Ertugliflozin Type 2 Diabetes Mellitus (T2DM) Pediatric Study (MK-8835/PF-04971729) (MK-8835-059)

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of ertugliflozin (MK-8835) in pediatric participants with T2DM on metformin with/without insulin. The primary hypothesis of the study is that the addition of ertugliflozin reduces hemoglobin A1C (HbA1C) more than the addition of placebo after 24 weeks of treatment.

Official Title
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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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ertugliflozin 5 mg
* Drug: Ertugliflozin 15 mg
* Drug: Placebo to ertugliflozin 15 mg
* Drug: Placebo to ertugliflozin 5 mg
* Biological: Insulin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has diabetes diagnosed by one of the American Diabetes Association (ADA) criteria. Has body mass index (BMI) ≥85th percentile at screening OR participant has a history of being overweight or obese at time of diagnosis of Type 2 diabetes mellitus (T2DM). T2DM for ≥2 years, OR T2DM for <2 years and a fasting C-peptide value >0.6 ng/mL at Screening. On stable metformin monotherapy (≥1500 mg/day, for ≥8 weeks prior to Screening, OR on a stable metformin dose (≥1500 mg/day, for ≥8 weeks prior to Screening and a stable dose of insulin for ≥8 weeks prior to Screening. Contraceptive use by male participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Is a non-sterilized female who is currently not sexually active OR who agrees to abstain from heterosexual activity OR who agrees to start contraception prior to initiating sexual activity and who agrees to use an adequate method of contraception. Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 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. Exclusion Criteria: Has known type 1 diabetes mellitus or documented evidence of positive diabetes autoantibodies performed when participant was diagnosed with diabetes. Has known monogenic diabetes, or secondary diabetes. Has symptomatic hyperglycemia and/or moderate to large ketonuria requiring immediate initiation of another antihyperglycemic agent, including insulin. Has a known hypersensitivity or intolerance to any sodium glucose co-transporter 2 (SGLT2) inhibitor. 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. Has previously taken an SGLT2 inhibitor (such as canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin) or was enrolled in a study for these agents. Has a history of idiopathic acute pancreatitis or chronic pancreatitis. Has a history of severe hypoglycemia while on insulin.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertugliflozin 5 mg/5 mg<br>All participants will initially receive ertugliflozin (ERTU) 5 mg once daily (QD) and placebo to ERTU 15 mg QD for 12 weeks. At the second randomization at Week 12 (WK12), all participants that do not meet the up-titration criteria will remain on ERTU 5 mg and placebo to ERTU 15 mg from WK12 to WK54. Approximately half the participants who meet the up-titration criteria at the second randomization at WK12 will also remain on ERTU 5 mg and placebo to ERTU 15 mg from WK12 to WK54. Note: For participants not on insulin, the up-titration criterion at the second randomization at WK12 is HbA1C ≥7.0% (53 mmol/mol) and for participants on insulin, a fasting fingerstick glucose (FFSG) of ≥110 mg/dL (6.1 mmol/L) will be required in addition to HbA1C ≥7.0% (53 mmol/mol). Participants will remain on their background metformin with/without insulin treatment throughout the study. | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin 5 mg, oral, 1 tablet QD<br>* Other names: MK-8835;Drug: Placebo to ertugliflozin 15 mg<br>* Placebo to ertugliflozin 15 mg, oral, 1 tablet QD<br>Biological: Insulin<br>* The initiation and titration of insulin will be at the discretion of the investigator, based on local/regional/country guidelines.<br>Drug: Metformin<br>* Participants will receive stable dose of background metformin.<br>|
| Experimental: Ertugliflozin 5 mg/15 mg<br>All participants will initially receive ERTU 5 mg QD and placebo to ERTU 15 mg QD for 12 weeks. At the second randomization at WK12, approximately half the participants who meet the up-titration criteria at the second randomization will up-titrate to ERTU 15 mg and placebo to ERTU 5 mg from WK12 to WK54. Note: For participants not on insulin, the up-titration criterion at the second randomization at WK12 is HbA1C ≥7.0% (53 mmol/mol) and for participants on insulin, a FFSG of ≥110 mg/dL (6.1 mmol/L) will be required in addition to HbA1C ≥7.0% (53 mmol/mol). Participants will remain on their background metformin with/without insulin treatment throughout the study. | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin 5 mg, oral, 1 tablet QD<br>* Other names: MK-8835;Drug: Ertugliflozin 15 mg<br>* Ertugliflozin 15 mg, oral, 1 tablet QD<br>* Other names: MK-8835;Drug: Placebo to ertugliflozin 15 mg<br>* Placebo to ertugliflozin 15 mg, oral, 1 tablet QD<br>Drug: Placebo to ertugliflozin 5 mg<br>* Placebo to ertugliflozin 5 mg, oral, 1 tablet QD<br>Biological: Insulin<br>* The initiation and titration of insulin will be at the discretion of the investigator, based on local/regional/country guidelines.<br>Drug: Metformin<br>* Participants will receive stable dose of background metformin.<br>|
| Placebo Comparator: Placebo<br>At the first randomization, participants receive placebo to ERTU 5 mg and placebo to ERTU 15 mg QD for 12 weeks. Participants in the placebo group with HbA1C ≥7.0% (53 mmol/mol) at WK12 will be mock titrated. Note: The up-titration criteria for participants on insulin will include a FFSG of ≥110 mg/dL (6.1 mmol/L) in addition to HbA1C ≥7.0% (53 mmol/mol) at WK12. Participants will continue to receive placebo to ERTU 5 mg and placebo to ERTU 15 mg QD from WK24 to WK54. Participants will remain on their background metformin with/without insulin treatment throughout the study. | Drug: Placebo to ertugliflozin 15 mg<br>* Placebo to ertugliflozin 15 mg, oral, 1 tablet QD<br>Drug: Placebo to ertugliflozin 5 mg<br>* Placebo to ertugliflozin 5 mg, oral, 1 tablet QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Hemoglobin A1C (HbA1C) at 24 weeks (pooled ertugliflozin 5 mg and 15 mg versus placebo) | Hemoglobin A1C is a measure of the percentage of glycated HbA1C in the blood. Participant whole blood samples are collected at baseline and Week 24 to determine the least squares mean HbA1C change from baseline (i.e., HbA1C at Week 24 minus HbA1C at baseline). | Baseline and 24 weeks | 
| Number of Participants Who Experience an Adverse Event (AE) | An adverse event is defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. | Up to 24 weeks | 
| Number of Participants Who Experience an AE | An adverse event is defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. | Up to 54 weeks | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An adverse event is defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. | Up to 24 weeks | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An adverse event is defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. | Up to 54 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Hemoglobin A1C at Week 24 (dose-optimized ertugliflozin versus placebo) | Hemoglobin A1C is a measure of the percentage of glycated HbA1C in the blood. Participant whole blood samples are collected at baseline and Week 24 to determine the least squares mean HbA1C change from baseline (i.e., HbA1C at Week 24 minus HbA1C at baseline). | Baseline and 24 weeks | 
| Change from Baseline in Hemoglobin A1C at Week 24 (ertugliflozin 5 mg versus placebo) | Hemoglobin A1C is a measure of the percentage of glycated HbA1C in the blood. Participant whole blood samples are collected at baseline and Week 24 to determine the least squares mean HbA1C change from baseline (i.e., HbA1C at Week 24 minus HbA1C at baseline). | Baseline and 24 weeks | 
| Change from Baseline in Fasting Plasma Glucose (FPG) at 24 Weeks | Blood glucose is measured on a fasting basis. FPG is expressed as mg/dL. Blood is drawn at predose on Day 1 and after 24 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 24 minus FPG at baseline). | Baseline and 24 weeks | 
| Change from Baseline in Hemoglobin A1C at 54 Weeks | Hemoglobin A1C is a measure of the percentage of glycated HbA1C in the blood. Participant whole blood samples are collected at baseline and Week 54 to determine the least squares mean HbA1C change from baseline (i.e., HbA1C at Week 54 minus HbA1C at baseline). | Baseline and 54 weeks | 
| Change from Baseline in FPG at 54 Weeks | Blood glucose is measured on a fasting basis. FPG is expressed as mg/dL. Blood is drawn at predose on Day 1 and after 54 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 54 minus FPG at baseline). | Baseline and 54 weeks |