A Study to Assess the Addition of Sitagliptin to Metformin Compared With the Addition of Dapagliflozin to Metformin in Participants With Type 2 Diabetes Mellitus (T2DM) and Mild Renal Impairment Who Have Inadequate Glycemic Control on Metformin With or Without a Sulfonylurea (MK-0431-838)

Study Overview
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Brief Summary
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The purpose of the study is to assess the effect of the addition of sitagliptin to metformin with or without a sulfonylurea compared with the addition of dapagliflozin to metformin with or without a sulfonylurea on hemoglobin A1c (A1C) over 24 weeks of treatment as well as the overall safety and tolerability of sitagliptin in comparison to that of dapagliflozin after 24 weeks of treatment. The primary hypothesis is that the change from baseline in A1C in participants treated with the addition of sitagliptin is non-inferior compared to that in participants treated with the addition of dapagliflozin after 24 weeks of treatment.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Active-Comparator Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Sitagliptin Compared With the Addition of Dapagliflozin in Subjects With Type 2 Diabetes Mellitus and Mild Renal Impairment Who Have Inadequate Glycemic Control on Metformin With or Without a Sulfonylurea

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Dapagliflozin
* Drug: Metformin
* Drug: Matching placebo to sitagliptin
* Drug: Matching placebo to dapagliflozin
* Drug: Sulfonylurea


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Have T2DM at Screening visit Be on metformin monotherapy ≥1500 mg/day alone or in combination with an sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) for ≥8 weeks Is a male or a female not of reproductive potential (defined as one who is postmenopausal or has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to Screening visit). If participant is a female of reproductive potential, must agree to remain abstinent from heterosexual activity or agrees to use (or have her partner use) acceptable contraception to prevent pregnancy while receiving blinded study drug and for 14 days after the last dose of blinded study drug Exclusion Criteria: Has a history of type 1 diabetes mellitus or a history of ketoacidosis Has a history of secondary causes of diabetes Has a known hypersensitivity or intolerance to any dipeptidyl peptidase IV (DPP-4) inhibitor or sodium-glucose cotransporter 2 (SGLT2) inhibitor Has been treated with any anti-hyperglycemic agents (AHA) other than metformin and for participants on dual combination therapy, a sulfonylurea within 12 weeks of screening Intends to initiate weight loss medication during the study period Has undergone bariatric surgery within 12 months of Screening visit Has started a weight loss medication or a medication associated with weight changes within the prior 12 weeks. Has a history of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, heart failure within 3 months of Screening visit Has a history of malignancy ≤5 years prior to study, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer Has human immunodeficiency virus (HIV) Has blood dyscrasias or any disorders causing hemolysis or unstable red blood cells, or clinically important hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) Has a medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease Is currently being treated for hyperthyroidism or is on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks prior to Screening visit Is on or likely to require treatment for ≥14 consecutive days or repeated courses of corticosteroids Is on or likely to require treatment for ≥7 consecutive days with non-steroidal anti-inflammatory drugs Is pregnant or breast-feeding, or is planning to conceive during the study, including 14 days following the last dose of blinded study drug Is planning to undergo hormonal therapy in preparation to donate eggs during the study, including 14 days following the last dose of blinded study drug Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week or engages in binge drinking Has donated blood or blood products within 6 weeks of Screening visit or who plans to donate blood or blood products at any time during the study

Ages Eligible for Study
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Minimum Age: 25 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin<br>Participants receive sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 5 mg once daily for 4 weeks followed by sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 10 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study. | Drug: Sitagliptin<br>* Sitagliptin 100 mg oral tablet<br>Drug: Metformin<br>* This medication is a standard-of-care medication and is administered in an open-label fashion. Supply of background metformin oral tablet(s) (at least 1500 mg daily) will be the responsibility of the participant throughout the duration of the study.<br>Drug: Matching placebo to dapagliflozin<br>* Matching placebo to dapagliflozin 5 mg or 10 mg oral capsule. Up-titration to matching placebo to dapagliflozin 10 mg daily may be delayed if participant is unable to tolerate up-titration in the opinion of the investigator. Matching placebo to dapagliflozin 10 mg daily may be down-titrated to matching placebo to dapagliflozin 5 mg daily if participant is unable to tolerate the higher dose in the opinion of the investigator.<br>Drug: Sulfonylurea<br>* This medication is a standard-of-care medication and is administered in an open-label fashion. The dose of the sulfonylurea agent will be required to be at least 50% of maximum labeled dose, consistent with near maximum efficacy of the sulfonylurea agent.<br>|
| Active Comparator: Dapagliflozin<br>Participants receive dapagliflozin 5 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 4 weeks followed by dapagliflozin 10 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study. | Drug: Dapagliflozin<br>* Dapagliflozin 5 mg or 10 mg oral capsule. Up-titration to dapagliflozin 10 mg daily may be delayed if participant is unable to tolerate up-titration in the opinion of the investigator. Dapagliflozin 10 mg daily may be down-titrated to dapagliflozin 5 mg daily if participant is unable to tolerate the higher dose in the opinion of the investigator.<br>Drug: Metformin<br>* This medication is a standard-of-care medication and is administered in an open-label fashion. Supply of background metformin oral tablet(s) (at least 1500 mg daily) will be the responsibility of the participant throughout the duration of the study.<br>Drug: Matching placebo to sitagliptin<br>* Matching placebo to sitagliptin 100 mg oral tablet<br>Drug: Sulfonylurea<br>* This medication is a standard-of-care medication and is administered in an open-label fashion. The dose of the sulfonylurea agent will be required to be at least 50% of maximum labeled dose, consistent with near maximum efficacy of the sulfonylurea agent.<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 24 | A1C is 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. Thus, this change from baseline reflects the Week 24 A1C minus the Week 0 A1C. | Baseline and Week 24 | 
| Percentage of Participants Who Experienced One or More Adverse Events | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product. The AE does not have to have a causal relationship with this treatment. The AE can include any unfavourable and unintended sign, symptom, or disease or any worsening (change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the pharmaceutical product. | Up to 26 weeks | 
| Percentage of Participants Who Discontinued Study Drug Due to an AE | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product. The AE does not have to have a causal relationship with this treatment. The AE can include any unfavourable and unintended sign, symptom, or disease or any worsening (change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the pharmaceutical product. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Incremental 2-hour (2-hr) Postprandial Glucose Excursion (PPGE) at Week 24 | The 2hr PPGE is the change from baseline in the mean incremental change in post meal glucose defined as T-120 minus T-0 for each participant: change from baseline PPGE = Week 24 mean (T-120 minus T-0) minus Baseline mean (T-120 minus T-0). The 2-point MMTT measured values at T-0 and T-120 while the 3-point MMTT measured values at T-0, T-60, and T-120: although only a subset of the study had the 3-point MMTT performed, all participants had a T-0 and T-120 time point. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. | Immediately before and 120 minutes after the standard meal at Baseline and Week 24 | 
| Change From Baseline in 2-hr Postprandial Glucose (PPG) at Week 24 | The 2hr PPG is the change from baseline in mean post prandial glucose (change from baseline PPG = Week 24 mean T-120 glucose minus Baseline mean T-120 glucose) and shows each drugs impact on PPG. The 2-point MMTT measured values at T-0 and T-120 while the 3-point MMTT measured values at T-0, T-60, and T-120: although only a subset of the study had the 3-point MMTT performed, all participants had a T-0 and T-120 time point. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. | Immediately before and 120 minutes after the standard meal at Baseline and Week 24 | 
| Change From Baseline in Glucagon Area Under the Curve (AUC0-120 Minutes) at Week 24 | AUC endpoints were analyzed for participants who underwent the 3-point MMTT. Blood samples were drawn immediately prior to (T=0 minutes) and 60 and 120 minutes after the administration of the standard meal. The AUC curve was generated with the 3 time points. If any time point for a given participant was missing, the AUC was not included. Change in Postprandial Glucagon AUC after the morning meal (t=0 to 120 minutes) was calculated from the glucagon AUC over the first 120 minutes following the morning meal at baseline minus glucagon AUC over the first 120 minutes following the morning meal at Week 24. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. | Immediately before and 60 and 120 minutes after the standard meal at Baseline and Week 24 | 
| Change From Baseline in Insulin AUC0-120 Minutes at Week 24 | AUC endpoints were analyzed for participants who underwent the 3-point MMTT. Blood samples were drawn immediately prior to (T=0 minutes) and 60 and 120 minutes after the administration of the standard meal. The AUC curve was generated with the 3 time points. If any time point for a given participant was missing, the AUC was not included. Change in Postprandial Insulin AUC after the morning meal (t=0 to 120 minutes) was calculated from insulin AUC over the first 120 minutes following the morning meal at baseline minus insulin AUC over the first 120 minutes following the morning meal at Week 24. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. | Immediately before and 60 and 120 minutes after the standard meal at Baseline and Week 24 | 
| Change From Baseline in Postprandial Insulin AUC0-120 Minutes to Glucagon AUC0-120 Minutes Ratio at Week 24 | AUC endpoints were analyzed for participants who underwent the 3-point MMTT. Blood samples were drawn immediately prior to (T=0 minutes) and 60 and 120 minutes after the administration of the standard meal. The AUC curve was generated with the 3 time points. If any time point for a given participant was missing, the AUC was not included. The endpoint was calculated from the ratio of (insulin AUC / glucagon AUC) over the first 120 minutes following the morning meal at baseline minus AUC over the first 120 minutes following the morning meal at Week 24. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. | Immediately before and 60 and 120 minutes after the standard meal at Baseline and Week 24 | 
| Percentage of Participants With A1C <7% (53 mmol/Mol) at Week 24 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. | Week 24 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Blood glucose was measured on a fasting basis. Blood was 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 Week 0). | Baseline and Week 24 |