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Ertugliflozin and Sitagliptin Co-administration Factorial Study (VERTIS FACTORAL, MK-8835-005)

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: NCT02099110
Recruitment Status : Completed
First Posted : March 28, 2014
Results First Posted : November 1, 2017
Last Update Posted : September 12, 2018
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:
This is a study of co-administration of ertugliflozin (MK-8835/PF-04971729) and sitagliptin given together or alone along with metformin in participants with Type 2 diabetes mellitus (T2DM) and inadequate glycemic control on metformin monotherapy. The primary hypothesis of this study is that ertugliflozin 15 mg daily plus sitagliptin 100 mg daily provides greater hemoglobin A1C (A1C)-lowering compared with sitagliptin 100 mg daily alone.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Matching Placebo to Ertugliflozin 5 mg Drug: Matching Placebo to Ertugliflozin 10 mg Drug: Matching Placebo to sitagliptin 100 mg Drug: Ertugliflozin 5 mg Drug: Ertugliflozin 10 mg Drug: Sitagliptin 100 mg Drug: Metformin >= 1500 mg/day Biological: Insulin Glargine Rescue Medication Drug: Glimepiride Rescue Medication Phase 3

Detailed Description:
This study will include a 1-week screening period; an up to 12-week metformin titration/dose stabilization period; a 2-week single-blind placebo run-in period; a 52-week (26-week Phase A and 26-week Phase B) double-blind treatment period and a post-treatment telephone contact 14 days after the last dose of study medication.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1233 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of the Combination of Ertugliflozin (MK-8835/PF-04971729) With Sitagliptin Compared With Ertugliflozin Alone and Sitagliptin Alone, in the Treatment of Subjects With T2DM With Inadequate Glycemic Control on Metformin Monotherapy
Actual Study Start Date : April 22, 2014
Actual Primary Completion Date : May 26, 2016
Actual Study Completion Date : May 26, 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Ertugliflozin 5 mg + sitagliptin 100 mg
Ertugliflozin 5 mg + sitagliptin 100 mg, oral, once daily for 52 weeks
 Drug: Matching Placebo to Ertugliflozin 10 mg
Placebo to ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period

Drug: Ertugliflozin 5 mg
Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Names:
  • MK-8835
  • PF-04971729

Drug: Sitagliptin 100 mg
Sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Name: JANUVIA®

Drug: Metformin >= 1500 mg/day
Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period
Other Names:
  • Glucophage
  • Glucophage XR

Biological: Insulin Glargine Rescue Medication
Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion
Other Name: Lantus

Drug: Glimepiride Rescue Medication
Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion
Other Name: AMARYL
Experimental: Ertugliflozin 15 mg + sitagliptin 100 mg
Ertugliflozin 15 mg + sitagliptin 100 mg, oral, once daily for 52 weeks
 Drug: Ertugliflozin 5 mg
Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Names:
  • MK-8835
  • PF-04971729

Drug: Ertugliflozin 10 mg
Ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Names:
  • MK-8835
  • PF-04971729

Drug: Sitagliptin 100 mg
Sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Name: JANUVIA®

Drug: Metformin >= 1500 mg/day
Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period
Other Names:
  • Glucophage
  • Glucophage XR

Biological: Insulin Glargine Rescue Medication
Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion
Other Name: Lantus

Drug: Glimepiride Rescue Medication
Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion
Other Name: AMARYL
Experimental: Ertugliflozin 5 mg
Ertugliflozin 5 mg, oral, once daily for 52 weeks
 Drug: Matching Placebo to Ertugliflozin 10 mg
Placebo to ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period

Drug: Matching Placebo to sitagliptin 100 mg
Placebo to sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period

Drug: Ertugliflozin 5 mg
Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Names:
  • MK-8835
  • PF-04971729

Drug: Metformin >= 1500 mg/day
Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period
Other Names:
  • Glucophage
  • Glucophage XR

Biological: Insulin Glargine Rescue Medication
Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion
Other Name: Lantus

Drug: Glimepiride Rescue Medication
Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion
Other Name: AMARYL
Experimental: Ertugliflozin 15 mg
Ertugliflozin, oral, once daily for 52 weeks
 Drug: Matching Placebo to sitagliptin 100 mg
Placebo to sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period

Drug: Ertugliflozin 5 mg
Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Names:
  • MK-8835
  • PF-04971729

Drug: Ertugliflozin 10 mg
Ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Names:
  • MK-8835
  • PF-04971729

Drug: Metformin >= 1500 mg/day
Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period
Other Names:
  • Glucophage
  • Glucophage XR

Biological: Insulin Glargine Rescue Medication
Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion
Other Name: Lantus

Drug: Glimepiride Rescue Medication
Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion
Other Name: AMARYL
Active Comparator: Sitagliptin 100 mg
Sitagliptin 100 mg, oral, once daily for 52 weeks
 Drug: Matching Placebo to Ertugliflozin 5 mg
Placebo to ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period

Drug: Matching Placebo to Ertugliflozin 10 mg
Placebo to ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period

Drug: Sitagliptin 100 mg
Sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Other Name: JANUVIA®

Drug: Metformin >= 1500 mg/day
Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period
Other Names:
  • Glucophage
  • Glucophage XR

Biological: Insulin Glargine Rescue Medication
Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion
Other Name: Lantus

Drug: Glimepiride Rescue Medication
Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion
Other Name: AMARYL


Outcome Measures
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Primary Outcome Measures :
  1. Change From Baseline in A1C at Week 26: Excluding Rescue Approach [ Time Frame: Baseline and Week 26 ]
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.

  2. Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach [ Time Frame: Up to 54 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. Including rescue approach data analysis included data following the initiation of rescue therapy.

  3. Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach [ Time Frame: Up to 52 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. Including rescue approach data analysis included data following the initiation of rescue therapy.


Secondary Outcome Measures :
  1. Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach [ Time Frame: Baseline and Week 26 ]
    This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.

  2. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach [ Time Frame: Baseline and Week 26 ]
    Blood glucose was measured on a fasting basis after at least a 10-hour fast. This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.

  3. Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach [ Time Frame: Week 26 ]
    A1C is blood marker used to report average blood glucose levels over a prolonged periods of time and is reported as a percentage (%). Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.

  4. Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach [ Time Frame: 30 min. before and 0, 15, 30, 60, 90, 120, and 180 minutes following the start of the standard meal at Baseline and Week 26 ]
    Static beta-cell sensitivity to glucose index (SBCSGI) estimates the ratio of insulin secretion (expressed in pmol/min) related to above-basal glucose concentration (expressed in mmol/L * L) following a meal. Blood samples were collected before and after a standard meal and glucose, insulin, and C-peptide levels were analyzed. The C-peptides minimal model was used to estimate the insulin secretion rate (ISR). Analysis included both non-model-based [including insulinogenic index with C-peptide, glucose area under the curve (AUC)/insulin AUC] and model-based [beta cell function and insulin secretion rate at 9 mM glucose] testing. Analysis was performed with non-linear least squares using the Software Architecture Analysis Method (SAAM) II software. SBCSGI was expressed in units of 10^-9 min^-1. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.

  5. Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach [ Time Frame: Baseline and Week 26 ]
    This change from baseline reflects the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.


Eligibility Criteria
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Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes mellitus as per American Diabetes Association guidelines
  • On metformin monotherapy (>=1500 mg/day) for >=8 weeks with a Visit 1/Screening A1C >=7.5% and <=11.0% (>=58 mmol/mol and <=97 mmol/mol) OR On metformin monotherapy (>=1500 mg/day) for <8 weeks with a Visit 1/Screening A1C >=7.5% and <=11.0% (>=58 mmol/mol and <=97 mmol/mol) OR On metformin monotherapy <1500 mg/day with a Visit 1/Screening A1C >=8.0% and <=11.5% (>=64 mmol/mol and <=102 mmol/mol)
  • Body mass index (BMI) >=18.0 kg/m^2
  • Male or female not of reproductive potential
  • Female of reproductive potential who agrees to remain abstinent from heterosexual activity or to use 2 acceptable combinations of contraception

Exclusion Criteria:

  • History of type 1 diabetes mellitus or ketoacidosis
  • History of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant
  • A known hypersensitivity or intolerance to any sodium glucose co-transporter 2 (SGLT2) inhibitor or sitagliptin
  • Has been treated with any of the following agents within 12 weeks of study start or during the pre-randomization period: Insulin of any type (except for short-term use [i.e., <=7 days] during concomitant illness or other stress), other injectable anti-hyperglycemic agents (e.g., pramlintide, exenatide, liraglutide), pioglitazone or rosiglitazone, other SGLT2 inhibitors, alpha glucosidase inhibitors or meglitinides, dipeptidyl-peptidase 4 inhibitor (DPP-4 inhibitor), sulfonylureas (SUs), bromocriptine (Cycloset™), colesevelam (Welchol™), any other antihyperglycemic agents (AHA) with the exception of the protocol-approved agents
  • Is on a weight-loss program or weight-loss medication or other medication associated with weight changes and is not weight stable prior to study start
  • Has undergone bariatric surgery within the past 12 months or >12 months and is not weight stable prior to study start
  • A 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 start
  • Active, obstructive uropathy or indwelling urinary catheter
  • History of malignancy <=5 years prior to study start, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
  • A known history of human immunodeficiency virus (HIV)
  • A blood dyscrasia or any disorder causing hemolysis or unstable red blood cells, or a clinically important hematological disorder (e.g. aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)
  • A medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease
  • Any clinically significant malabsorption condition
  • Current treatment for hyperthyroidism
  • On thyroid replacement therapy and not on a stable dose for at least 6 weeks prior study start
  • On a previous clinical study with ertugliflozin
  • Estimated glomerular filtration rate (eGFR) (using the 4-variable Modification of Diet in Renal Disease Study Equation (MDRD) equation) <60 mL/min/1.73 m^2
  • Serum creatinine >= 1.3 mg/dL (115 µmol/L) for males and >= 1.2 mg/dL (106 µmol/L) for females
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times upper limit of normal
  • Hemoglobin <12 g/dL (120 g/L) for males and <11 g/dL (110 g/L) for females.
  • Participated in other studies involving investigational drug(s) 30 days prior to study start
  • Surgical procedure within 6 weeks prior to study start or major surgery planned during the trial
  • Positive urine pregnancy test
  • Pregnant or breast-feeding, or planning to conceive during the trial, including 14 days following the last dose of study medication
  • Planning to undergo hormonal therapy in preparation for egg donation during the trial, including 14 days following the last dose of study medication
  • Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week or engages in binge drinking
  • Donated blood or blood products within 6 weeks of study start
Contacts and Locations
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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): NCT02099110


Sponsors and Collaborators
Merck Sharp & Dohme LLC
Pfizer
Investigators
Layout table for investigator information
Study Director: Medical Director Merck Sharp & Dohme LLC
More Information
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Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT02099110    
Other Study ID Numbers: 8835-005
MK-8835-005 ( Other Identifier: Merck, Sharp & Dohme )
B1521019 ( Other Identifier: Pfizer )
2013-003698-82 ( EudraCT Number )
First Posted: March 28, 2014    Key Record Dates
Results First Posted: November 1, 2017
Last Update Posted: September 12, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Ertugliflozin
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Insulin Glargine
Sitagliptin Phosphate
Glimepiride
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
Sodium-Glucose Transporter 2 Inhibitors