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)

NCT ID: NCT02532855

Last Updated: 2018-11-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 614 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-20
• Study Completion Date: 2017-10-10

Brief Summary

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.

Conditions

Type 2 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Sitagliptin

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.

Group Type: EXPERIMENTAL

Sitagliptin

Intervention Type: DRUG

Sitagliptin 100 mg oral tablet

Metformin

Intervention Type: DRUG

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.

Matching placebo to dapagliflozin

Intervention Type: DRUG

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.

Sulfonylurea

Intervention Type: DRUG

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.

Dapagliflozin

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.

Group Type: ACTIVE_COMPARATOR

Dapagliflozin

Intervention Type: DRUG

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.

Metformin

Intervention Type: DRUG

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.

Matching placebo to sitagliptin

Intervention Type: DRUG

Matching placebo to sitagliptin 100 mg oral tablet

Sulfonylurea

Intervention Type: DRUG

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.

Interventions

Sitagliptin

Sitagliptin 100 mg oral tablet

Intervention Type: DRUG

Dapagliflozin

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.

Intervention Type: DRUG

Metformin

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.

Intervention Type: DRUG

Matching placebo to sitagliptin

Matching placebo to sitagliptin 100 mg oral tablet

Intervention Type: DRUG

Matching placebo to dapagliflozin

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.

Intervention Type: DRUG

Sulfonylurea

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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

References

Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2024 May 21;5(5):CD015588. doi: 10.1002/14651858.CD015588.pub2.

Reference Type: DERIVED

PMID: 38770818 (View on PubMed)

Scott R, Morgan J, Zimmer Z, Lam RLH, O'Neill EA, Kaufman KD, Engel SS, Raji A. A randomized clinical trial of the efficacy and safety of sitagliptin compared with dapagliflozin in patients with type 2 diabetes mellitus and mild renal insufficiency: The CompoSIT-R study. Diabetes Obes Metab. 2018 Dec;20(12):2876-2884. doi: 10.1111/dom.13473. Epub 2018 Aug 16.

Reference Type: DERIVED

PMID: 30019498 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2014-005525-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MK-0431-838

Identifier Type: OTHER

Identifier Source: secondary_id

0431-838

Identifier Type: -

Identifier Source: org_study_id