CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`209803Orig1s000
`209805Orig1s000
`209806Orig1s000
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`
`
`
` CLINICAL REVIEW
`Application Type New Drug Application (NDA)
`Application Number(s) NDA 209803, NDA 209805, and NDA 209806
`Priority or Standard Standard
`
`
`Submit Date(s) December 19, 2016
`Received Date(s) December 19, 2016
`PDUFA Goal Date December 19, 2017
`Division/Office Division of Metabolism and Endocrinology Products (DMEP)
`
`
`Reviewer Name(s) Frank Pucino, PharmD, MPH
`
`
`Established Name NDA 209803: Ertugliflozin
`NDA 209805: Ertugliflozin and Sitagliptin Fixed Combination
`Drug Product (FCDP)
`NDA 209806: Ertugliflozin and Metformin FCDP
`
`
`(Proposed) Trade Name STEGLATRO
`STEGLUJAN
`SEGLUROMET
`
`
`Applicant Merck Sharpe and Dohme Corp.
`
`
`Formulation(s) Ertugliflozin 5 mg and 15 mg tablet
`Ertugliflozin/Sitagliptin FCDP:
`mg/100 mg, and 15 mg/100 mg tablets
`Ertugliflozin/Metformin FCDP: 2.5 mg/500 mg, 2.5 mg/1000 mg,
`7.5 mg/500 mg, and 7.5 mg/1000 mg tablets
`
`
`Dosing Regimen Taken once daily in the morning (STEGLATRO and STEGLUJAN) and
`Taken twice daily with meals (SEGLUROMET)
`
`
`Proposed Indication(s) NDA 209803: As an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus (T2D)
`
`NDA 209805: As an adjunct to diet and exercise to improve
`glycemic control in adults with T2D when treatment with both
`ertugliflozin and sitagliptin is appropriate
`
`NDA 209806: As an adjunct to diet and exercise to improve
`glycemic control in adults with T2D
`
`
` 5
`
`
`
`
`
`1
`
`
`
`Reference ID: 4189412
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`
`
`Intended Population(s) Patients with T2D
`
`
`Recommended Indication(s) NDA 209803: As an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus (T2D)
`
`NDA 209805: As an adjunct to diet and exercise to improve
`glycemic control in adults with T2D when treatment with both
`ertugliflozin and sitagliptin is appropriate
`
`NDA 209806: As an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`
`
`
`
`
`Recommendation on
`Regulatory Action
`
`
`
`
`Approval (pending labeling negotiations)
`
`
`
`
`Reference ID: 4189412
`
`
`
`
`
`2
`
`(b) (4)
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`Table of Contents
`
`Glossary ......................................................................................................................................... 10
`
`1
`
`Executive Summary ............................................................................................................... 16
`
` Product Introduction ...................................................................................................... 16
`
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 17
`
` Benefit-Risk Assessment ................................................................................................ 19
`
` Patient Experience Data ................................................................................................. 25
`
`2
`
`Therapeutic Context .............................................................................................................. 25
`
` Analysis of Condition ...................................................................................................... 25
`
` Analysis of Current Treatment Options ......................................................................... 26
`
`3
`
`Regulatory Background ......................................................................................................... 28
`
` U.S. Regulatory Actions and Marketing History ............................................................. 28
`
`
`
`
`
`Summary of Presubmission/Submission Regulatory Activity ........................................ 31
`
`Foreign Regulatory Actions and Marketing History ....................................................... 35
`
`4
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety................................................................................................................. 35
`
` Office of Scientific Investigations (OSI) .......................................................................... 35
`
` Product Quality .............................................................................................................. 36
`
` Clinical Microbiology ...................................................................................................... 37
`
` Nonclinical Pharmacology/Toxicology ........................................................................... 37
`
` Clinical Pharmacology/Biopharmaceutics ...................................................................... 38
`
` Mechanism of Action/Pharmacodynamics ............................................................. 39
`
` Pharmacokinetics .................................................................................................... 40
`
` Devices and Companion Diagnostic Issues .................................................................... 41
`
` Consumer Study Reviews ............................................................................................... 41
`
`5
`
`Sources of Clinical Data and Review Strategy ....................................................................... 41
`
` Table of Clinical Studies .................................................................................................. 41
`
` Review Strategy .............................................................................................................. 45
`
`6
`
`Review of Relevant Individual Trials Used to Support Efficacy ............................................. 45
`
`
`
`
`Reference ID: 4189412
`
`
`
`
`
`3
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
` Phase 3 Trials .................................................................................................................. 45
`
` Study Designs .......................................................................................................... 45
`
` Inclusion and Exclusion Criteria .............................................................................. 46
`
` Study Treatments .................................................................................................... 47
`
` Administrative Structure of the Ertugliflozin Development Program .................... 49
`
` Protocol Procedures and Schedule ......................................................................... 49
`
` Study Endpoints ...................................................................................................... 52
`
` Statistical Analysis Plan ........................................................................................... 53
`
` Study Results ........................................................................................................... 55
`
`7
`
`Integrated Review of Effectiveness ....................................................................................... 70
`
` Assessment of Efficacy Across Trials .............................................................................. 70
`
` Primary Endpoints ................................................................................................... 70
`
` Secondary and Other Endpoints ............................................................................. 70
`
` Subpopulations ....................................................................................................... 71
`
` Dose and Dose-Response........................................................................................ 71
`
` Onset, Duration, and Durability of Efficacy Effects ................................................ 72
`
` Additional Efficacy Considerations ................................................................................. 72
`
` Considerations on Benefit in the Postmarket Setting ............................................ 72
`
` Other Relevant Benefits .......................................................................................... 72
`
`
`
`Integrated Assessment of Effectiveness ........................................................................ 73
`
`8
`
`Review of Safety .................................................................................................................... 75
`
`
`
`Safety Review Approach ................................................................................................ 75
`
` Review of the Safety Database ...................................................................................... 75
`
` Overall Exposure ..................................................................................................... 75
`
` Relevant characteristics of the safety population: ................................................. 77
`
` Adequacy of the safety database: .......................................................................... 80
`
` Adequacy of Applicant’s Clinical Safety Assessments .................................................... 80
`
` Issues Regarding Data Integrity and Submission Quality ....................................... 80
`
` Categorization of Adverse Events ........................................................................... 80
`
` Routine Clinical Tests .............................................................................................. 82
`
`
`
`
`Reference ID: 4189412
`
`
`
`
`
`4
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`
`
`
`
`
`Safety Results ................................................................................................................. 82
`
` Deaths ..................................................................................................................... 84
`
` Serious Adverse Events ........................................................................................... 86
`
` Dropouts and/or Discontinuations Due to Adverse Effects ................................... 96
`
` Significant Adverse Events .................................................................................... 101
`
` Treatment Emergent Adverse Events and Adverse Reactions ............................. 101
`
` Laboratory Findings .............................................................................................. 107
`
` Vital Signs .............................................................................................................. 122
`
` Electrocardiograms (ECGs) .................................................................................... 124
`
` QT .......................................................................................................................... 124
`
`
`
`Immunogenicity ............................................................................................. 124
`
` Analysis of Submission-Specific Safety Issues .............................................................. 125
`
` Malignancies ......................................................................................................... 125
`
` Osmotic Diuresis ................................................................................................... 129
`
` Volume Depletion ................................................................................................. 129
`
` Renal Failure/Impairment ..................................................................................... 130
`
` Genital Infections .................................................................................................. 130
`
` Urinary Tract Infections ........................................................................................ 131
`
` Hypoglycemia ........................................................................................................ 133
`
` Bone Safety / Fractures......................................................................................... 135
`
` Adjudicated Hepatic Events .................................................................................. 137
`
`
`
`
`
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`
`
`Adjudicated Pancreatitis Events .................................................................... 138
`
`Hypersensitivity Reactions ............................................................................ 139
`
`Venous Thromboembolism ........................................................................... 142
`
`Ketoacidosis ................................................................................................... 143
`
`Lower Limb Amputations and Peripheral Revascularization Procedures ..... 146
`
`Cardiovascular Safety .................................................................................... 149
`
`Other AEs Associated with DPP-4 Inhibitors and SGLT2 Inhibitors ............... 150
`
`
`
`Specific Safety Studies/Clinical Trials ........................................................................... 150
`
` Additional Safety Explorations ..................................................................................... 150
`
` Human Carcinogenicity or Tumor Development .................................................. 150
`
`
`
`
`
`5
`
`Reference ID: 4189412
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
` Human Reproduction and Pregnancy ................................................................... 151
`
` Pediatrics and Assessment of Effects on Growth ................................................. 152
`
` Overdose, Drug Abuse Potential, Withdrawal, and Rebound .............................. 153
`
`
`
`Safety in the Postmarket Setting.................................................................................. 154
`
` Safety Concerns Identified Through Postmarket Experience ............................... 154
`
` Expectations on Safety in the Postmarket Setting ............................................... 154
`
` Additional Safety Issues from Other Disciplines .......................................................... 154
`
`
`
`Integrated Assessment of Safety .............................................................................. 158
`
`9 Advisory Committee Meeting and Other External Consultations ....................................... 159
`
`10 Labeling Recommendations ................................................................................................ 159
`
`
`
`
`
`
`
`Prescribing Information ............................................................................................ 159
`
`Patient Labeling ........................................................................................................ 162
`
`Non-Prescription Labeling ........................................................................................ 162
`
`11 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 162
`
`
`
`
`
`
`
`Safety Issue(s) that Warrant Consideration of a REMS ............................................ 162
`
`Conditions of Use to Address Safety Issue(s) ........................................................... 162
`
`Recommendations on REMS .................................................................................... 162
`
`12 Postmarketing Requirements and Commitments ............................................................... 163
`
`13 Appendices .......................................................................................................................... 164
`
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`References ................................................................................................................ 164
`
`Antihyperglycemic Products Approved in the United States ................................... 177
`
`Study Designs for the Relevant Phase 3 Trials ......................................................... 226
`
`Adverse Events of Special Interest (System/Custom MedDRA Queries) ................. 233
`
`Custom Query of AEs/Laboratory Assessments of Renal Impairment ..................... 258
`
`Hypoglycemic Events in the Phase 3 Clinical Program ............................................. 260
`
`Case Definitions of Ketoacidosis ............................................................................... 262
`
`Subjects with Lower Limb Amputations ................................................................... 263
`
`Narrative Summaries and Graphical Profiles of Subjects with Amputations ........... 266
`
` Follow-Up-Adjusted Incidence Rate of Amputations (Trial P004/1021) .................. 290
`
`
`
`
`Reference ID: 4189412
`
`
`
`
`
`6
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`Table of Tables
`
`
`Table 1: Approved Therapeutic Options for the Management of Type 2 Diabetes Mellitus ....... 28
`Table 2: Summary of Relevant Presubmission/Submission Regulatory History .......................... 31
`Table 3: Listing of Phase 3 Clinical Trials Relevant to this NDA .................................................... 42
`Table 4: Summary of Key Inclusion and Exclusion Criteria by Phase 3 Trial ................................. 46
`Table 5: Criteria for Initiation of Antihyperglycemic Rescue Therapy .......................................... 51
`Table 6: Cumulative Trial Disposition (Randomized Population)* ............................................... 56
`Table 7: Demographics, Clinical Characteristics and Concomitant Medications (Phase 3 Trials) 58
`Table 8: HbA1c Change from Baseline (FAS, Excluding Rescue Approach) Trial P001/1016........ 61
`Table 9: HbA1c Change from Baseline Analyses (Phase 3 Trials) ................................................. 62
`Table 10: Applicant’s Reanalysis (RTB) of Key Secondary Endpoints (Change from Baseline)..... 65
`Table 11: Pooled Analysis of Mean Change in HbA1c from Baseline to Week 26 ─ Placebo-
`Controlled Trials (P003/1022, P007/1017, and P006/1015) ........................................................ 70
`Table 12: Integrated Safety Populations, Size and Duration of Exposure (Placebo, 4-MSU and
`Ertu/Met Pools) ............................................................................................................................. 76
`Table 13: Ertugliflozin/Sitagliptin FDCP Safety Population, Size and Duration of Exposure (Trials
`P005/1019, P006/1015, and P017/1047) ..................................................................................... 77
`Table 14: Demographics and Clinical Characteristics (Broad Pool)* ............................................ 78
`Table 15: Summary of Adverse Events (Placebo and Broad Pools) .............................................. 83
`Table 16: Subjects with Fatal Adverse Events (4-MSU) ................................................................ 84
`Table 17: Summary of Serious Adverse Events (Placebo Pool) .................................................... 86
`Table 18: Summary of Non-Fatal Serious Adverse Events by System Organ Class (4-MSU) ........ 89
`Table 19: Summary of Discontinuations Due to Adverse Events (4-MSU) ................................... 97
`Table 20: Summary of Applicant’s Common TEAEs (Placebo Pool) ............................................ 101
`Table 21: Summary of Common TEAEs (Placebo Pool) .............................................................. 102
`Table 22: Analysis of SOCs with a Higher Incidence in the Ertugliflozin Treatment Arms (Placebo
`Pool) ............................................................................................................................................ 104
`Table 23: Summary of Common TEAEs (4-MSU) ........................................................................ 106
`Table 24: Summary of Predefined Laboratory Limits of Change (Placebo and Broad Pools) .... 108
`Table 25: Summary of Treatment-Emergent Renal Adverse Events (4-MSU) ............................ 115
`Table 26: PTH and Bone Biomarker Changes from Baseline (Trials P001/1016 and P007/1017)
`..................................................................................................................................................... 118
`Table 27: Percent Lipid (mg/dL) Changes from Baseline to Week 26 (Placebo Pool) ................ 120
`Table 28: Subjects with Adverse Events of Dyslipidemia (Placebo Pool and 4-MSU) ................ 121
`Table 29: Vital Sign Changes from Baseline to Week 26 (Placebo Pool)* .................................. 122
`Table 30: Subjects with Adverse Events of Abnormal Vital Signs (Placebo Pool and 4-MSU) ... 123
`Table 31: Summary of Malignancies and Premalignant Conditions (4-MSU) ............................ 126
`Table 32: Summary of Volume Depletion Related Adverse Events (4-MSU) ............................. 130
`Table 33: Summary of Urinary Tract Infections and Related Adverse Events (4-MSU) ............. 132
`Table 34: Summary of Hypoglycemic Events (Placebo Pool)* .................................................... 133
`Table 35: Summary of Hypoglycemia Related Adverse Events (4-MSU) .................................... 134
`
`
`
`
`Reference ID: 4189412
`
`
`
`
`
`7
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`Table 36: Summary of Confirmed Fractures (4-MSU) ................................................................ 136
`Table 37: Summary of Hypersensitivity Adverse Effects (4-MSU) .............................................. 140
`Table 38: Subjects with Amputations (All Subjects As Treated*) ............................................... 148
`Table 39: Active and Ongoing Tracked Safety Issues for SGLT2 Inhibitors and DPP-4 Inhibitors
`..................................................................................................................................................... 155
`Table 40: Nephrolithiasis and Related Adverse Events (4-MSU) ................................................ 156
`Table 41: Adverse Outcomes from Trial P001/1016 and 4-MSU for Subjects with an eGFR <60
`mL/min/1.73 m2 .......................................................................................................................... 161
`Table 42: Summary Table of Approved Antihyperglycemic Products ........................................ 177
`Table 43: Renal Impairment AEs and Laboratory Assessments (Placebo and Broad Pools) ...... 258
`Table 44: Documented and Severe Hypoglycemia in Individual Phase 3 Trials ......................... 260
`Table 45: Case Definitions for the Diagnosis of Ketoacidosis ..................................................... 262
`Table 46: Amputations (4-MSU): n=11 Ertugliflozin vs. n=1 Non-Ertugliflozin .......................... 263
`Table 47: Subjects with Amputations (All Post-Randomization Follow-up*) ............................. 290
`
`
`
`
`Reference ID: 4189412
`
`
`
`
`
`8
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`Table of Figures
`
`
`Figure 1: LS Mean Change in HbA1c from Baseline to Week 52 (cLDA)* ..................................... 68
`Figure 2: Mean (SD) Changes from Baseline to Week 26 in Hemoglobin and Hematocrit (Placebo
`Pool) ............................................................................................................................................ 111
`Figure 3: Mean (SD) Changes from Baseline to Week 26 in Serum Electrolytes (Placebo Pool) 113
`Figure 4: Mean (SD) Changes from Baseline to Week 26 in Serum Creatinine and Estimated
`Glomerular Filtration Rate (Placebo Pool) .................................................................................. 114
`Figure 5: Study Design of Trial P003/1022.................................................................................. 226
`Figure 6: Study Design of Trial P007/1017.................................................................................. 227
`Figure 7: Study Design of Trial P006/1015.................................................................................. 228
`Figure 8: Study Design of Trial P002/1013.................................................................................. 229
`Figure 9: Study Design of Trial P005/1019.................................................................................. 230
`Figure 10: Study Design of Trial P017/1047................................................................................ 231
`Figure 11: Study Design of Trial P001/1016................................................................................ 232
`Figure 12: Graphical Patient Profile of Subject 0200351 (Non-Ertugliflozin Arm) ..................... 267
`Figure 13: Graphical Patient Profile of Subject 0200632 (Ertugliflozin 5 mg Arm) .................... 269
`Figure 14: Graphical Patient Profile of Subject 0600812 (Ertugliflozin 5 mg Arm) .................... 271
`Figure 15: Graphical Patient Profile of Subject 0710151 (Ertugliflozin 5 mg Arm) .................... 273
`Figure 16: Graphical Patient Profile of Subject 0101246 (Ertugliflozin 15 mg Arm) .................. 275
`Figure 17: Graphical Patient Profile of Subject 0102405 (Ertugliflozin 15 mg Arm) .................. 277
`Figure 18: Graphical Patient Profile of Subject 0102476 (Ertugliflozin 15 mg Arm) .................. 279
`Figure 19: Graphical Patient Profile of Subject 0102483 (Ertugliflozin 15 mg Arm) .................. 281
`Figure 20: Graphical Patient Profile of Subject 0201036 (Ertugliflozin 15 mg Arm) .................. 283
`Figure 21: Graphical Patient Profile of Subject 0500303 (Ertugliflozin 15 mg Arm) .................. 285
`Figure 22: Graphical Patient Profile of Subject 0710088 (Ertugliflozin 15 mg Arm) .................. 287
`Figure 23: Graphical Patient Profile of Subject 0710319 (Ertugliflozin 15 mg Arm) .................. 289
`
`
`
`
`Reference ID: 4189412
`
`
`
`
`
`9
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`Glossary
`
`4-MSU
`AACE
`
`AC
`
`ACE
`
`ACEI
`
`ACP
`
`ADA
`
`AE
`
`AESI
`
`AHA
`
`AKI
`
`ALP
`
`ALT
`
`ANCOVA
`ARB
`
`ASaT
`
`AST
`
`AUC
`
`B-CELL
`BE
`
`BID
`
`BILI
`
`BL
`
`BMD
`
`BMI
`
`BPCA
`
`BPM
`
`BUN
`
`BW
`
`Ca
`
`CAC
`
`CANVAS
`CANVAS-R
`CDC
`
`CDER
`
`CEC
`
`CFR
`
`
`
`
`
`Reference ID: 4189412
`
`4-Month Safety Update
`American Association of Clinical Endocrinologists
`Advisory Committee
`American College of Endocrinology
`Angiotensin Converting Enzyme Inhibitor
`American College of Physicians
`American Diabetes Association
`Adverse Event
`Adverse Event of Special Interest
`Antihyperglycemic Agent
`Acute Kidney Injury
`Alkaline Phosphatase
`Alanine Aminotransferase
`Analysis of Covariance
`Angiotensin Receptor Blocker
`All Subjects As Treated
`Aspartate Aminotransferase
`Area-Under-the-Curve
`Beta-Cell
`Bioequivalence
`Twice Daily (‘Bis in Die’)
`Bilirubin
`Baseline
`Bone Mineral Density
`Body Mass Index
`Best Pharmaceuticals for Children Act
`Beats Per Minute
`Blood Urea Nitrogen
`Body Weight
`Calcium
`Clinical Adjudication Committee
`Canagliflozin Cardiovascular Assessment Study
`Study of the Effects of Canagliflozin on Renal Endpoints
`Center for Disease Control and Prevention
`Center for Drug Evaluation and Research
`Clinical Events Committee
`Code of Federal Regulations
`
`
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`
`
`10
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`
`CI
`
`CK
`
`CKD
`
`CL/F
`
`cLDA
`
`CMAX
`
`CMC
`
`CMQ
`
`CO2
`
`CrCl
`CREAT
`CRF
`
`CRP
`
`CRRT
`
`CRT
`
`CSR
`
`CT
`
`CV
`
`CVD
`
`CVMA
`CVOT
`
`CYP3A4/5
`DBP
`
`DCCT
`
`DKA
`
`DMC
`
`DMF
`
`DPP-4
`Dx
`
`DXA
`
`EASD
`
`EC
`
`eCRF
`
`ECG
`
`eGFR
`
`EMA
`
`ER
`
`ERTU
`
`ERCP
`
`ESRD
`
`EU
`
`FAERS
`
`
`
`
`Reference ID: 4189412
`
`Confidence Interval
`Creatine Kinase
`Chronic Kidney Disease
`Clearance/Fraction
`Constrained Longitudinal Data Analysis
`Maximum Plasma Concentration
`Chemistry, Manufacturing, and Controls
`Custom MedDRA Query
`Total Carbon Dioxide (Bicarbonate)
`Creatinine Clearance
`Creatinine
`Case Report Form
`C-Reactive Protein
`Continuous Renal Replacement Therapy
`Clinical Review Template
`Clinical Study Report
`Computerized Tomography
`Cardiovascular
`Cardiovascular Disease
`Cardiovascular Meta-Analysis
`Cardiovascular Outcomes Trial
`Cytochrome P450 3A4/5
`Diastolic Blood Pressure
`Diabetes Control and Complication Trial
`Diabetic Ketoacidosis
`Data Monitoring Committee
`Drug Master File
`Dipeptidyl Peptidase-4
`Diagnosis
`Dual-Energy X-Ray Absorptiometry
`European Association for the Study of Diabetes
`Ethics Committee
`Electronic Case Report Form
`Electrocardiogram
`Estimated Glomerular Filtration Rate
`European Medicines Agency
`Emergency Room
`Ertugliflozin
`Endoscopic Retrograde Cholangiopancreatography
`End Stage Renal Disease
`European Union
`FDA Adverse Event Reporting System
`
`
`
`
`
`11
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`
`FAS
`
`FBG
`
`FCDP
`
`FDA
`FDAAA
`FDASIA
`FDCA
`
`FEV
`
`FPG
`
`G6PD
`
`GAD
`
`GCP
`
`GI
`
`GIP
`
`GLIM
`
`GLP-1
`GM
`
`HbA1c
`HCl
`
`HCO3
`
`HCT
`
`HDL-C
`Hgb
`
`HLGT
`
`HLT
`
`hOAT-3
`Hx
`
`ICH
`
`ICRC
`
`IM
`
`IND
`
`INF
`
`INR
`
`IP
`
`iPSP
`
`IRB
`
`ISE
`
`ISS
`
`IU
`
`ITT
`
`IV
`
`IVRS
`
`
`
`
`
`Reference ID: 4189412
`
`Full Analysis Set
`Fasting Blood Glucose
`Fixed Combination Drug Product
`Food and Drug Administration
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`Food Drug and Cosmetic Act
`Forced Expiratory Volume
`Fasting Plasma Glucose
`Glucose-6-Phosphate Dehydrogenase
`Glutamic Acid Decarboxylase
`Good Clinical Practice
`Gastrointestinal
`Glucose-Dependent Insulinotropic Polypeptide
`Glimepiride
`Glucagon-Like Peptide-1
`Geometric Mean
`Hemoglobin A1c (Glycosylated Hemoglobin)
`Hydrochloride
`Bicarbonate
`Hematocrit
`High-Density Lipoprotein Cholesterol
`Hemoglobin
`High Level Group Term
`High Level Term
`Human Organic Anion Transporter-3
`History
`International Conference on Harmonization
`Internal Case Review Committee
`Intramuscular
`Investigational New Drug
`Infinity
`International Normalized Ratio
`Investigational Product
`Initial Pediatric Study Plan
`Institutional Review Board
`Integrated Summary of Effectiveness
`Integrated Summary of Safety
`International Unit
`Intent-to-treat
`Intravenous
`Interactive Voice Response System
`
`
`
`
`
`12
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209803 (Ertugliflozin) / NDA 209805 (Ertugliflozin/Sitagliptin FCDP) / NDA 209806
`(Ertugliflozin/Metformin FCDP)
`
`
`
`Integrated Web Response System
`
`IWRS
`Juvenile Diabetes Research Foundation
`
`JDRF
`Potassium
`
`K
`Lactate Dehydrogenase
`
`LDH
`Low-Density Lipoprotein Cholesterol
`
`LDL-C
`Lower Limit of Normal
`
`LLN
`L-pyroglutamic acid
`
`LPGA
`Lymphocyte
`Lymph
`Major Adverse Cardiovascular Events
`MACE
`Mean Corpuscular Hemoglobin
`MCH
`
`Mean Corpuscular Hemoglobin Concentration
`MCHC
`Mean Corpuscular Volume
`MCV
`
`Modification in Diet and Renal Disease
`MDRD
`Medical Dictionary for Regulatory Activities
`MedDRA
`Multiple Endocrine Neoplasia Syndrome Type 2
`MEN2
`Metformin
`MET
`
`Magnesium
`Mg
`
`MHDECODE Medical History Decode
`MI
`
`Myocardial Infarction
`MMTT
`Mixed Meal Tolerance Test
`MRHD
`Maximum Recommended Human Dose
`MTC
`
`Medullary Thyroid Carcinoma
`NA
`
`Sodium
`NCI-CTCAE
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`NCT
`
`National Clinical Trial
`NDA
`
`New Drug Application
`NGS