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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01986881
Recruitment Status : Completed
First Posted : November 19, 2013
Results First Posted : February 15, 2021
Last Update Posted : February 15, 2021
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE November 12, 2013
First Posted Date  ICMJE November 19, 2013
Results First Submitted Date  ICMJE December 16, 2020
Results First Posted Date  ICMJE February 15, 2021
Last Update Posted Date February 15, 2021
Actual Study Start Date  ICMJE November 4, 2013
Actual Primary Completion Date December 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 26, 2021)
  • Time to First Occurrence of MACE (Composite Endpoint of Major Adverse Cardiovascular Events [Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke]) (On-Treatment + 365-day Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to the first occurrence of any of the following adjudicated components of the primary composite endpoint (3-point major adverse cardiovascular events (MACE)): cardiovascular (CV) death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI, and non-fatal stroke. The on-treatment approach included confirmed events that occurred between the date of first dose of study medication and the on-treatment censor date. Person-years was calculated as the sum of participants' time to first event or time to censoring (the earliest of participants' end of study date, death date, last contact date, or 365 days after the last dose).
  • Baseline Hemoglobin A1C (A1C) (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This baseline reflects the Week 0 A1C.
  • Change From Baseline in Hemoglobin A1C (A1C) at Week 18 - Excluding Rescue Approach (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 18 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Baseline Hemoglobin A1C (A1C) (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Baseline ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This baseline reflects the Week 0 A1C.
  • Change From Baseline in Hemoglobin A1C (A1C) at Week 18 - Excluding Rescue Approach (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Baseline and Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 18 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Baseline Hemoglobin A1C (A1C) (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Baseline ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This baseline reflects Week 0 A1C.
  • Change From Baseline in Hemoglobin A1C (A1C) at Week 18 - Excluding Rescue Approach (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 18 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
Original Primary Outcome Measures  ICMJE
 (submitted: November 12, 2013)
Time to First Occurrence of Any Component of the Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke [ Time Frame: Up to 6.3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2021)
  • Time to Occurrence of Cardiovascular (CV) Death or Hospitalization for Heart Failure (HHF) (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to the occurrence of any of the following adjudicated components of cardiovascular (CV) death (including fatal stroke and fatal myocardial infarction (MI)) or hospitalization for heart failure. The on-study approach included confirmed events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to event or time to censoring (the earliest of participants' end of study date, death date, or last contact date).
  • Time to Occurrence of Cardiovascular Death (On-study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to the occurrence of cardiovascular (CV) death (including fatal stroke and fatal myocardial infarction (MI)). The on-study approach included confirmed events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to CV death or time to censoring (the earliest of participants' end of study date or date last known to be alive).
  • Time to First Occurrence of the Renal Composite: the Composite of Renal Death, Renal Dialysis/Transplant, or Doubling of Serum Creatinine From Baseline (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Renal composite endpoint was defined as a composite of renal death, renal dialysis/transplant, or doubling of serum creatinine from baseline. The on-study approach included events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to first event or time to censoring (the earliest of participants' end of study date, death date, or last contact date). The on-study approach included events that occurred between the randomization date and the on-study censor date.
  • Time to First Occurrence of MACE Plus (Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke or Hospitalization for Unstable Angina) (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to the first occurrence of any of the following adjudicated components 4-point MACE: cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina pectoris. The on-study approach included confirmed events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to first event or time to censoring (the earliest of participants' end of study date, death date, or last contact date). The on-study approach included events that occurred between the randomization date and the on-study censor date.
  • Time to First Occurrence of Fatal or Non-fatal Myocardial Infarction (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to First Occurrence of Fatal or Non-fatal Myocardial Infarction. The on-study approach included confirmed events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to first event or time to censoring (the earliest of participants' end of study date, death date, or last contact date).
  • Time to First Occurrence of Fatal or Non-fatal Stroke (FNF Stroke) (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to the first occurrence of fatal and no-fatal stroke. The on-study approach included confirmed events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to first event or time to censoring (the earliest of participants' end of study date, death date, or last contact date). The on-study approach included events that occurred between the randomization date and the on-study censor date.
  • Time to First Occurrence of Hospitalization for Heart Failure (HHF) (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to the first occurrence of heart failure requiring hospitalization (adjudicated). The on-study approach included confirmed events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to first event or time to censoring (the earliest of participants' end of study date, death date, or last contact date). The on-study approach included events that occurred between the randomization date and the on-study censor date.
  • Time to Occurrence of Death From Any Cause (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Time to the occurrence of death from any cause. The on-study approach included confirmed events that occurred between the randomization date and the on-study censor date. Person-years was calculated as the sum of participants' time to event or time to censoring (the earliest of participants' end of study date, death date, last contact date, or date last known to be alive. The on-study approach included events that occurred between the randomization date and the on-study censor date.
  • Andersen-Gill Model for Total MACE (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    All events (first and recurrent) of the composite of MACE (3-point major adverse cardiovascular events: cardiovascular (CV) death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI, and non-fatal stroke) were assessed using Andersen-Gill model. The on-study approach included events that occurred between the randomization date and the on-study censor date.
  • Andersen-Gill Model for All Cardiovascular Death (CV Death) or Hospitalizations for Heart Failure (HFF) (On-Study Approach) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    All events (first and recurrent) of the composite of CV death and HHF were assessed using an Andersen-Gill model. Person-years were calculated as the sum of time from randomization to end of follow-up. The on-study approach included events that occurred between the randomization date and the on-study censor date.
  • Change From Baseline in Hemoglobin A1C (A1C) at Week 18 - Excluding Rescue Approach (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 18 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in A1C at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 52 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in A1C at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Month 24 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in A1C at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Month 36 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in A1C at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Month 48 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in A1C at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Month 60 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in A1C at Month 72 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 72 ]
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Month 72 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Week 18 (Overall Cardiovascular Study) [ Time Frame: Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Week 52 (Overall Cardiovascular Study) [ Time Frame: Week 52 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Month 24 (Overall Cardiovascular Study) [ Time Frame: Month 24 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Month 36 (Overall Cardiovascular Study) [ Time Frame: Month 36 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Month 48 (Overall Cardiovascular Study) [ Time Frame: Month 48 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Month 60 (Overall Cardiovascular Study) [ Time Frame: Month 60 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <6.5% (<48 mmol/Mol) at Week 18 (Overall Cardiovascular Study) [ Time Frame: Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <6.5% (<48 mmol/Mol) at Week 52 (Overall Cardiovascular Study) [ Time Frame: Week 52 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <6.5% (<48 mmol/Mol) at Month 24 (Overall Cardiovascular Study) [ Time Frame: Month 24 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <6.5% (<48 mmol/Mol) at Month 36 (Overall Cardiovascular Study) [ Time Frame: Month 36 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <6.5% (<48 mmol/Mol) at Month 48 (Overall Cardiovascular Study) [ Time Frame: Month 48 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With an A1C <6.5% (<48 mmol/Mol) at Month 60 (Overall Cardiovascular Study) [ Time Frame: Month 60 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 18 (Excluding Rescue Approach) (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding rescue", excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Week 52 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Month 24 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Month 36 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Month 48 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Month 60 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Month 72 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 72 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Month 72 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Time to the First Occurrence of a Participant Receiving Glycemic Rescue Therapy Through Week 18 (Overall Cardiovascular Study) [ Time Frame: Up to 18 weeks ]
    Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication.
  • Time to Initiation of Insulin for Participants Not on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    Participants who were not on insulin therapy at the start of study medication.
  • Baseline Insulin Dose for Participants Who Were on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Baseline ]
    Baseline reflects Week 0 insulin dose.
  • Change From Baseline in Insulin Dose at Week 18 for Participants Who Were on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 insulin dose minus the Week 0 insulin dose. A negative number indicates a reduction in the insulin dose.
  • Change From Baseline in Insulin Dose at Week 52 for Participants Who Were on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    This change from baseline reflects the Week 52 insulin dose minus the Week 0 insulin dose. A negative number indicates a reduction in the insulin dose.
  • Change From Baseline in Insulin Dose at Month 24 for Participants Who Were on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    This change from baseline reflects the Month 24 insulin dose minus the Week 0 insulin dose. A negative number indicates a reduction in the insulin dose.
  • Change From Baseline in Insulin Dose at Month 36 for Participants Who Were on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    This change from baseline reflects the Month 36 insulin dose minus the Week 0 insulin dose. A negative number indicates a reduction in the insulin dose.
  • Change From Baseline in Insulin Dose at Month 48 for Participants Who Were on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    This change from baseline reflects the Month 48 insulin dose minus the Week 0 insulin dose. A negative number indicates a reduction in the insulin dose.
  • Change From Baseline in Insulin Dose at Month 60 for Participants Who Were on Insulin at Baseline (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    This change from baseline reflects the Month 60 insulin dose minus the Week 0 insulin dose. A negative number indicates a reduction in the insulin dose.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 18 (Excluding Rescue Approach) (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding rescue", excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    This change from baseline reflects the Week 52 sitting SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    This change from baseline reflects the Month 24 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    This change from baseline reflects the Month 36 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    This change from baseline reflects the Month 48 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    This change from baseline reflects the Month 60 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Month 72 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 72 ]
    This change from baseline reflects the Month 72 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Week 18 (Excluding Rescue Approach) (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding rescue", excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    This change from baseline reflects the Week 52 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    This change from baseline reflects the Month 24 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    This change from baseline reflects the Month 36 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    This change from baseline reflects the Month 48 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    This change from baseline reflects the Month 60 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Month 72 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 72 ]
    This change from baseline reflects the Month 72 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Body Weight at Week 18 (Excluding Rescue Approach) (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Body Weight at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    This change from baseline reflects the Week 52 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Body Weight at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    This change from baseline reflects the Month 24 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Body Weight at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    This change from baseline reflects the Month 36 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Body Weight at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    This change from baseline reflects the Month 48 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Body Weight at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    This change from baseline reflects the Month 60 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Body Weight at Month 72 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 72 ]
    This change from baseline reflects the Month 72 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 18 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 eGFR minus the Week 0 eGFR. A negative number indicates a reduction in the eGFR level.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    This change from baseline reflects the Week 52 eGFR minus the Week 0 eGFR. A negative number indicates a reduction in eGFR level.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    This change from baseline reflects the Month 24 eGFR minus the Week 0 eGFR. A negative number indicates a reduction in the eGFR level.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    This change from baseline reflects the Month 36 eGFR minus the Week 0 eGFR. A negative number indicates a reduction in the eGFR level.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    This change from baseline reflects the Month 48 eGFR minus the Week 0 eGFR. A negative number indicates a reduction in eGFR level.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    This change from baseline reflects the Month 60 eGFR minus the Week 0 eGFR. A negative number indicates a reduction in the eGFR level.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Month 72 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 72 ]
    This change from baseline reflects the Month 72 eGFR minus the Week 0 eGFR. A negative number indicates a reduction in the eGFR level.
  • Baseline Serum Creatinine (Overall Cardiovascular Study) [ Time Frame: Baseline ]
    Baseline reflects Week 0 serum creatinine.
  • Change From Baseline in Serum Creatinine at Week 18 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 serum creatinine minus the Week 0 serum creatinine. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Serum Creatinine at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    This change from baseline reflects the Week 52 serum creatinine minus the Week 0 serum creatinine. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Serum Creatinine at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    This change from baseline reflects the Month 24 serum creatinine minus the Week 0 serum creatinine. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Serum Creatinine at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    This change from baseline reflects the Month 36 serum creatinine minus the Week 0 serum creatinine. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Serum Creatinine at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    This change from baseline reflects the Month 48 serum creatinine minus the Week 0 serum creatinine. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Serum Creatinine at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    This change from baseline reflects the Month 60 serum creatinine minus the Week 0 serum creatinine. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Change From Baseline in Serum Creatinine at Month 72 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 72 ]
    This change from baseline reflects the Month 72 serum creatinine minus the Week 0 serum creatinine. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Baseline Urinary Albumin/Creatinine Ratio (Overall Cardiovascular Study) [ Time Frame: Baseline ]
    Baseline reflects Week 0 albumin/creatinine ratio.
  • Percent Change From Baseline in Urinary Albumin/Creatinine Ratio at Week 18 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 18 ]
    This percent change relative to baseline reflects the Week 18 albumin/creatinine ratio minus the Week 0 albumin/creatinine ratio. This difference was divided by the baseline to obtain the percent change. A negative number indicates a reduction in the urinary albumin/creatinine ratio. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percent Change From Baseline in Urinary Albumin/Creatinine Ratio at Week 52 (Overall Cardiovascular Study) [ Time Frame: Baseline and Week 52 ]
    This percent change relative to baseline reflects the Week 52 albumin/creatinine ratio minus the Week 0 albumin/creatinine ratio. This difference was divided by the baseline to obtain the percent change. A negative number indicates a reduction in the albumin/creatinine ratio. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percent Change From Baseline in Urinary Albumin/Creatinine Ratio at Month 24 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 24 ]
    This percent change relative to baseline reflects the Month 24 albumin/creatinine ratio minus the Week 0 albumin/creatinine ratio. This difference was divided by the baseline to obtain the percent change. A negative number indicates a reduction in urinary albumin/creatinine ratio. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percent Change From Baseline in Urinary Albumin/Creatinine Ratio at Month 36 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 36 ]
    This percent change relative to baseline reflects the Month 36 albumin/creatinine ratio minus the Week 0 albumin/creatinine ratio. This difference was divided by the baseline to obtain the percent change. A negative number indicates a reduction in urinary albumin/creatinine ratio. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percent Change From Baseline in Urinary Albumin/Creatinine Ratio at Month 48 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 48 ]
    This percent change relative to baseline reflects the Month 48 albumin/creatinine ratio minus the Week 0 albumin/creatinine ratio. This difference was divided by the baseline to obtain the percent change. A negative number indicates a reduction in albumin/creatinine ratio. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percent Change From Baseline in Urinary Albumin/Creatinine Ratio at Month 60 (Overall Cardiovascular Study) [ Time Frame: Baseline and Month 60 ]
    This percent change relative to baseline reflects the Month 60 albumin/creatinine ratio minus the Week 0 albumin/creatinine ratio. This difference was divided by the baseline to obtain the percent change. A negative number indicates a reduction in albumin/creatinine ratio. Participants who met glycemic rescue criteria received glycemic rescue medication.
  • Percentage of Participants With Albuminuria Progression or Regression at Week 18 (Overall Cardiovascular Study) [ Time Frame: Week 18 ]
    Albuminuria progression and regression were assessed relative to the baseline albuminuria category. Progression was defined as either a change from having normal-albuminuria at baseline to micro-albuminuria at the respective visit, or micro-albuminuria at baseline to macro-albuminuria at the respective visit, or normal albuminuria at baseline to macro-albuminuria at the respective visit. Regression was defined as either a change from having micro-albuminuria at baseline to normal albuminuria at the respective visit, or macro-albuminuria at baseline to micro-albuminuria at the respective visit, or macro-albuminuria at baseline to normal albuminuria at the respective visit. Normal albuminuria: urine albumin to urinary creatinine ratio (UACR) <30 (mg/g); Micro-albuminuria: UACR ≥30 and ≤300 (mg/g); Macro-albuminuria: UACR>300 (mg/g).
  • Percentage of Participants With Albuminuria Progression or Regression at Week 52 (Overall Cardiovascular Study) [ Time Frame: Week 52 ]
    Albuminuria progression and regression were assessed relative to the baseline albuminuria category. Progression was defined as either a change from having normal albuminuria at baseline to micro-albuminuria at the respective visit, or micro-albuminuria at baseline to macro-albuminuria at the respective visit, or normal albuminuria at baseline to macro-albuminuria at the respective visit. Regression was defined as either a change from having micro-albuminuria at baseline to normal albuminuria at the respective visit, or macro-albuminuria at baseline to micro-albuminuria at the respective visit, or macro-albuminuria at baseline to normal albuminuria at the respective visit. Normal albuminuria: urine albumin to urinary creatinine ratio (UACR) <30 (mg/g); Micro-albuminuria: UACR ≥30 and ≤300 (mg/g); Macro-albuminuria: UACR>300 (mg/g).
  • Percentage of Participants With Albuminuria Progression or Regression at Month 24 (Overall Cardiovascular Study) [ Time Frame: Month 24 ]
    Albuminuria progression and regression were assessed relative to the baseline albuminuria category. Progression was defined as either a change from having normal albuminuria at baseline to micro-albuminuria at the respective visit, or micro-albuminuria at baseline to macro-albuminuria at the respective visit, or normal albuminuria at baseline to macro-albuminuria at the respective visit. Regression was defined as either a change from having micro-albuminuria at baseline to normal albuminuria at the respective visit, or macro-albuminuria at baseline to micro-albuminuria at the respective visit, or macro-albuminuria at baseline to normal albuminuria at the respective visit. Normal albuminuria: urine albumin to urinary creatinine ratio (UACR) <30 (mg/g); Micro-albuminuria: UACR ≥30 and ≤300 (mg/g); Macro-albuminuria: UACR>300 (mg/g).
  • Percentage of Participants With Albuminuria Progression or Regression at Month 36 (Overall Cardiovascular Study) [ Time Frame: Month 36 ]
    Albuminuria progression and regression were assessed relative to the baseline albuminuria category. Progression was defined as either a change from having normal albuminuria at baseline to micro-albuminuria at the respective visit, or micro-albuminuria at baseline to macro-albuminuria at the respective visit, or normal albuminuria at baseline to macro-albuminuria at the respective visit. Regression was defined as either a change from having micro-albuminuria at baseline to normal albuminuria at the respective visit, or macro-albuminuria at baseline to micro-albuminuria at the respective visit, or macro-albuminuria at baseline to normal albuminuria at the respective visit. Normal albuminuria: urine albumin to urinary creatinine ratio (UACR) <30 (mg/g); Micro-albuminuria: UACR ≥30 and ≤300 (mg/g); Macro-albuminuria: UACR>300 (mg/g).
  • Percentage of Participants With Albuminuria Progression or Regression at Month 48 (Overall Cardiovascular Study) [ Time Frame: Month 48 ]
    Albuminuria progression and regression were assessed relative to the baseline albuminuria category. Progression was defined as either a change from having normal albuminuria at baseline to micro-albuminuria at the respective visit, or micro-albuminuria at baseline to macro-albuminuria at the respective visit, or normal albuminuria at baseline to macro-albuminuria at the respective visit. Regression was defined as either a change from having micro-albuminuria at baseline to normal albuminuria at the respective visit, or macro-albuminuria at baseline to micro-albuminuria at the respective visit, or macro-albuminuria at baseline and normal albuminuria at the respective visit. Normal albuminuria: urine albumin to urinary creatinine ratio (UACR) <30 (mg/g); Micro-albuminuria: UACR ≥30 and ≤300 (mg/g); Macro-albuminuria: UACR>300 (mg/g).
  • Percentage of Participants With Albuminuria Progression or Regression at Month 60 (Overall Cardiovascular Study) [ Time Frame: Month 60 ]
    Albuminuria progression and regression were assessed relative to the baseline albuminuria category. Progression was defined as either a change from having normal albuminuria at baseline to micro albuminuria at the respective visit, or micro-albuminuria at baseline to macro-albuminuria at the respective visit, or normal albuminuria at baseline to macro-albuminuria at the respective visit. Regression was defined as either a change from having micro-albuminuria at baseline to normal albuminuria at the respective visit, or macro-albuminuria at baseline to micro-albuminuria at the respective visit, or macro-albuminuria at baseline to normal albuminuria at the respective visit. Normal albuminuria: urine albumin to urinary creatinine ratio (UACR) <30 (mg/g); Micro-albuminuria: UACR ≥30 and ≤300 (mg/g); Macro-albuminuria: UACR>300 (mg/g).
  • Percentage of Participants Experiencing an Adverse Event (AE) (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Percentage of Participants Experiencing an Adverse Event (AE) (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Up to 18 weeks ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Percentage of Participants Experiencing an Adverse Event (AE) (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Up to 18 weeks ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Percentage of Participants Experiencing an Adverse Event (AE) (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Up to 18 weeks ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Percentage of Participants Discontinuing Study Treatment Due to An AE (Overall Cardiovascular Study) [ Time Frame: Up to approximately 6 years ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Percentage of Participants Discontinuing Study Treatment Due to An AE (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Up to 18 weeks ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Percentage of Participants Discontinuing Study Treatment Due to An AE (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Up to 18 weeks ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Percentage of Participants Discontinuing Study Treatment Due to An AE (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Up to 18 weeks ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 18 (Excluding Rescue Approach) (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. A negative number indicates a reduction in the FPG. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Body Weight at Week 18 (Excluding Rescue Approach) (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 body weight minus the Week 0 body weight. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Week 18 (Excluding Rescue Approach) (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 18 (Excluding Rescue Approach) (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Week 18 (Excluding Rescue Approach) (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 DBP minus the Week 0 BBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Baseline Insulin Dose for Participants Receiving Insulin at Baseline - (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline ]
    Baseline reflects Week 0 insulin dose.
  • Change From Baseline at Week 18 in Insulin Dose for Participants Receiving Insulin at Baseline - Including Rescue Approach (Insulin With or Without Metformin Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 insulin dose minus the Week 0 insulin dose. A negative number indicates a decrease in insulin dose. Participants who met glycemic rescue criteria received glycemic rescue medication. "Including rescue", included data following the initiation of rescue therapy.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 18 (Excluding Rescue Approach) (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Baseline and Week 18 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Body Weight at Week 18 (Excluding Rescue Approach) (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Week 18 (Excluding Rescue Approach) (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 18 (Excluding Rescue Approach) (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Diastolic Blood (DBP) Pressure at Week 18 (Excluding Rescue Approach) (Sulfonylurea Monotherapy Add-on Glycemic Sub-Study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 18 (Excluding Rescue Approach) (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    FPG was analyzed after an overnight fast. This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. A negative number indicates a reduction in FPG. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Body Weight at Week 18 (Excluding Rescue Approach) (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 body weight minus the Week 0 body weight. A negative number indicates a reduction in body weight. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Percentage of Participants With an A1C <7% (<53 mmol/Mol) at Week 18 (Excluding Rescue Approach) (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Week 18 ]
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 18 (Excluding Rescue Approach) (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 SBP minus the Week 0 SBP. A negative number indicates a reduction in SBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
  • Change From Baseline in Sitting Diastolic Blood (DBP) Pressure at Week 18 (Excluding Rescue Approach) (Metformin With Sulfonylurea Add-on Glycemic Sub-study) [ Time Frame: Baseline and Week 18 ]
    This change from baseline reflects the Week 18 DBP minus the Week 0 DBP. A negative number indicates a reduction in DBP. Participants who met glycemic rescue criteria received glycemic rescue medication. "Excluding Rescue" excluded all data following the initiation of rescue in order to avoid the confounding influence of the rescue therapy.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2013)
  • Time to First Occurrence of any of the Components of the Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke or Hospitalization for Unstable Angina [ Time Frame: Up to 6.3 years ]
  • Number of Participants Experiencing An Adverse Event (AE) [ Time Frame: Up to 6.3 years ]
  • Number of Participants Discontinuing Study Treatment Due to an AE [ Time Frame: Up to 6.3 years ]
  • Change from Baseline In Hemoglobin A1c (HbA1c) at Week 18 [ Time Frame: Baseline and Week 18 ]
  • Change from Baseline In HbA1c at the End of Study (up to 6.3 years) [ Time Frame: Baseline and at the End of Study (up to 6.3 years) ]
  • Change from Baseline in Fasting Plasma Glucose (FPG) at Week 18 [ Time Frame: Baseline and Week 18 ]
  • Change from Baseline in Body Weight at Week 18 [ Time Frame: Baseline and Week 18 ]
  • Change from Baseline in Body Weight at the End of Study (up to 6.3 years) [ Time Frame: Baseline and at the End of Study (up to 6.3 years) ]
  • Number of Participants with a HbA1c <7% at Week 18 [ Time Frame: Week 18 ]
  • Number of Participants with a HbA1c <7% at the End of Study (up to 6.3 years) [ Time Frame: At the End of Study (up to 6.3 years) ]
  • Change from Baseline in Systolic Blood Pressure at Week 18 [ Time Frame: Baseline and Week 18 ]
  • Change from Baseline in Systolic Blood Pressure at the End of Study (up to 6.3 years) [ Time Frame: Baseline and at the End of Study (up to 6.3 years) ]
  • Change from Baseline in Diastolic Blood Pressure at Week 18 [ Time Frame: Baseline and Week 18 ]
  • Change from Baseline in Diastolic Blood Pressure at the End of Study (up to 6.3 years) [ Time Frame: Baseline and at the End of Study (up to 6.3 years) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004)
Official Title  ICMJE Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess Cardiovascular Outcomes Following Treatment With Ertugliflozin (MK-8835/PF-04971729) in Subjects With Type 2 Diabetes Mellitus and Established Vascular Disease, The VERTIS CV Study
Brief Summary

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.

Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Type 2 Diabetes Mellitus
Intervention  ICMJE
  • Drug: Ertugliflozin
    Oral, once daily, for up to approximately 6 years
    Other Name: MK-8835, PF-04971729, Steglatro
  • Drug: Placebo
    Matching placebo to ertugliflozin administered orally, once daily, for up to approximately 6 years
  • Drug: Glycemic Rescue
    Doses of background anti-hyperglycemic agents (AHA), medications will be required to be held constant in all participants enrolled for the initial 18 weeks of the trial with 2 exceptions: First, participant will be prescribed glycemic rescue therapy if they meet specific, progressively more stringent, glycemic thresholds based on repeated, confirmed fasting plasma glucose (FPG) measured at a central laboratory. Second, a participant experiencing clinically significant hypoglycemia according to the investigator at any time during the trial is permitted to have the dose of appropriate background AHA (e.g., insulin, sulfonylurea [SU], glinide) reduced or discontinued as per the judgment of the investigator or the treating physician. Choice and dosing of glycemic rescue will be at the discretion of the investigator or the treating physician consistent with standards of care for management of patients with Type 2 diabetes mellitus (T2DM) within the country of the investigational site.
Study Arms  ICMJE
  • Experimental: Ertugliflozin, 15 mg
    Ertugliflozin 15 mg administered orally once daily for up to approximately 6 years
    Interventions:
    • Drug: Ertugliflozin
    • Drug: Glycemic Rescue
  • Experimental: Ertugliflozin, 5 mg
    Ertugliflozin 5 mg administered orally once daily for up to approximately 6 years
    Interventions:
    • Drug: Ertugliflozin
    • Drug: Placebo
    • Drug: Glycemic Rescue
  • Placebo Comparator: Placebo
    Matching placebo to ertugliflozin administered orally once daily for up to approximately 6 years
    Interventions:
    • Drug: Placebo
    • Drug: Glycemic Rescue
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 13, 2020)
8246
Original Estimated Enrollment  ICMJE
 (submitted: November 12, 2013)
3900
Actual Study Completion Date  ICMJE December 27, 2019
Actual Primary Completion Date December 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Argentina,   Australia,   Bulgaria,   Canada,   Colombia,   Croatia,   Czech Republic,   Czechia,   Georgia,   Greece,   Hong Kong,   Hungary,   Israel,   Italy,   Korea, Republic of,   Latvia,   Lithuania,   Mexico,   Netherlands,   New Zealand,   Philippines,   Poland,   Romania,   Russian Federation,   Serbia,   Slovakia,   South Africa,   Sweden,   Taiwan,   Thailand,   Turkey,   Ukraine,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT01986881
Other Study ID Numbers  ICMJE 8835-004
2013-002518-11 ( EudraCT Number )
B1521021 ( Other Identifier: Pfizer Protocol Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP