Study to Assess Safety & Efficacy of Sitagliptin as Initial Oral Therapy for Treatment of Type 2 Diabetes Mellitus in Pediatric Participants. (MK-0431-083)

Study Overview
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Brief Summary
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The purpose of the study is to assess the safety of the addition of sitagliptin, and its effect on hemoglobin A1c (A1C) in pediatric participants 10-17 years of age with type 2 diabetes mellitus (T2DM) with inadequate glycemic control. The primary hypothesis for this study is that sitagliptin reduces A1C more than placebo after 20 weeks of treatment.

Detailed Description
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This trial is of approximately 56 weeks in duration, including a screening period of up to 1 week, a 1-week single-blind placebo run-in period, a 20-week placebo-controlled, double blind treatment period [Phase A] and a 34-week double-blind active controlled treatment period [Phase B] during which participants randomized to the placebo arm who have not initiated glycemic rescue therapy with metformin during Phase A will receive metformin (in a blinded manner). A telephone contact will be performed 14 days after the last dose of study medication to assess for any serious adverse events (SAEs). Participants enrolled in the metformin and placebo/sitagliptin arms prior to implementation of Protocol Amendment 05 completed the study on their original treatment assignments. EUPASS4468 is a follow-up, non-interventional, observational assessment of safety of participants who participated in the MK-0431-083 study for up to 5 years.

Official Title
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A Phase III, Multicenter, Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Sitagliptin in Pediatric Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control

Conditions
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Diabetes Mellitus, Type 2 Diabetes

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Metformin
* Drug: Placebo to sitagliptin
* Drug: Placebo to metformin
* Drug: Glycemic Rescue 1
* Biological: Glycemic Rescue 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes Mellitus (T2DM) Has not received treatment with an antihyperglycemic agent (AHA) for ≥12 weeks prior to the Screening Visit/Visit 1, or is on a stable dose of insulin (without any other AHA) for at least 12 weeks prior to the Screening Visit/Visit 1. At screening, participants on insulin doses that are not stable can have their insulin doses adjusted and be eligible to participate after their dose remains stable for ≥12 weeks, if they meet all other eligibility criteria. In India, only participants on stable doses of insulin will be eligible. An A1C of ≥6.5% and ≤10.0% (For participants on insulin: an A1C ≥7.0% and ≤10.0%). Exclusion Criteria: History of type 1 diabetes mellitus, autoimmune diabetes mellitus or has a positive antibody screen for anti-GAD (Glutamic Acid Decarboxylase) or (Islet cell autoantigen) ICA-512. Known monogenic diabetes, secondary diabetes, or a genetic syndrome or disorder known to affect glucose tolerance other than diabetes. Symptomatic hyperglycemia and/or moderate to large ketonuria and/or positive test for ketonemia requiring immediate initiation of antihyperglycemic therapy. Previously taken a DPP-4 (Dipeptidyl peptidase-4) inhibitor (such as sitagliptin, vildagliptin, alogliptin, or saxagliptin) or GLP-1 (Glucagon-like peptide-1) receptor agonist (such as exenatide or liraglutide). Hypersensitivity or contraindication (according to the product circular in the country of the investigational site) to metformin. Chronic treatment with a medication known to cause weight gain within 30 days of study start or weight loss or increased blood glucose within 8 weeks of study start or treated with an anti-psychotic within the past 12 weeks. On a weight loss program and not in the maintenance phase or have undergone bariatric surgery within 12 months prior to study start. On or likely to require treatment with ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids. Undergone a surgical procedure within the prior 4 weeks or has major surgery planned during the study. History of congenital heart disease or cardiovascular disease other than hypertension. Medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease. Active nephropathy (i.e., nephrotic syndrome or glomerulonephritis). Chronic myopathy, mitochondrial disorder, or a progressive neurological or neuromuscular disorder (e.g., polymyositis, or multiple sclerosis). Human immunodeficiency virus (HIV) as assessed by medical history. Clinically significant hematological disorder (such as aplastic anemia, thrombocytopenia, myeloproliferative or myelodysplastic syndrome). Under treatment for hyperthyroidism. Exhibits abnormal growth patterns or is being treated with growth hormone. History of malignancy or clinically important hematologic disorder. History of idiopathic acute pancreatitis or chronic pancreatitis. Known history of recreational or illicit drug use, or of alcohol abuse or dependence (within the past year). 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 products within the projected duration of the study. Pregnant, has a positive urine pregnancy test at Screening Visit/Visit 1, is expecting to conceive within the projected duration of the study, or is breast-feeding. Exclusionary laboratory values.

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin<br>Participants will receive 1 tablet of sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will continue to receive 1 tablet of sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 20-54. | Drug: Sitagliptin<br>* Sitagliptin 100 mg tablet administered orally once daily<br>* Other names: Januvia®, Tesavel®, Xelevia®, Ristaben®, Glactiv®;Drug: Placebo to metformin<br>* Matching placebo to metformin 500 mg tablets, 2 tablets administered orally twice daily<br>Drug: Glycemic Rescue 1<br>* Participants in the sitagliptin arm who require glycemic rescue will receive metformin during Weeks 0-20 and Weeks 20-54. Participants in the placebo arm who require glycemic rescue will receive metformin during Weeks 0-20. Participants in the placebo arm who have switched to metformin during Weeks 20-54 and require glycemic rescue will receive sitagliptin.<br>Biological: Glycemic Rescue 2<br>* Participants who require glycemic rescue after Glycemic Rescue 1 will receive open-label insulin. Participants on background insulin therapy will have the dose of their background insulin up-titrated.<br>|
| Placebo Comparator: Placebo/Metformin<br>Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of metformin 500 mg prior to both the morning and evening meals during Weeks 20-54. | Drug: Metformin<br>* Metformin 500 mg tablets administered orally starting at 500 mg/day and uptitrated by 500 mg every week to a final dose of 1000 mg twice daily<br>* Other names: Glucophage®, Metgluco®, Glycoran®;Drug: Placebo to sitagliptin<br>* Matching placebo to sitagliptin 100 mg tablet administered orally once daily<br>Drug: Placebo to metformin<br>* Matching placebo to metformin 500 mg tablets, 2 tablets administered orally twice daily<br>Drug: Glycemic Rescue 1<br>* Participants in the sitagliptin arm who require glycemic rescue will receive metformin during Weeks 0-20 and Weeks 20-54. Participants in the placebo arm who require glycemic rescue will receive metformin during Weeks 0-20. Participants in the placebo arm who have switched to metformin during Weeks 20-54 and require glycemic rescue will receive sitagliptin.<br>Biological: Glycemic Rescue 2<br>* Participants who require glycemic rescue after Glycemic Rescue 1 will receive open-label insulin. Participants on background insulin therapy will have the dose of their background insulin up-titrated.<br>|
| Active Comparator: Metformin<br>Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will continue to receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of metformin 500 mg prior to both the morning and evening meals during Weeks 20-54. | Drug: Metformin<br>* Metformin 500 mg tablets administered orally starting at 500 mg/day and uptitrated by 500 mg every week to a final dose of 1000 mg twice daily<br>* Other names: Glucophage®, Metgluco®, Glycoran®;|
| Placebo Comparator: Placebo/Sitagliptin<br>Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will receive 1 tablet of sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 20-54. | Drug: Sitagliptin<br>* Sitagliptin 100 mg tablet administered orally once daily<br>* Other names: Januvia®, Tesavel®, Xelevia®, Ristaben®, Glactiv®;Drug: Placebo to sitagliptin<br>* Matching placebo to sitagliptin 100 mg tablet administered orally once daily<br>Drug: Placebo to metformin<br>* Matching placebo to metformin 500 mg tablets, 2 tablets administered orally twice daily<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 (A1C) at Week 20 | Glycated hemoglobin (A1C) is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Change from baseline was estimated as the Week 20 A1C minus the Week 0 A1C. | Baseline and Week 20 | 
| Baseline Glycated Hemoglobin (A1C) for the Placebo (Pooled) Arm | A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The Placebo (pooled) arm was a pooling of the Placebo/Metformin and Placebo/Sitagliptin arms for analysis purposes. | Baseline | 
| Change From Baseline In A1C at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled)) | Glycated hemoglobin (A1C) is a blood marker used to report average blood glucose levels over time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Mean change from baseline was estimated as the Week 20 A1C minus the Week 0 A1C from a longitudinal data analysis (LDA) model. The placebo arm in this comparison is a pooling of the Placebo/Metformin and Placebo/Sitagliptin arms. The Statistical Analysis Plan (SAP) did not specify for the Metformin arm to be included in statistical comparisons, so results for this arm are provided separately. | Baseline and Week 20 | 
| Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56 | The number of participants experiencing ≥1 adverse event during Weeks 0-56 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to Week 56 | 
| Percentage of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56 (Analysis of Selected Arms: Sitagliptin and Placebo/Metformin) | The number of participants experiencing ≥1 adverse event during Weeks 0-56 was reported. An adverse event is any untoward medical occurrence in a person administered a pharmaceutical product and does not have to have a causal relationship with this treatment. The SAP did not specify for the Metformin arm to be included in statistical comparisons, so results for this arm are provided separately. | Up to Week 56 | 
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event During Weeks 0-54 | The number of participants who discontinued from study drug due to an adverse event during Weeks 0-54 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to Week 54 | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event During Weeks 0-54 (Analysis of Selected Arms: Sitagliptin and Placebo/Metformin) | The percentage of participants who discontinued from study drug due to an adverse event during Weeks 0-54 was reported. An adverse event is any untoward medical occurrence in a person administered a pharmaceutical product and does not have to have a causal relationship with this treatment. The SAP did not specify for the Metformin arm to be included in statistical comparisons, so results for this arm are provided separately. | Up to Week 54 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in A1C at Week 54 | A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. This change from baseline reflects the Week 54 A1C minus the Week 0 A1C. | Baseline and Week 54 | 
| Percentage of Participants With A1C at Goal (<7.0%) at Week 20 | The percentage of participants with A1C at goal (<7.0%) at Week 20 was presented. All numbers shown in each individual treatment arm are based on the observed values (Missing = Not at Goal). | Week 20 | 
| Percentage of Participants With A1C at Goal (<7.0%) at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled)) | The percentage of participants with A1C at goal (<7.0%) at Week 20 was presented. The analysis table includes the observed values for each treatment arm (Missing = Not at Goal) and the estimated treatment difference (Missing = Multiple Imputation). The current outcome measure focused on comparing results from participants randomized to sitagliptin or placebo. The Placebo arm in this comparison was a pooling of the Placebo/Metformin and Placebo/Sitagliptin arms. The SAP did not specify for the Metformin arm to be included in statistical comparisons, so results for this arm are provided separately. | Week 20 | 
| Percentage of Participants With A1C at Goal (<6.5%) at Week 20 | The percentage of participants with A1C at goal (<6.5%) at Week 20 was presented. All numbers shown in each individual treatment arm are based on the observed values (Missing = Not at Goal). | Week 20 | 
| Percentage of Participants With A1C at Goal (<6.5%) at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled)) | The percentage of participants with A1C at goal (<6.5%) at Week 20 was presented. The analysis table includes the observed values for each treatment arm (Missing = Not at Goal) and the estimated treatment difference (Missing = Multiple Imputation). The current outcome measure focused on comparing results from participants randomized to sitagliptin or placebo. The Placebo arm in this comparison was a pooling of the Placebo/Metformin and Placebo/Sitagliptin arms. The SAP did not specify for the Metformin arm to be included in statistical comparisons, so results for this arm are provided separately. | Week 20 | 
| Percentage of Participants With A1C at Goal (<7.0%) at Week 54 | The percentage of participants with A1C at goal (<7.0%) at Week 54 was presented. All numbers shown in each individual treatment arm are based on the observed values (Missing = Not at Goal). | Week 54 | 
| Percentage of Participants With A1C at Goal (<6.5%) at Week 54 | The percentage of participants with A1C at goal (<6.5%) at Week 54 was presented. All numbers shown in each individual treatment arm are based on the observed values (Missing = Not at Goal). | Week 54 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20 | Blood glucose was measured on a fasting basis. Change in plasma glucose levels was FPG at Week 20 minus FPG at baseline. | Baseline and Week 20 | 
| Baseline Fasting Plasma Glucose (FPG) for the Placebo (Pooled) Arm | Blood glucose was measured on a fasting basis. The Placebo (pooled) arm was a pooling of the Placebo/Metformin and Placebo/Sitagliptin arms for analysis purposes. | Baseline | 
| Change From Baseline in FPG at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled)) | Blood glucose was measured on a fasting basis. Change in plasma glucose levels was FPG at Week 20 minus FPG at baseline and was estimated from a longitudinal data analysis model. The current outcome measure focused on results from participants randomized to sitagliptin or placebo. The Week 20 treatment comparison of Sitagliptin vs Placebo included all participants treated with Sitagliptin or Placebo. The Placebo arm in this comparison was a pooling of the Placebo/Metformin and Placebo/Sitagliptin arms. The SAP did not specify for the Metformin arm to be included in statistical comparisons, so results for this arm are provided separately. | Baseline and Week 20 | 
| Change From Baseline in FPG at Week 54 | Blood glucose was measured on a fasting basis. Change in plasma glucose levels was FPG at Week 54 minus FPG at baseline. | Baseline and Week 54 | 
| Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 20 | PMG endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 20 2-hour PMG minus the Week 0 2-hour PMG. | Baseline and Week 20 | 
| Change From Baseline in 2-hour PMG at Week 54 | PMG endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 54 2-hour PMG minus the Week 0 2-hour PMG. | Baseline and Week 54 | 
| Change From Baseline in 2-hour Incremental PMG at Week 20 | 2-Hour incremental PMG = Glucose at 120 minutes - glucose at 0 minutes. PMG endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 20 2-hour incremental PMG minus the Week 0 2-hour incremental PMG. | Baseline and Week 20 | 
| Change From Baseline in 2-Hour Incremental PMG at Week 54 | 2-Hour incremental PMG = Glucose at 120 minutes - glucose at 0 minutes. PMG endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 54 2-hour incremental PMG minus the Week 0 2-hour incremental PMG. | Baseline and Week 54 | 
| Change From Baseline in Insulin at Week 20 for Participants Not on Background Insulin | This change from baseline reflects the Week 20 insulin minus the Week 0 insulin. | Baseline and Week 20 | 
| Change From Baseline in Insulin at Week 54 For Participants Not on Background Insulin | This change from baseline reflects the Week 54 insulin minus the Week 0 insulin. | Baseline and Week 54 | 
| Change From Baseline in Proinsulin at Week 20 For Participants Not on Background Insulin | This change from baseline reflects the Week 20 proinsulin minus the Week 0 proinsulin. | Baseline and Week 20 | 
| Change From Baseline in Proinsulin at Week 54 For Participants Not on Background Insulin | This change from baseline reflects the Week 54 proinsulin minus the Week 0 proinsulin. | Baseline and Week 54 | 
| Change From Baseline in Proinsulin/Insulin Ratio at Week 20 for Participants Not on Background Insulin | Change from baseline was the Week 20 proinsulin/insulin ratio minus the Week 0 proinsulin/insulin ratio. | Baseline and Week 20 | 
| Change From Baseline in Proinsulin/Insulin Ratio at Week 54 For Participants Not on Background Insulin | The change from baseline was Week 54 proinsulin/insulin ratio minus the Week 0 proinsulin/insulin ratio. | Baseline and Week 54 | 
| Change From Baseline in Homeostatic Model Assessment of β-cell Function (HOMA-β) at Week 20 For Participants Not on Background Insulin | HOMA-β = 20 × fasting insulin (in mcIU/mL) ÷ {[FPG (in mg/dL)/18] - 3.5}. The change from baseline was Week 20 HOMA-β minus the Week 0 HOMA-β. | Baseline and Week 20 | 
| Change From Baseline in HOMA-β at Week 54 For Participants Not on Background Insulin | HOMA-β = 20 × fasting insulin (in mcIU/mL) ÷ {[FPG (in mg/dL)/18] - 3.5}. This change from baseline was Week 54 HOMA-β minus the Week 0 HOMA-β. | Baseline and Week 54 | 
| Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at Week 20 For Participants Not on Background Insulin | HOMA-IR = fasting insulin (in mcIU/mL) × FPG (in mg/dL) / (22.5×18). This change from baseline was Week 20 HOMA-IR minus the Week 0 HOMA-IR. | Baseline and Week 20 | 
| Change From Baseline in HOMA-IR at Week 54 For Participants Not on Background Insulin | HOMA-IR = fasting insulin (in mcIU/mL) × FPG (in mg/dL) / (22.5×18). This change from baseline was Week 54 HOMA-IR minus the Week 0 HOMA-IR. | Baseline and Week 54 | 
| Change From Baseline in Glucose 3-Hour Total Area Under the Curve (AUC) at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 20 glucose 3-hour AUC minus the Week 0 glucose 3-hour AUC. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin 3-hour AUC at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 20 insulin 3-hour AUC minus the Week 0 insulin 3-hour AUC. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in C-peptide 3-Hour AUC at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 20 C-peptide 3-hour AUC minus the Week 0 C-peptide 3-hour AUC. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin 3-Hour AUC/ Glucose 3-Hour AUC Ratio at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 20 insulin total AUC/glucose total AUC ratio minus the Week 0 insulin total AUC/glucose total AUC ratio. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Glucose Excursion 3-Hour AUC at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 20 glucose Excursion 3-hour AUC minus the Week 0 glucose Excursion 3-hour AUC. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin Excursion 3-Hour AUC at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 20 insulin Excursion 3-hour AUC minus the Week 0 insulin Excursion 3-hour AUC. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in C-peptide Excursion 3-Hour AUC at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 20 C-peptide Excursion 3-hour AUC minus the Week 0 C-peptide Excursion 3-hour AUC. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin Excursion 3-Hour AUC/Glucose Excursion 3-Hour AUC Ratio at Week 20 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 20 insulin Excursion 3-hour AUC/glucose Excursion 3-hour AUC ratio minus the Week 0 insulin Excursion 3-hour AUC/glucose Excursion 3-hour AUC ratio. | Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Glucose 3-Hour AUC at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 54 glucose 3-hour AUC minus the Week 0 glucose 3-hour AUC. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin 3-Hour AUC at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 54 insulin 3-hour AUC minus the Week 0 insulin 3-hour AUC. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in C-peptide 3-Hour AUC at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 54 C-peptide 3-hour AUC minus the Week 0 C-peptide 3-hour AUC. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin 3-Hour AUC/Glucose 3-Hour AUC Ratio at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. This change from baseline was Week 54 insulin 3-hour AUC/glucose 3-hour AUC ratio minus the Week 0 insulin 3-hour AUC/glucose 3-hour AUC ratio. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Glucose Excursion 3-Hour AUC at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 54 glucose Excursion 3-hour AUC minus the Week 0 glucose Excursion 3-hour AUC. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin Excursion 3-Hour AUC at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 54 insulin Excursion 3-hour AUC minus the Week 0 insulin Excursion 3-hour AUC. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in C-Peptide Excursion 3-Hour AUC at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 54 C-peptide Excursion 3-hour AUC minus the Week 0 C-peptide Excursion 3-hour AUC. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Change From Baseline in Insulin Excursion 3-Hour AUC/Glucose Excursion 3-Hour AUC Ratio at Week 54 | AUC endpoints were derived via the trapezoidal rule using 9-point Meal Tolerance Test (MTT) measurements. Excursion AUC = Incremental AUC above the level at the start of the meal. AUC below the level at the start of the meal did not contribute to the Excursion AUC. This change from baseline was Week 54 insulin Excursion 3-hour AUC/glucose Excursion 3-hour AUC ratio minus the Week 0 insulin Excursion 3-hour AUC/glucose Excursion 3-hour AUC ratio. | Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal) | 
| Percentage of Participants Initiating Glycemic Rescue Therapy by Week 20 | The percentage of participants who initiated glycemic rescue therapy prior to Week 20 was reported. | Up to Week 20 | 
| Percentage of Participants Initiating Glycemic Rescue Therapy by Week 54 | The percentage of participants who initiated glycemic rescue therapy prior to Week 54 was reported. | Up to Week 54 | 
| Change From Baseline in Body Mass Index (BMI) at Week 20 | This change from baseline was Week 20 BMI minus the Week 0 BMI. | Baseline and Week 20 | 
| Change From Baseline in BMI at Week 54 | This change from baseline was Week 54 BMI minus the Week 0 BMI. | Baseline and Week 54 | 
| Mean Percent Change of Peripheral Blood Mononuclear Cells Expressing CD26 From Baseline at Week 20 | The percent change from baseline in CD26 = ([CD26 value at Week 20] - [baseline CD26 value]) ÷ baseline CD26 value × 100. | Baseline and Week 20 | 
| Mean Percent Change of Peripheral Blood Mononuclear Cells Expressing CD26 From Baseline at Week 54 | The percent change from baseline in CD26 = ([CD26 value at Week 54] - [baseline CD26 value]) ÷ baseline CD26 value × 100. | Baseline and Week 54 | 
| Change From Baseline in Calcitonin at Week 20 - Females | Calcitonin, along with parathyroid hormone, is a hormone that regulates calcium and bone metabolism. This change from baseline was Week 20 calcitonin minus the Week 0 calcitonin. | Baseline and Week 20 | 
| Change From Baseline in Calcitonin at Week 54 - Females | Calcitonin, along with parathyroid hormone, is a hormone that regulates calcium and bone metabolism. This change from baseline was Week 54 calcitonin minus the Week 0 calcitonin. | Baseline and Week 54 | 
| Change From Baseline in Calcitonin at Week 20 - Males | Calcitonin, along with parathyroid hormone, is a hormone that regulates calcium and bone metabolism. This change from baseline was Week 20 calcitonin minus the Week 0 calcitonin. | Baseline and Week 20 | 
| Change From Baseline in Calcitonin at Week 54 - Males | Calcitonin, along with parathyroid hormone, is a hormone that regulates calcium and bone metabolism. This change from baseline was Week 54 calcitonin minus the Week 0 calcitonin. | Baseline and Week 54 | 
| Change From Baseline in Urine N-terminal Cross-linking Telopeptide of Bone Collagen [u-NTx]/Creatinine Ratio at Week 20 - Females | Urine N-terminal cross-linking telopeptide of bone collagen [u-NTx]/creatinine ratio is a biochemical marker of bone turnover/resorption. BCE = Bone Collagen Equivalents | Baseline and Week 20 | 
| Change From Baseline u-NTx/Creatinine Ratio at Week 20 - Males | Urine N-terminal cross-linking telopeptide of bone collagen [u-NTx]/creatinine ratio is a biochemical marker of bone turnover/resorption. BCE = Bone Collagen Equivalents | Baseline and Week 20 | 
| Change From Baseline in u-NTx/Creatinine Ratio at Week 54 - Females | Urine N-terminal cross-linking telopeptide of bone collagen [u-NTx]/creatinine ratio is a biochemical marker of bone turnover/resorption. Bone Collagen Equivalents | Baseline and Week 54 | 
| Change From Baseline in u-NTx/Creatinine Ratio at Week 54 - Males | Urine N-terminal cross-linking telopeptide of bone collagen [u-NTx]/creatinine ratio is a biochemical marker of bone turnover/resorption. All participants in the Metformin arm were missing baseline or Week 54 measurements. BCE = Bone Collagen Equivalents | Baseline and Week 54 | 
| Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 20 - Females | Bone-specific alkaline phosphatase is a biochemical marker of bone turnover. This change from baseline was Week 20 bone-specific alkaline phosphatase minus the Week 0 bone-specific alkaline phosphatase. | Baseline and Week 20 | 
| Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 54 - Females | Bone-specific alkaline phosphatase is a biochemical marker of bone turnover. This change from baseline was Week 54 bone-specific alkaline phosphatase minus the Week 0 bone-specific alkaline phosphatase. | Baseline and Week 54 | 
| Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 20 - Males | Bone-specific alkaline phosphatase is a biochemical marker of bone turnover. This change from baseline was Week 20 bone-specific alkaline phosphatase minus the Week 0 bone-specific alkaline phosphatase. | Baseline and Week 20 | 
| Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 54 - Males | Bone-specific alkaline phosphatase is a biochemical marker of bone turnover. This change from baseline was Week 54 bone-specific alkaline phosphatase minus the Week 0 bone-specific alkaline phosphatase. | Baseline and Week 54 | 
| Percent Change From Baseline in Insulin-like Growth Factor-1 (IGF-1) at Week 20 - Females | IGF-1 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-1 = ([IGF-1 value at Week 20] - [baseline IGF-1 value]) ÷ [baseline IGF-1 value] × 100. | Baseline and Week 20 | 
| Percent Change From Baseline in IGF-1 at Week 54 - Females | IGF-1 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-1 = ([IGF-1 value at Week 54] - [baseline IGF-1 value]) ÷ [baseline IGF-1 value] × 100. | Baseline and Week 54 | 
| Percent Change From Baseline in IGF-1 at Week 20 - Males | IGF-1 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-1 = ([IGF-1 value at Week 20] - [baseline IGF-1 value]) ÷ [baseline IGF-1 value] × 100. | Baseline and Week 20 | 
| Percent Change From Baseline in IGF-1 at Week 54 - Males | IGF-1 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-1 = ([IGF-1 value at Week 54] - [baseline IGF-1 value]) ÷ [baseline IGF-1 value] × 100. | Baseline and Week 54 | 
| Percent Change From Baseline in Insulin-like Growth Factor Binding Protein 3 (IGF-BP3) at Week 20 - Females | IGF-BP3 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-BP3 = ([IGF-BP3 value at Week 20] - [baseline IGF-BP3 value]) ÷ [baseline IGF-BP3 value] × 100. | Baseline and Week 20 | 
| Percent Change From Baseline in IGF-BP3 at Week 54 - Females | IGF-BP3 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-BP3 = ([IGF-BP3 value at Week 54] - [baseline IGF-BP3 value]) ÷ [baseline IGF-BP3 value] × 100. | Baseline and Week 54 | 
| Percent Change From Baseline in IGF-BP3 at Week 20 - Males | IGF-BP3 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-BP3 = ([IGF-BP3 value at Week 20] - [baseline IGF-BP3 value]) ÷ [baseline IGF-BP3 value] × 100. | Baseline and Week 20 | 
| Percent Change From Baseline in IGF-BP3 at Week 54 - Males | IGF-BP3 is a biochemical marker of growth hormone action and growth. The percent change from baseline in IGF-BP3 = ([IGF-BP3 value at Week 54] - [baseline IGF-BP3 value]) ÷ [baseline IGF-BP3 value] × 100. | Baseline and Week 54 | 
| Growth Velocity at Week 20 - Females | Growth Velocity (cm/year) = (Change from Baseline in height)/(Change from Baseline in chronologic age). | Week 20 | 
| Growth Velocity at Week 54 - Females | Growth Velocity (cm/year) = (Change from Baseline in height)/(Change from Baseline in chronologic age). | Week 54 | 
| Growth Velocity at Week 20 - Males | Growth Velocity (cm/year) = (Change from Baseline in height)/(Change from Baseline in chronologic age). | Week 20 | 
| Growth Velocity at Week 54 - Males | Growth Velocity (cm/year) = (Change from Baseline in height)/(Change from Baseline in chronologic age). | Week 54 | 
| Skeletal Maturation at Week 20 - Females | Skeletal Maturation = (Change from Baseline in bone age)/(Change from Baseline in chronologic age). Bone age was determined from an X-ray of left hand and wrist. | Week 20 | 
| Skeletal Maturation at Week 54 - Females | Skeletal Maturation = (Change from Baseline in bone age)/(Change from Baseline in chronologic age). Bone age was determined from X-ray of left hand and wrist. All participants in the Placebo/Sitagliptin arm were missing baseline or Week 54 measurements. | Week 54 | 
| Skeletal Maturation at Week 20 - Males | Skeletal Maturation = (Change from Baseline in bone age)/(Change from Baseline in chronologic age). Bone age was determined from X-ray of left hand and wrist. | Week 20 | 
| Skeletal Maturation at Week 54 - Males | Skeletal Maturation = (Change from Baseline in bone age)/(Change from Baseline in chronologic age). Bone age was determined from X-ray of left hand and wrist. All participants in the Metformin and Placebo/Sitagliptin arms were missing baseline or Week 54 measurements. | Week 54 | 
| Change From Baseline in Tanner Staging for Genitalia at Week 20 - Males | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in male participants. Tanner staging includes an assessment of genital development (males) with a score of range 1 to 5 where 1=no development and 5=adult genitals. This change from baseline was Week 20 Tanner Staging for Genitalia minus the Week 0 Tanner Staging for Genitalia. | Baseline and Week 20 | 
| Change From Baseline in Tanner Staging for Genitalia at Week 54 - Males | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in male participants. Tanner staging includes an assessment of genital development (males) with a score of range 1 to 5 where 1=no development and 5=adult genitals. This change from baseline was Week 54 Tanner Staging for Genitalia minus the Week 0 Tanner Staging for Genitalia. All participants in the Metformin arm were missing baseline or Week 54 measurements. | Baseline and Week 54 | 
| Change From Baseline in Tanner Staging for Breasts at Week 20 - Females | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in female participants. Tanner staging includes an assessment of breast development (females). Tanner stage (breast) is a score of range 1 to 5 where 1=no development and 5=adult breast. This change from baseline was Week 20 Tanner Staging for Breasts minus the Week 0 Tanner Staging for Breasts. | Baseline and Week 20 | 
| Change From Baseline in Tanner Staging for Breasts at Week 54 - Females | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in female participants. Tanner staging includes an assessment of breast development (females). Tanner stage (breast) is a score of range 1 to 5 where 1=no development and 5=adult breast. This change from baseline was Week 54 Tanner Staging for Breasts minus the Week 0 Tanner Staging for Breasts. | Baseline and Week 54 | 
| Change From Baseline in Tanner Stage for Pubic Hair at Week 20 - Females | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in female participants. Tanner staging includes an assessment of pubic hair development (females). Tanner stage (pubic hair) is a score of range 1 to 5 where 1=no development and 5=adult pubic hair. This change from baseline was Week 20 Tanner Staging for Pubic Hair minus the Week 0 Tanner Staging for Pubic Hair. | Baseline and Week 20 | 
| Change From Baseline in Tanner Stage for Pubic Hair at Week 54 - Females | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in female participants. Tanner staging includes an assessment of pubic hair development (females). Tanner stage (pubic hair) is a score of range 1 to 5 where 1=no development and 5=adult pubic hair. This change from baseline was Week 54 Tanner Staging for Pubic Hair minus the Week 0 Tanner Staging for Pubic Hair. | Baseline and Week 54 | 
| Change From Baseline in Tanner Stage for Pubic Hair at Week 20 - Males | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in male participants. Tanner staging includes an assessment of pubic hair development (males). Tanner stage (pubic hair) is a score of range 1 to 5 where 1=no development and 5=adult pubic hair. This change from baseline was Week 20 Tanner Staging for Pubic Hair minus the Week 0 Tanner Staging for Pubic Hair. | Baseline and Week 20 | 
| Change From Baseline in Tanner Stage for Pubic Hair at Week 54 - Males | Participant's stage of sexual maturation was assessed using the Tanner staging measure for determining pubertal development in male participants. Tanner staging includes an assessment of pubic hair development (males). Tanner stage (pubic hair) is a score of range 1 to 5 where 1=no development and 5=adult pubic hair. This change from baseline was Week 54 Tanner Staging for Pubic Hair minus the Week 0 Tanner Staging for Pubic Hair. | Baseline and Week 54 | 
| Participants With Worsening in Dental Status at Week 20 | Participants were evaluated with a visual oral exam; a subset had dental photographs. Teeth worsening was defined as worsening of tooth fracture, tooth discoloration, or enamel defect as determined by an independent reviewer. Worsening in these categories was a change in dental defect assessments made by comparing Week 20 dental assessments versus baseline dental assessments. | Week 20 | 
| Participants With Worsening in Dental Status at Week 54 | Participants were evaluated with a visual oral exam; a subset had dental photographs. Teeth worsening was defined as worsening of tooth fracture, tooth discoloration, or enamel defect as determined by an independent reviewer. Worsening in these categories was a change in dental defect assessments made by comparing Week 54 dental assessments versus baseline dental assessments. | Week 54 |