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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)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02036515
First Posted: January 15, 2014
Last Update Posted: November 13, 2017
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.
Collaborator:
Pfizer
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
  Purpose
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.

Condition Intervention Phase
Type 2 Diabetes Mellitus Drug: Ertugliflozin 5 mg Drug: Ertugliflozin 15 mg Drug: Placebo for ertugliflozin 5 mg Drug: Metformin Drug: Sitagliptin Drug: Glimepiride Biological: Insulin Drug: Placebo for ertugliflozin 10 mg Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial to Evaluate the Safety and Efficacy of Ertugliflozin (MK-8835/PF-04971729) in the Treatment of Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin and Sitagliptin

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Change From Baseline in Hemoglobin A1C at Week 26 [ Time Frame: Baseline and Week 26 ]
    A1C is measured as percent. Thus this change from baseline reflects the Week 26 A1C percent minus the Week 0 A1C percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.

  • Percentage of Participants Experiencing An Adverse Event (AE) [ Time Frame: Up to Week 54 ]
    An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy.

  • Percentage of Participants Discontinuing Study Treatment Due to an AE [ Time Frame: Up to Week 52 ]
    An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy.


Secondary Outcome Measures:
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 [ Time Frame: Baseline and Week 26 ]
    The change from baseline is the Week 26 FPG minus the Week 0 FPG. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in Body Weight at Week 26 [ Time Frame: Baseline and Week 26 ]
    The change from baseline is the Week 26 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy.

  • Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 26 [ Time Frame: Week 26 ]
    A1C is measured as percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in Sitting Systolic Blood Pressure at Week 26 [ Time Frame: Baseline and Week 26 ]
    The change from baseline is the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in Hemoglobin A1C at Week 52 [ Time Frame: Baseline and Week 52 ]
    A1C is measured as percent. Thus this change from baseline reflects the Week 52 A1C percent minus the Week 0 A1C percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in FPG at Week 52 [ Time Frame: Baseline and Week 52 ]
    The change from baseline is the Week 52 FPG minus the Week 0 FPG. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in Body Weight at Week 52 [ Time Frame: Baseline and Week 52 ]
    The change from baseline is the Week 52 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy.

  • Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52 [ Time Frame: Week 52 ]
    A1C is measured as percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in Sitting Systolic Blood Pressure at Week 52 [ Time Frame: Baseline and Week 52 ]
    The change from baseline is the Week 52 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 [ Time Frame: Baseline and Week 26 ]
    The change from baseline is the Week 26 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 [ Time Frame: Baseline and Week 52 ]
    The change from baseline is the Week 52 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.

  • Percentage of Participants Receiving Glycemic Rescue Medication by Week 26 [ Time Frame: Week 26 ]
    Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant).

  • Percentage of Participants Receiving Glycemic Rescue Medication by Week 52 [ Time Frame: Week 52 ]
    Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant).

  • Time to Initiation of Glycemic Rescue by Week 26 [ Time Frame: Up to Week 26 (plus 30 days for 1 placebo participant) ]
    Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days. Below data include data from 1 participant in the Placebo arm who continued Phase A treatment for an additional 30 days.

  • Time to Initiation of Glycemic Rescue by Week 52 [ Time Frame: Up to week 52 ]
    Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days.

  • Baseline Homeostasis Model Assessment of β-cell Function (HOMA-%β) Value [ Time Frame: Baseline ]
    HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = [20 x fasting insulin (μU/mL)] / [fasting plasma glucose (mmol/L) - 3.5]

  • Change From Baseline in HOMA-%β at Week 26 [ Time Frame: Baseline and Week 26 ]
    HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = [20 x fasting insulin (μU/mL)] / [fasting plasma glucose (mmol/L) - 3.5]. Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in HOMA-%β at Week 52 [ Time Frame: Baseline and Week 52 ]
    HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = [20 x fasting insulin (μU/mL)] / [fasting plasma glucose (mmol/L) - 3.5]. Data presented exclude data following the initiation of rescue therapy.

  • Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score [ Time Frame: Baseline ]
    The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 1-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ visual analogue score (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best).

  • Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26 [ Time Frame: Baseline and Week 26 ]
    The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy.

  • Change From Baseline in EQ-5D-3L Score at Week 52 [ Time Frame: Baseline and Week 52 ]
    The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy.


Enrollment: 464
Actual Study Start Date: March 12, 2014
Study Completion Date: June 6, 2016
Primary Completion Date: June 6, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ertugliflozin 5 mg
Ertugliflozin, 5 mg, oral, once daily for 52 weeks
Drug: Ertugliflozin 5 mg
Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks
Other Names:
  • MK-8835
  • PF-04971729
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.
Other Names:
  • Glucophage
  • Glucophage XR
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.
Other Name: JANUVIA®
Drug: Glimepiride
Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion
Other Name: AMARYL
Biological: 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.
Drug: Placebo for ertugliflozin 10 mg
Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks
Experimental: Ertugliflozin 15 mg
Ertugliflozin, 15 mg, oral, once daily for 52 weeks
Drug: Ertugliflozin 15 mg
Ertugliflozin, oral, 5 mg and 10 mg tablet once daily for 52 weeks
Other Names:
  • MK-8835
  • PF-04971729
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.
Other Names:
  • Glucophage
  • Glucophage XR
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.
Other Name: JANUVIA®
Drug: Glimepiride
Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion
Other Name: AMARYL
Biological: 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.
Placebo Comparator: Placebo
Matching placebo to ertuglifozin, oral, once daily for 52 weeks
Drug: Placebo for ertugliflozin 5 mg
Matching placebo for ertugliflozin 5 mg, oral, once daily for 52 weeks
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.
Other Names:
  • Glucophage
  • Glucophage XR
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.
Other Name: JANUVIA®
Drug: Glimepiride
Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion
Other Name: AMARYL
Biological: 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.
Drug: Placebo for ertugliflozin 10 mg
Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks

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.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02036515


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Pfizer
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Publications:
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT02036515     History of Changes
Other Study ID Numbers: 8835-006
2013-003697-26 ( EudraCT Number )
B1521015 ( Other Identifier: Pfizer Study Number )
First Submitted: January 13, 2014
First Posted: January 15, 2014
Results First Submitted: May 19, 2017
Results First Posted: July 24, 2017
Last Update Posted: November 13, 2017
Last Verified: October 2017

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glimepiride
Insulin
Metformin
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Arrhythmia Agents
Immunosuppressive Agents
Immunologic Factors