Safety and Efficacy of Ertugliflozin in the Treatment of Participants With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin and Sitagliptin (MK-8835-006; VERTIS SITA2)

NCT ID: NCT02036515

Last Updated: 2018-09-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 464 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-12
• Study Completion Date: 2016-06-06

Brief Summary

This is a safety and efficacy study of ertugliflozin (MK-8835/PF-04971729) in the treatment of participants with type 2 diabetes mellitus who have inadequate glycemic control on metformin and sitagliptin. The primary objective of the trial is to assess the hemoglobin A1C (A1C)-lowering efficacy of the addition of ertugliflozin compared to the addition of placebo with an underlying hypothesis that addition of treatment with ertugliflozin provides greater reduction in A1C compared with the addition of placebo; the primary objective will be tested for both 5-mg and 15-mg doses of ertugliflozin.

Detailed Description

The duration of the trial will be approximately 69 weeks. This will include a 1-week Screening Period, an up to 12-week wash-off/titration /dose-stabilization period, a 2-week single-blind, placebo run-in period, a 52-week double-blind, placebo-controlled treatment period (including a 26-week Phase A and 26-week Phase B), and a post-treatment telephone contact 14 days after the last dose of blinded investigational product.

Conditions

Type 2 Diabetes Mellitus

Study Design

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

Study Groups

Ertugliflozin 5 mg

Ertugliflozin, 5 mg, oral, once daily for 52 weeks

Group Type: EXPERIMENTAL

Ertugliflozin 5 mg

Intervention Type: DRUG

Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks

Metformin

Intervention Type: DRUG

Participants are to remain on their stable doses of metformin (oral, \>=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period.

Sitagliptin

Intervention Type: DRUG

Participants are to remain on their stable doses of sitagliptin (oral, 100 mg once daily) while receiving blinded investigational product during the double-blind treatment period.

Glimepiride

Intervention Type: DRUG

Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion

Insulin

Intervention Type: BIOLOGICAL

Insulin glargine rescue medication, injectable, as required. In the event that an investigator considers use of glimepiride to not be appropriate for a participant meeting protocol specified glycemic rescue criteria, insulin glargine can be initiated as the rescue medication, and managed by the investigator according to clinical practice guidelines of the local country.

Placebo for ertugliflozin 10 mg

Intervention Type: DRUG

Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks

Ertugliflozin 15 mg

Ertugliflozin, 15 mg, oral, once daily for 52 weeks

Group Type: EXPERIMENTAL

Ertugliflozin 15 mg

Intervention Type: DRUG

Ertugliflozin, oral, 5 mg and 10 mg tablet once daily for 52 weeks

Metformin

Intervention Type: DRUG

Participants are to remain on their stable doses of metformin (oral, \>=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period.

Sitagliptin

Intervention Type: DRUG

Participants are to remain on their stable doses of sitagliptin (oral, 100 mg once daily) while receiving blinded investigational product during the double-blind treatment period.

Glimepiride

Intervention Type: DRUG

Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion

Insulin

Intervention Type: BIOLOGICAL

Insulin glargine rescue medication, injectable, as required. In the event that an investigator considers use of glimepiride to not be appropriate for a participant meeting protocol specified glycemic rescue criteria, insulin glargine can be initiated as the rescue medication, and managed by the investigator according to clinical practice guidelines of the local country.

Placebo

Matching placebo to ertuglifozin, oral, once daily for 52 weeks

Group Type: PLACEBO_COMPARATOR

Placebo for ertugliflozin 5 mg

Intervention Type: DRUG

Matching placebo for ertugliflozin 5 mg, oral, once daily for 52 weeks

Metformin

Intervention Type: DRUG

Participants are to remain on their stable doses of metformin (oral, \>=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period.

Sitagliptin

Intervention Type: DRUG

Participants are to remain on their stable doses of sitagliptin (oral, 100 mg once daily) while receiving blinded investigational product during the double-blind treatment period.

Glimepiride

Intervention Type: DRUG

Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion

Insulin

Intervention Type: BIOLOGICAL

Insulin glargine rescue medication, injectable, as required. In the event that an investigator considers use of glimepiride to not be appropriate for a participant meeting protocol specified glycemic rescue criteria, insulin glargine can be initiated as the rescue medication, and managed by the investigator according to clinical practice guidelines of the local country.

Placebo for ertugliflozin 10 mg

Intervention Type: DRUG

Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks

Interventions

Ertugliflozin 5 mg

Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks

Intervention Type: DRUG

Ertugliflozin 15 mg

Ertugliflozin, oral, 5 mg and 10 mg tablet once daily for 52 weeks

Intervention Type: DRUG

Placebo for ertugliflozin 5 mg

Matching placebo for ertugliflozin 5 mg, oral, once daily for 52 weeks

Intervention Type: DRUG

Metformin

Participants are to remain on their stable doses of metformin (oral, \>=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period.

Intervention Type: DRUG

Sitagliptin

Participants are to remain on their stable doses of sitagliptin (oral, 100 mg once daily) while receiving blinded investigational product during the double-blind treatment period.

Intervention Type: DRUG

Glimepiride

Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion

Intervention Type: DRUG

Insulin

Insulin glargine rescue medication, injectable, as required. In the event that an investigator considers use of glimepiride to not be appropriate for a participant meeting protocol specified glycemic rescue criteria, insulin glargine can be initiated as the rescue medication, and managed by the investigator according to clinical practice guidelines of the local country.

Intervention Type: BIOLOGICAL

Placebo for ertugliflozin 10 mg

Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks

Intervention Type: DRUG

Other Intervention Names

MK-8835; PF-04971729; MK-8835; PF-04971729; Glucophage; Glucophage XR; JANUVIA®; AMARYL

Eligibility Criteria

Inclusion Criteria

• Diagnosis of type 2 diabetes mellitus (T2DM)
• On stable diabetes therapy of metformin with either sitagliptin or another dipeptidyl peptidase-4 (DPP-4) inhibitor or a sulfonylurea (SU) prior to study participation and is willing to wash-off/switch from another DPP-4 inhibitor/SU to sitagliptin
• Body Mass Index (BMI) greater than or equal to 18.0 kg/m^2
• Male, postmenopausal female or surgically sterile female
• If a female of reproductive potential, agrees to remain abstinent or to use (or have their partner use) 2 acceptable combinations of birth control while participating in the trial and for 14 days after the last use of study drug

Exclusion Criteria

• History of type 1 diabetes mellitus or a history of ketoacidosis
• History of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrine disorders, drug- or chemical-induced, and post-organ transplant)
• A known hypersensitivity or intolerance to any sodium-glucose co-transporter 2 (SGLT2) or DPP-4 inhibitor
• On a weight-loss program or weight-loss medication or other medication associated with weight changes and is not weight stable
• Has undergone bariatric surgery within the past 12 months or >12 months and is not weight stable
• Has been treated with insulin (except for short-term use [<= 7 days]), injectable antihyperglycemic agents (AHAs) (e.g., pramlintide, exenatide, liraglutide), pioglitazone or rosiglitazone, other sodium-glucose co-transporter 2 (SGLT2) inhibitors, alpha glucosidase inhibitors or meglitinides, bromocriptine (Cycloset™), colesevelam (Welchol™), or any other non-protocol approved AHAs within 12 weeks of study participation
• Has active, obstructive uropathy or indwelling urinary catheter
• History of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or New York Heart Association (NYHA) functional class III-IV heart failure within 3 months of study participation
• A history of malignancy ≤5 years prior to study participation, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer
• Known history of Human Immunodeficiency Virus (HIV)
• Has blood dyscrasias or any disorders causing hemolysis or unstable red blood cells or any other clinically significant hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)
• A medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or active symptomatic gallbladder disease
• Has any clinically significant malabsorption condition
• If taking thyroid replacement therapy, has not been on a stable dose for at least 6 weeks prior to study participation
• Has been previously randomized in a study with ertugliflozin
• Has participated in other studies involving an investigational drug within 30 days prior or during study participation
• Has undergone a surgical procedure within 6 weeks prior to or planned major surgery during study participation
• Has a positive urine pregnancy test
• Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of study medication
• Planning to undergo hormonal therapy in preparation to donate eggs during the trial, including 14 days following the last dose of study medication
• Excessive consumption of alcoholic beverages or binge drinking
• Has donated blood or blood products within 6 weeks of study participation or plans to donate blood or blood products at any time during the trial

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

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

Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, Liao Y, Huyck S, Golm G, Terra SG, Mancuso JP, Engel SS, Lauring B. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab. 2018 Mar;20(3):530-540. doi: 10.1111/dom.13116. Epub 2017 Oct 23.

Reference Type: RESULT

PMID: 28921862 (View on PubMed)

Gallo S, Raji A, Calle RA, Pong A, Meyer C. The effects of ertugliflozin on beta-cell function: Pooled analysis from four phase 3 randomized controlled studies. Diabetes Obes Metab. 2020 Dec;22(12):2267-2275. doi: 10.1111/dom.14149. Epub 2020 Aug 27.

Reference Type: DERIVED

PMID: 32700393 (View on PubMed)

Gallo S, Calle RA, Terra SG, Pong A, Tarasenko L, Raji A. Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials. Diabetes Ther. 2020 Aug;11(8):1849-1860. doi: 10.1007/s13300-020-00867-1. Epub 2020 Jul 9.

Reference Type: DERIVED

PMID: 32648108 (View on PubMed)

Patel S, Hickman A, Frederich R, Johnson S, Huyck S, Mancuso JP, Gantz I, Terra SG. Safety of Ertugliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Seven Phase 3 Randomized Controlled Trials. Diabetes Ther. 2020 Jun;11(6):1347-1367. doi: 10.1007/s13300-020-00803-3. Epub 2020 May 5.

Reference Type: DERIVED

PMID: 32372382 (View on PubMed)

Liu J, Tarasenko L, Pong A, Huyck S, Wu L, Patel S, Hickman A, Mancuso JP, Gantz I, Terra SG. Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus. Curr Med Res Opin. 2020 Aug;36(8):1277-1284. doi: 10.1080/03007995.2020.1760228. Epub 2020 May 13.

Reference Type: DERIVED

PMID: 32324082 (View on PubMed)

Liu J, Tarasenko L, Pong A, Huyck S, Patel S, Hickman A, Mancuso JP, Ellison MC, Gantz I, Terra SG. Efficacy and safety of ertugliflozin in Hispanic/Latino patients with type 2 diabetes mellitus. Curr Med Res Opin. 2020 Jul;36(7):1097-1106. doi: 10.1080/03007995.2020.1760227. Epub 2020 May 13.

Reference Type: DERIVED

PMID: 32324065 (View on PubMed)

Liu J, Patel S, Cater NB, Wu L, Huyck S, Terra SG, Hickman A, Darekar A, Pong A, Gantz I. Efficacy and safety of ertugliflozin in East/Southeast Asian patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2020 Apr;22(4):574-582. doi: 10.1111/dom.13931. Epub 2020 Jan 3.

Reference Type: DERIVED

PMID: 31797522 (View on PubMed)

Liu J, Pong A, Gallo S, Darekar A, Terra SG. Effect of ertugliflozin on blood pressure in patients with type 2 diabetes mellitus: a post hoc pooled analysis of randomized controlled trials. Cardiovasc Diabetol. 2019 May 7;18(1):59. doi: 10.1186/s12933-019-0856-7.

Reference Type: DERIVED

PMID: 31064361 (View on PubMed)

Other Identifiers

2013-003697-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

B1521015

Identifier Type: OTHER

Identifier Source: secondary_id

8835-006

Identifier Type: -

Identifier Source: org_study_id