A Study to Evaluate the Efficacy and Safety of Ertugliflozin in Asian Participants With Type 2 Diabetes and Inadequate Glycemic Control on Metformin Monotherapy (MK-8835-012)

NCT02630706 | Completed Phase 3 Results DMC

• 3 other identifiers: 8835-012B1521045MK-8835-012
• Study Type: interventional
• Target: 506
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a study to evaluate the efficacy and safety of the addition of ertugliflozin to metformin monotherapy in Asian participants with Type 2 diabetes mellitis (T2DM) who have inadequate glycemic control on metformin monotherapy. The primary hypothesis is that the mean reduction from baseline in HbA1C for 15 mg and 5 mg ertugliflozin (tested sequentially) is greater than for placebo.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (6)

• Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach)

  A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 26 A1C minus the Week 0 A1C (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.

  Baseline and Week 26

• Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) (China Subpopulation)

  A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 26 A1C minus the Week 0 A1C (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.

  Baseline and Week 26

• Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)

  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.

  Up to 28 weeks

• Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) (China Subpopulation)

  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.

  Up to 28 weeks

• Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)

  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.

  Up to 26 weeks

• Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) (China Subpopulation)

  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.

  Up to 26 weeks

Secondary Outcomes (28)

• Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)

  Baseline and Week 26

• Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) (China Subpopulation)

  Baseline and Week 26

• Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach)

  Baseline and Week 26

• Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) (China Subpopulation)

  Baseline and Week 26

• Percentage of Participants With HbA1c of <7.0% (53 mmol/Mol) (Logistic Regression Using Multiple Imputation Based on cLDA Model: Excluding Rescue Approach)

  Week 26

Study Arms (3)

Ertugliflozin 5 mg

EXPERIMENTAL

Ertugliflozin 5 mg oral and matching placebo for ertugliflozin 10 mg, oral, once daily for 26 weeks, while maintaining metformin at a stable dose (\>=1500 mg/day). Glycemic rescue therapy with open-label glimepiride was initiated in participants with glucose values exceeding protocol-specified values.

Drug: Ertugliflozin 5 mg; Drug: Placebo matching ertugliflozin; Drug: Metformin; Drug: Glimepiride

Ertugliflozin 15 mg

EXPERIMENTAL

Ertugliflozin 15 mg (ertugliflozin 5 mg + ertugliflozin 10 mg) administered orally once daily for 26 weeks, while maintaining metformin at a stable dose (\>=1500 mg/day). Glycemic rescue therapy with open-label glimepiride was initiated in participants with glucose values exceeding protocol-specified values.

Drug: Ertugliflozin 15 mg; Drug: Metformin; Drug: Glimepiride

Placebo

PLACEBO COMPARATOR

Placebo matching ertugliflozin administered orally once daily for 26 weeks, while maintaining metformin at a stable dose (\>=1500 mg/day). Glycemic rescue therapy with open-label glimepiride was initiated in participants with glucose values exceeding protocol-specified values.

Drug: Placebo matching ertugliflozin; Drug: Metformin; Drug: Glimepiride

Interventions

Ertugliflozin 5 mg DRUG

Ertugliflozin 5 mg oral tablet taken once daily

Also known as: MK-8835, PF-04971729

Ertugliflozin 5 mg

Ertugliflozin 15 mg DRUG

Ertugliflozin 15 mg (5-mg and 10-mg tablets) oral taken once daily

Also known as: MK-8835, PF-04971729

Ertugliflozin 15 mg

Placebo matching ertugliflozin DRUG

Placebo matching ertugliflozin (5-mg and/or 10-mg tablet) oral taken once daily

Ertugliflozin 5 mg; Placebo

Metformin DRUG

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

Ertugliflozin 15 mg; Ertugliflozin 5 mg; Placebo

Glimepiride DRUG

Glycemic rescue therapy with open-label glimepiride will be initiated in participants with glucose values exceeding protocol-specified values. Dosing and titration of open-label glimepiride rescue therapy will be at the Investigator's discretion.

Ertugliflozin 15 mg; Ertugliflozin 5 mg; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Asian participants ≥18 years of age at the time of initial Screening.
• Type 2 diabetes mellitus as per American Diabetes Association guidelines.
• Metformin monotherapy (≥1500 mg/day) with an initial Screening A1C of 7.0-10.5% (53-91 mmol/mol) OR metformin monotherapy (\<1500 mg/day) with an initial Screening A1C of 7.5-11.0% (58-97 mmol/mol) OR dual combination therapy with metformin + sulfonylurea, dipeptidyl peptidase-4 (DDP-4) inhibitor, meglitinide, or alpha-glucosidase inhibitor with an initial Screening A1C of 6.5-9.5% (48-80 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.

You may not qualify if:

• 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 endocrinopathies, drug- or chemical-induced, and post-organ transplant.)
• 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.
• Mean value for triplicate screening sitting systolic blood pressure \>160 mm Hg and/or diastolic blood pressure \>90 mm Hg after at least a 5-minute seated rest at screening
• 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.
• Routinely consumes \>2 alcoholic drinks per day or \>14 alcoholic drinks per week or engages in binge drinking.
• Any clinically significant malabsorption condition.
• 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 known hypersensitivity or intolerance to any sodium glucose co-transporter (SGLT2) inhibitor.
• On a previous clinical study with ertugliflozin.
• Is taking blood pressure or lipid altering medications that have not been on a stable dose for at least 4 weeks prior to study start.
• Current treatment for hyperthyroidism.
• Male participants with a serum creatinine \>=1.3 mg/dL (\>=115 mol/L) or female participants with a serum creatinine \>=1.2 mg/dL (\>=106 mol/L) or participants with an estimated glomerular filtration rate (eGFR) \<55 mL/min/1.73m\^2 according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation at screening.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead
• Pfizer: collaborator

Related Publications (4)

• Ji L, Liu J, Xu ZJ, Wei Z, Zhang R, Malkani S, Cater NB, Frederich R. Efficacy and Safety of Ertugliflozin Added to Metformin: A Pooled Population from Asia with Type 2 Diabetes and Overweight or Obesity. Diabetes Ther. 2023 Feb;14(2):319-334. doi: 10.1007/s13300-022-01345-6. Epub 2023 Feb 3.

  PMID: 36763328 DERIVED

• Xu H, O'Gorman MT, Nepal S, James LP, Ginman K, Pithavala YK. Phase 1 Study Evaluating the Effects of the Proton Pump Inhibitor Rabeprazole and Food on the Pharmacokinetics of Lorlatinib in Healthy Participants. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1395-1404. doi: 10.1002/cpdd.1000. Epub 2021 Jul 20.

  PMID: 34288547 DERIVED

• Fediuk DJ, Sahasrabudhe V, Dawra VK, Zhou S, Sweeney K. Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1297-1306. doi: 10.1002/cpdd.970. Epub 2021 Jul 2.

  PMID: 34213819 DERIVED

• Ji L, Liu Y, Miao H, Xie Y, Yang M, Wang W, Mu Y, Yan P, Pan S, Lauring B, Liu S, Huyck S, Qiu Y, Terra SG. Safety and efficacy of ertugliflozin in Asian patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: VERTIS Asia. Diabetes Obes Metab. 2019 Jun;21(6):1474-1482. doi: 10.1111/dom.13681. Epub 2019 Apr 5.

  PMID: 30830724 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

ertugliflozin; Metformin; glimepiride

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Sponsor was masked.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2015
• First Posted: December 15, 2015
• Study Start: December 16, 2015
• Primary Completion: December 27, 2017
• Study Completion: December 27, 2017
• Last Updated: December 7, 2018
• Results First Posted: December 7, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will share