoff value. If the median was greater than the cutoff, this was counted 
as a decision to down-titrate the participants who were up-titrated to the 15 mg ertugliflozin
dose and discontinue the second randomization; if median was less than or equal to the 
cutoff, this was counted as a decision to keep the 15 mg ertugliflozin dose and keep the 
second randomization. Given the linearity of ertugliflozin PK and Week 6, 12, and 24 
troughs are at steady state regardless of the dose the participant is taking immediately prior to 
the PK draw, the random sampling of the dose-normalized trough concentrations does not 
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differentiate whether a participant is on the 5 mg ertugliflozin dose or the 15 mg ertugliflozin 
qd dose. A thousand simulations were run for each sample size, and the percentage of times 
that a decision to drop the 15 mg dose was made was calculated.
Scenario 2) The pediatric AUC24 is 1.67 times that of the adults given the same dose: 
Trough concentrations were simulated using a modified ertugliflozin adult population PK 
model where the typical value of CL/F (7.2 L/hr) is 60% of the typical value of CL/F 
(12.0 L/hr) in the final adult population PK model. The input dataset for this simulation was a 
subset of the input dataset of the final adult population PK model with only participants from 
the 3 Phase 3 studies (P003/1022, P005/1019, and P007/1017). In this scenario, it was 
assumed that the mean (typical value) for all PK parameters, eg, the volume of distribution 
and rate of absorption, as well as intersubject variability of CL/F and intrasubject variability 
(residual error) were the same between the adult phase 3 population and the pediatric 
population, the only difference being the mean CL/F was set to 60% of the mean CL/F of the 
adults. Thus, in the population PK model used to simulate the pediatric trough 
concentrations, all parameters (fixed effects and random effects) were set to the same values 
as in adults, with the exception of typical value of the clearance changed from 12.0 L/hr to 
7.2 L/hr. 
To obtain the hypothetical trough levels, simulations were run to generate 200 sets of the 
1335 Phase 3 participants using the observed Phase 3 dosing times and PK sampling times. 
For each participant, a maximum of 3 troughs were used. If a participant had more than 
3 troughs, the first 3 were used.
Using the simulated trough concentrations from 1335x200=267,000 participants, random 
samples of N=15, N=20, or N=25 participants were drawn for each iteration. In each iteration
to simulate N participants with Week 6 PK sample collections, the following assumptions 
were used: 1) Assume a total enrollment rate of 2 participants (placebo+ertugliflozin) per 
month (based on sitagliptin pediatric T2DM recruitment rate). 2) In each iteration, for 2 
participants (with only Week 6 PK sample collection), if the participant had more than 1 
trough, only the first 1 was used. 3) In each iteration, for 4 participants (with both Week 6 
and Week 12 PK collections) if the participant had more than 2 troughs, only the first 2 were 
used. 4) In each iteration, for the remaining participants a maximum of 3 troughs (as 
discussed in previous paragraph) were used. These trough concentrations from the sampled 
participants were dose normalized and the median was compared to a cutoff value. If the 
median was greater than the cutoff, this was counted as a decision to down-titrate the 
participants who were up-titrated to the 15 mg dose and discontinue the second 
randomization; if median was less than or equal to the cutoff, this was counted as a decision 
to keep the 15 mg dose and the second randomization. Given the linearity of ertugliflozin PK 
and Week 6, Week 12, and Week 24 troughs are at steady state regardless of the dose the 
participant is taking immediately prior to the PK draw, the random sampling of the 
dose-normalized trough concentrations does not differentiate whether a participant is on the 5 
mg or the 15 mg qd ertugliflozin dose. One thousand iterations were run for each condition 
(sample size and cutoff), and the percentage of times that the 15 mg dose was dropped was 
calculated.
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Nonlinear mixed effects modeling using NONMEM 7.3 was used to generate the population 
PK simulations for the trough concentrations. All other data processing and simulation were 
conducted using R 3.4.3. 
Results
Simulation results showing the proportion of trials in which the 15 mg dose met the criteria 
for recommendation to be dropped under Scenario 1 and Scenario 2 are reported in Table 15. 
As a reference, the adult pop-PK model predicted median of the dose-normalized Ctrough
(including inter and intra participant variability) is 1.18 ng/mL/mg.
Table 15
Simulation Results: Estimated Probability that the 15 mg Dose Could be 
Discontinued Based on the PK IA
Cutoff 
(ng/mL/mg)
Scenario 1: CL/F is the same for adults and 
pediatrics
Scenario 2: CL/F of the pediatrics is 60% that 
of adults
N=15
N=20
N=25
N=15
N=20
N=25
2.0
<1%
<1%
<1%
90.0%
90.9%
94.8%
2.1
<1%
<1%
<1%
86.0%
86.6%
91.1%
CL/F=apparent clearance
The cutoff is compared to the median of the dose-normalized trough. N is the sample size (number of 
participants on ertugliflozin) assuming 1-3 trough PK samples per participant. 1000 simulations were 
conducted per Scenario, cutoff value, and sample number.
Based on the results presented in Table 15, given a cutoff of 2.0 ng/mL/mg, a sample size of 
20 ertugliflozin participants would provide a <1% chance of incorrectly deciding to drop the 
15 mg dose if the exposure in pediatrics and adults is the same and a 90.9% probability that a 
correct decision to drop the 15 mg dose would be made if the exposure in pediatrics is 
equivalent to 25 mg dose in adults. PK sample collection in Phase 3 may be less well 
controlled, and it is expected that not all planned troughs will be available for the IA due to 
missing samples or sample collection outside of the defined 20-28-hour window. With N=15 
and a cutoff of 2.0 ng/mL/mg, it is expected that a correct decision to drop the 15 mg dose 
would be made 90.0% of the time under the condition that the pediatric exposure was 
1.67 times that in adults.
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10.13 Appendix 13: Tanner Staging 
Tanner Stages of Maturation
In male participants, Tanner Staging will be assessed by testicular volume and pubic hair 
distribution as denoted in the listings below. An orchidometer (Prader) will be used to 
evaluate testicular volume. The testes will be palpated with a gloved hand and the wooden 
ball of the orchidometer that most closely matches the testicular size is determined. For each 
male participant, Tanner Staging will be recorded for both pubic hair and testicular volume. 
When both are Stage V, then no further exam is required.
In female participants, Tanner Staging will be evaluated by the stage of breast development 
and pubic hair distribution as denoted in the listings below. If breast development is 
asymmetrical, the development should be characterized using more advanced stage. 
Additionally, each female participant will be asked at each visit if menarche has occurred and 
this information will be captured at each visit. For each female participant, Tanner Staging 
will be recorded for both pubic hair and breast. When both are Stage V, then no further exam 
is required. 
Pubic hair (both male and female)

Tanner I – none (prepubertal state)

Tanner II – small amount of long, downy hair with slight pigmentation at the base

Tanner III – hair becomes more coarse and curly and begins to extend laterally

Tanner IV – adult-like hair quality, extending across pubis but sparing medial thighs

Tanner V—hair extends to medial surface of the thigh
Genitals (male)

Tanner I – prepubertal (testicular volume less than 4.0 mL; small penis)

Tanner II – testicular volume between 4.0 and 8 mL; skin on scrotum thins, reddens 
and enlarges; penis length unchanged

Tanner III – testicular volume between 9 and 12 mL; scrotum enlarges further; penis 
begins to lengthen

Tanner IV – testicular volume between 15 and 20 mL; scrotum enlarges further and 
darkens; penis increases in length and circumference

Tanner V – testicular volume greater than 20 mL; adult scrotum and penis
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Breast (female)

Tanner I – no glandular tissue; areola follows the skin contours of the chest 
(prepubertal)

Tanner II – breast bud forms, with small area of surrounding glandular tissue; breast 
but within area of areola; areola begins to widen

Tanner III – breast begins to become more elevated, and extends beyond the borders 
of the areola which continues to widen but remains in contour with surrounding 
breast

Tanner IV – increase breast size and elevation; areola and papilla form a secondary 
mound projecting from the contour of the surrounding breast

Tanner V – breast reaches final adult size; areola returns to contour of the 
surrounding breast, with a projecting central papilla
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10.14 Appendix 14: Abbreviations
Abbreviation
Expanded Term
A1C
glycosylated hemoglobin
ADA
American diabetic association
AE
adverse event
AHA
antihyperglycemic agent
ALP
Alkaline phosphatase
ALT
alanine transaminase
ANCOVA
analysis of covariance
APaT
all participants as treated
APRFU
all post-randomization follow-up
AST
aspartate transaminase
AUC
area under the curve
BICR
blinded independent central review
BMI
body mass index
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulation
CI
confidence interval
CL/F
apparent clearance
cLDA
constrained longitudinal data analysis
CMQ
custom MedDRA query
CONSORT
consolidated standards of reporting trials
CSR
clinical study report
CTFG
clinical trial facilitation group
DBP
diastolic blood pressure
DCCT
diabetes control and complications trial
DILI
drug-induced liver injury
DMC
data monitoring committee 
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
ECI
events of clinical interest
eCRF
electronic case report form
EDC
electronic data collection
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ER
excluding data after initiation of glycemic rescue/intensification therapy
ERC
ethics review committee
ESS
Effective Sample Size
EU
European Union
FAS
full analysis set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFSG
fasting fingerstick glucose
FPG
fasting plasma glucose
FS
fingerstick
FSG
fingerstick glucose
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
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Abbreviation
Expanded Term
GLUT1-4
glucose transporters
HA
hypoglycemia assessment
HIV
human immunodeficiency virus
HRT
hormone replacement therapy 
IA
interim analysis
IB
investigator brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee 
IR
including data after initiation of glycemic rescue/intensification therapy
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
J2R
jump to reference
LDL-C
low-density lipoprotein cholesterol
LS
least-squares
M&N
Miettinen and Nurminen
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities 
MI
multiple imputations
MNAR
missing not at random
N/A
not applicable
NGSP
National glycohemoglobin standardization program
NHANES
National Health and Nutrition Examination Survey
NSAE
non-serious adverse event
OGTT
oral glucose tolerance test
Pbo
placebo
PDLC
predefined limits of change
PE
physical exam
PK
pharmacokinetics
qd
once daily
RD
retrieved dropout
REML
restricted (or residual) maximum likelihood
RMSE
root mean squared error
RNA
ribonucleic acid
RTB
return-to-baseline
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SCR
screening
SE
standard error
SGLT1
sodium glucose co-transporter 1
SGLT2
sodium glucose co-transporter 2
SMBG
self-monitoring of blood glucose
SoA
schedule of activities
sSAP
supplemental statistical analysis plan 
SUSAR
suspected unexpected serious adverse reactions
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Abbreviation
Expanded Term
T2DM
type 2 diabetes mellitus
TC
telephone call/telephone contact
TE
treatment effect
TP
treatment policy
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
USA / US
United States of America
UTI
urinary tract infection
WHO
World Health Organization
WI
washout imputation
Wk
week
WOCBP
woman of childbearing potential
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11
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