A Pooled Analysis of the Safety and Efficacy of MK-0431A and MK-0431A XR in Pediatric Participants With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Therapy (Alone or in Combination With Insulin) (MK-0431A-170/MK-0431A-289)

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of the addition of sitagliptin (administered as MK-0431A or MK-0431A XR) relative to the addition of placebo on glycated hemoglobin (A1C), and the safety and tolerability of the addition of sitagliptin, in pediatric participants (ages 10-17 years) with type 2 diabetes mellitus with inadequate glycemic control on metformin therapy (alone or in combination with insulin). The primary hypothesis is that the addition of sitagliptin reduces glycated hemoglobin (A1C) more than the addition of placebo after 20 weeks of treatment.

Official Title
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A Pooled Analysis of the Safety and Efficacy of MK-0431A and MK-0431A XR in Pediatric Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Therapy (Alone or in Combination With Insulin)

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sitagliptin plus metformin
* Drug: Placebo to metformin
* Drug: Metformin
* Drug: Placebo to sitagliptin plus metformin
* Drug: Sitagliptin plus metformin XR
* Drug: Placebo to metformin XR
* Drug: Insulin
* Drug: Placebo to sitagliptin plus metformin XR
* Drug: Metformin XR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For MK-0431A-170 base study and MK-0431A-289: Has type 2 diabetes mellitus (T2DM) Is on metformin monotherapy (≥1500 mg/day) for ≥12 weeks with glycated hemoglobin (A1C) ≥6.5% and ≤10.0% OR is on stable doses of metformin (≥1500 mg/day) and insulin for ≥12 weeks with an A1C ≥7.0% and ≤10%. NOTE: Participants on a daily dose of metformin greater than or equal to 1000 mg/day, but less than 1500 mg/day may be eligible if there is documentation that higher doses are not tolerated. Participant and a family member or adult closely involved in the daily activities will participate in the participant's treatment and study protocol (i.e., available for telephone calls, study visits and administration of study medication as needed). Male, or female who is unlikely to conceive (non-sterilized, and is not sexually active or agrees to abstain from heterosexual activity or agrees to use an adequate method of contraception) during the study and for 14 days after the last dose of study drug For MK-0431A-170 extension protocol: Has completed the P170 base study Participant and a family member or adult closely involved in the daily activities will participate in the participant's treatment and study protocol (i.e., available for telephone calls, study visits and administration of study medication as needed). Male, or female who is unlikely to conceive (non-sterilized, and is not sexually active or agrees to abstain from heterosexual activity or agrees to use an adequate method of contraception) during the study and for 14 days after the last dose of study drug Exclusion Criteria: For MK-0431A-170 base study and MK-0431A-289: Has type 1 diabetes mellitus Has monogenic diabetes or secondary diabetes Has symptomatic hyperglycemia and/or moderate to large ketonuria and/or positive test for ketonemia, requiring immediate initiation of another antihyperglycemic agent Has previously taken a dipeptidyl peptidase IV (DPP-4) inhibitor (such as sitagliptin, vildagliptin, alogliptin, saxagliptin, or linagliptin) or glucagon-like peptide-1 (GLP-1) receptor agonist (such as exenatide or liraglutide) Is on or likely to require treatment for ≥2 consecutive weeks or repeated courses of corticosteroids (inhaled, nasal and topical corticosteroids are permitted) Has undergone a surgical procedure within 4 weeks of study participation or has planned major surgery during the study History of congenital heart disease or cardiovascular disease other than hypertension History of active liver disease (other than non-alcoholic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease Active neuropathy (such as nephrotic syndrome or glomerulonephritis) Chronic myopathy, mitochondrial disorder or a progressive neurological or neuromuscular disorder Human immunodeficiency virus (HIV) Hematological disorder (such as aplastic anemia, thrombocytopenia, myeloproliferative or myelodysplastic syndromes) Is currently being treated for hyperthyroidism or is on thyroid hormone therapy and has not been on a stable dose for at least 6 weeks History of malignancy for ≤5 years prior to study participation, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer History of idiopathic acute pancreatitis or chronic pancreatitis History of recreational or illicit drug use, or of alcohol abuse or dependence (within the past year) Has donated blood products or has had phlebotomy of >10% of estimated total blood volume within 8 weeks of study participation, or intends to donate blood products or receive blood products within the projected duration of the study 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 drug For MK-0431A-170 extension protocol: Participant meets a study medication discontinuation criterion at the last visit of the MK-0431A-170 base study (Week 20) Has taken the last dose of study medication for the MK-0431A-170 base study more than 14 days prior to Extension Visit 1 Has initiated another oral antihyperglycemic agent Participant does not agree to refrain from participating in any other double-blind interventional study while participating in the P170 extension study

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
Interventional Model Description: Participants enrolled in protocol MK-0431A-170 were randomized between the arms Sitagliptin/Metformin and Metformin. Participants enrolled in protocol MK-0431A-289 were randomized between the arms Sitagliptin/Metformin XR and Metformin XR.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin/Metformin<br>Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, for up to 20 weeks in the base study alone, or for up to 54 weeks if the participant also entered the extension study. Participants in this arm were enrolled in protocol MK-0431A-170. | Drug: Sitagliptin plus metformin<br>* Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 100 mg of sitagliptin and 1000 mg, 1700 mg or 2000 mg of metformin. Dosage of metformin was based on each participant's daily metformin dose prior to enrollment.<br>* Other names: MK-0431A;Drug: Placebo to metformin<br>* Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to metformin.<br>Drug: Insulin<br>* Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue. During Weeks 20-54, for participants who were not on background insulin or rescued with insulin during Weeks 0-20 in the Sitagliptin/Metformin and Metformin arms (protocol MK-0431A-170), and during Weeks 0-54 for participants not on background insulin in the Sitagliptin/Metformin XR and Metformin XR arms (protocol MK-0431A-289), the type of insulin for glycemic rescue was specified to be insulin glargine.<br>|
| Placebo Comparator: Metformin<br>Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, for up to 20 weeks in the base study alone, or for up to 54 weeks if the participant also entered the extension study. Participants in this arm were enrolled in protocol MK-0431A-170. | Drug: Metformin<br>* Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 1000 mg, 1700 mg or 2000 mg of metformin. Dosage was based on each participant's daily metformin dose prior to enrollment.<br>Drug: Placebo to sitagliptin plus metformin<br>* Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to sitagliptin plus metformin.<br>* Other names: Placebo to MK-0431A;Drug: Insulin<br>* Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue. During Weeks 20-54, for participants who were not on background insulin or rescued with insulin during Weeks 0-20 in the Sitagliptin/Metformin and Metformin arms (protocol MK-0431A-170), and during Weeks 0-54 for participants not on background insulin in the Sitagliptin/Metformin XR and Metformin XR arms (protocol MK-0431A-289), the type of insulin for glycemic rescue was specified to be insulin glargine.<br>|
| Experimental: Sitagliptin/Metformin XR<br>Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, for up to 54 weeks. Participants in this arm were enrolled in protocol MK-0431A-289. | Drug: Sitagliptin plus metformin XR<br>* Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 100 mg of sitagliptin and 1000 mg, 1500 mg or 2000 mg of metformin. Dosage of metformin XR was based on each participant's daily metformin dose prior to enrollment.<br>* Other names: MK-0431A XR;Drug: Placebo to metformin XR<br>* Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to metformin XR.<br>Drug: Insulin<br>* Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue. During Weeks 20-54, for participants who were not on background insulin or rescued with insulin during Weeks 0-20 in the Sitagliptin/Metformin and Metformin arms (protocol MK-0431A-170), and during Weeks 0-54 for participants not on background insulin in the Sitagliptin/Metformin XR and Metformin XR arms (protocol MK-0431A-289), the type of insulin for glycemic rescue was specified to be insulin glargine.<br>|
| Placebo Comparator: Metformin XR<br>Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, for up to 54 weeks. Participants in this arm were enrolled in protocol MK-0431A-289. | Drug: Insulin<br>* Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue. During Weeks 20-54, for participants who were not on background insulin or rescued with insulin during Weeks 0-20 in the Sitagliptin/Metformin and Metformin arms (protocol MK-0431A-170), and during Weeks 0-54 for participants not on background insulin in the Sitagliptin/Metformin XR and Metformin XR arms (protocol MK-0431A-289), the type of insulin for glycemic rescue was specified to be insulin glargine.<br>Drug: Placebo to sitagliptin plus metformin XR<br>* Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to sitagliptin plus metformin XR.<br>* Other names: Placebo to MK-0431A XR;Drug: Metformin XR<br>* Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 1000 mg, 1500 mg or 2000 mg of metformin XR. Dosage was based on each participant's daily metformin dose prior to enrollment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 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. Mean change from baseline at Week 20 was estimated from a longitudinal data analysis model. | Baseline and Week 20 | 
| Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-20 | The number of participants experiencing ≥1 adverse event during Weeks 0-20 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 20 | 
| Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-20 | The number of participants who discontinued from study drug due to an adverse event during Weeks 0-20 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 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 were 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 approximately Week 56 | 
| Number of Participants Who Discontinued Study Drug Due to Experiencing 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 | 

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. Mean change from baseline at Week 54 was estimated from a longitudinal data analysis model. | Baseline and Week 54 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20 | Blood glucose was measured on a fasting basis. Mean change from baseline at Week 20 was estimated from a longitudinal data analysis model. | Baseline and Week 20 | 
| Change From Baseline in FPG at Week 54 | Blood glucose was measured on a fasting basis. Mean change from baseline at Week 54 was estimated from a longitudinal data analysis model. | Baseline and Week 54 | 
| Percentage of Participants With A1C at Goal (<7.0%) 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. Percentage of participants with A1C at goal (<7.0%) at Week 20 was presented. | Week 20 | 
| Percentage of Participants With A1C at Goal (<6.5%) 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. Percentage of participants with A1C at goal (<6.5%) at Week 20 was presented. | Week 20 | 
| Percentage of Participants With A1C at Goal (<7.0%) at Week 54 | 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. Percentage of participants with A1C at goal (<7.0%) at Week 54 was presented. | Week 54 | 
| Percentage of Participants With A1C at Goal (<6.5%) at Week 54 | 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. Percentage of participants with A1C at goal (<6.5%) at Week 54 was presented. | Week 54 | 
| Percentage of Participants Initiating Glycemic Rescue Therapy by Week 20 | Percentage of participants who initiated glycemic rescue therapy prior to Week 20 was reported. | Up to Week 20 | 
| Percentage of Participants Initiating Insulin Glargine During Weeks 20-54 | Percentage of participants who initiated insulin glargine therapy from Weeks 20 through 54 was reported. | Week 20 up to Week 54 |