Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 3

Conditions: Type 2 Diabetes Mellitus

Treatments: Drug: Ertugliflozin; Drug: Glycemic Rescue; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT01986881

B1521021 (Other Identifier)

2013-002518-11 (EudraCT Number)

8835-004

Details and patient eligibility

About

An overall study of the cardiovascular outcomes following treatment with ertugliflozin in participants with type 2 diabetes mellitus (T2DM) and established vascular disease. The main objective of this study is to assess the cardiovascular safety of ertugliflozin. This trial includes 3 pre-defined glycemic sub-studies; 1. In participants receiving background insulin with or without metformin, 2. In participants receiving background sulfonylurea monotherapy, and 3. In participants receiving background metformin with sulfonylurea (all fully-enrolled).

Participants enrolled prior to Amendment 1 were in the overall study as well as a sub-study, if they met certain entry criteria. Participants enrolled following the start of Amendment 1 were only enrolled in the overall study. The sub-studies were the initial 18 weeks of the overall study period.

Full description

The primary hypotheses for the 4 studies are:

1. Overall Cardiovascular Study:

   The time to first occurrence of the composite endpoint of MACE: cardiovascular death, non-fatal myocardial infarction [MI] or non-fatal stroke in participants treated with ertugliflozin is non-inferior compared to that in participants treated with placebo.

2. The 3 Glycemic Sub-studies:

   1. The mean reduction from baseline in hemoglobin A1c (A1C) for 15 mg ertugliflozin is greater than that for placebo.
   2. The mean reduction from baseline in A1C for 5 mg ertugliflozin is greater than that for placebo.

Enrollment: 8,246 patients

Sex: All

Ages: 40+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (Overall Cardiovascular Study):

• Diagnosis of T2DM in accordance with American Diabetes Association (ADA) guidelines
• Hemoglobin A1c (A1C) at the start of study participation of 7.0-10.5% (53-91 mmol/mol)
• On stable allowable anti-hyperglycemic agents (AHA) or on no background AHA for at least 8 weeks prior to the study participation
• Body Mass Index (BMI) > or = to 18.0 kg/m^2
• Evidence or a history of atherosclerosis involving the coronary, cerebral or peripheral vascular systems
• There is adequate documentation of the objective evidence that the participant has established vascular disease such as investigational site's medical records, copies of such records from other institutions, or a letter from a referring physician that specifically states the diagnosis and date of the most recent occurrence of the qualifying event(s) or procedure(s).
• Male, female not or reproductive potential, or female of reproductive potential who agrees to be abstinent from heterosexual activity or agrees to use or have their partner use 2 acceptable methods of contraception

Exclusion Criteria (Overall Cardiovascular Study):

• Previous randomization into this trial
• Experiencing a cardiovascular event (myocardial infarction or stroke) or undergoing coronary angioplasty or peripheral intervention procedure between the Screening Visit and randomization
• Undergoing any cardiovascular surgery (valvular surgery) within 3 months of study participation
• Planned revascularization or peripheral intervention procedure or other cardiovascular surgery
• New York Heart Association (NYHA) IV heart failure at study participation
• History of type 1 diabetes mellitus or a history of ketoacidosis

Key Inclusion Criteria for the 3 Glycemic Sub-studies:

1. Insulin With or Without Metformin Sub-study: Stable doses of insulin (>=20 units/day, with variations up to 10% in the daily dose permitted) with or without metformin (>=1500 mg/day) for at least 8 weeks prior to the time of the Screening Visit (V1) and during the period between the Screening Visit (V1) and randomization.
2. Sulfonylurea (SU) Monotherapy Sub-study: Participants receiving a stable dose of SU monotherapy for at least 8 weeks prior to the time of the Screening Visit (V1) and during the period between the Screening Visit (V1) and randomization.
3. Metformin with SU Sub-study: Participants receiving a stable dose metformin (≥1500 mg/day) with a SU for at least 8 weeks prior to the time of the Screening Visit (V1) and during the period between the Screening Visit (V1) and randomization.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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8,246 participants in 3 patient groups, including a placebo group

Ertugliflozin, 15 mg

Experimental group

Description:

Ertugliflozin 15 mg administered orally once daily for up to approximately 6 years

Treatment:

Drug: Ertugliflozin

Drug: Glycemic Rescue

Ertugliflozin, 5 mg

Experimental group

Description:

Ertugliflozin 5 mg administered orally once daily for up to approximately 6 years

Treatment:

Drug: Ertugliflozin

Drug: Glycemic Rescue

Drug: Placebo

Placebo

Placebo Comparator group

Description:

Matching placebo to ertugliflozin administered orally once daily for up to approximately 6 years

Treatment:

Drug: Glycemic Rescue

Drug: Placebo