Clinical trial NCT01999218: Ertugliflozin vs. Glimepiride in Type 2 Diabetes Mellitus (T2DM) Participants on Metformin (MK-8835-002)
Official title: A Phase III, Multicenter, Randomized, Double-Blind, Active-Comparator-Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Ertugliflozin (MK-8835/PF-04971729) Compared With the Addition of Glimepiride in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2013-12-03
Enrollment: 1326
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the efficacy and safety of the addition of ertugliflozin (MK-8835/PF-04971729) compared with the addition of glimepiride in participants with T2DM who have inadequate glycemic control on metformin. The primary hypothesis of this study is that after 52 weeks, the change from baseline in hemoglobin A1c (A1C) in participants treated with the addition of ertugliflozin 15 mg once daily is non-inferior compared with that in participants treated with the addition of glimepiride.

Detailed description: The duration of the trial will be up to approximately 122 weeks. This will include a 1-week screening period, an up to 13-week wash-off/titration/dose stabilization period, a 2-week placebo run-in period, a 104-week double-blind, active comparator-controlled treatment period, and a post-treatment telephone contact 14 days after the last dose of study drug.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of T2DM in accordance to American Diabetes Association guidelines
* On metformin monotherapy or metformin in combination with a single allowable anti-hyperglycemic agent (AHA), DPP-4 inhibitors, meglitinides and AGIs are listed as allowable AHAs along with sulfonylureas prior to study participation.
* Body Mass Index (BMI) ≥18.0 kg/m\^2
* Male or female not of reproductive potential
* If a female of reproductive potential, agree 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 or presence of type 1 diabetes mellitus or a history of ketoacidosis
* History of other specific types of diabetes (eg, 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
* Use of the following prohibited therapeutic agents within 12 weeks of study participation: insulin, injectable anti-hyperglycemic agents, pioglitazone or rosiglitazone, another SGLT2 inhibitor, bromocriptine (Cycloset®), colesevelam (Welchol®), and any other non-approved anti-hyperglycemic therapy
* Known hypersensitivity or intolerance to metformin or glimepiride
* On a weight-loss program or medication or medication associated with weight changes and is not weight-stable (\>=5% change in body weight in the last 6 months)
* History of bariatric surgery less than 12 months prior to study participation
* 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
* Active, obstructive uropathy or an indwelling urinary catheter
* 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)
* Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells
* A medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or symptomatic gallbladder disease
* Any clinically significant malabsorption condition
* Being treated for hyperthyroidism, or on thyroid replacement therapy that has not been at a stable dose for at least 6 weeks prior to study participation
* Previous randomization in a study with ertugliflozin
* Participation in other studies involving investigational drug(s) within 30 days of study participation and/or during the pre-randomization period
* A surgical procedure within 6 weeks prior to study participation or planned major surgery during the trial
* A positive urine pregnancy test
* Pregnant or breast-feeding, or expecting to conceive during the trial, including 14 days following the last dose of study drug
* Undergoing hormonal therapy in preparation to donate eggs during the period of the trial, including 14 days following the last dose of study drug
* Consumption of more than 2 alcoholic drinks per day or engages in binge drinking
* Donation of blood or blood products within 6 weeks of study participation or plans to donate blood or blood products at any time during the trial

Primary outcomes:
measure: Change From Baseline in Hemoglobin A1C (A1C) at Week 52: Excluding Rescue Approach
timeFrame: Baseline and Week 52
measure: Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106
timeFrame: Up to Week 106
measure: Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104
timeFrame: Up to Week 104
Secondary outcomes:
measure: Percentage of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach
timeFrame: Up to Week 52
measure: Change From Baseline in Body Weight at Week 52 Excluding Rescue Approach
timeFrame: Baseline and Week 52
measure: Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach
timeFrame: Baseline and Week 52
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Hollander P, Hill J, Johnson J, Wei Jiang Z, Golm G, Huyck S, Terra SG, Mancuso JP, Engel SS, Lauring B, Liu J. Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin. Curr Med Res Opin. 2019 Aug;35(8):1335-1343. doi: 10.1080/03007995.2019.1583450. Epub 2019 Mar 25.
citation: Gallo S, Calle RA, Terra SG, Pong A, Tarasenko L, Raji A. Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials. Diabetes Ther. 2020 Aug;11(8):1849-1860. doi: 10.1007/s13300-020-00867-1. Epub 2020 Jul 9.
citation: Patel S, Hickman A, Frederich R, Johnson S, Huyck S, Mancuso JP, Gantz I, Terra SG. Safety of Ertugliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Seven Phase 3 Randomized Controlled Trials. Diabetes Ther. 2020 Jun;11(6):1347-1367. doi: 10.1007/s13300-020-00803-3. Epub 2020 May 5.
citation: Liu J, Tarasenko L, Pong A, Huyck S, Wu L, Patel S, Hickman A, Mancuso JP, Gantz I, Terra SG. Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus. Curr Med Res Opin. 2020 Aug;36(8):1277-1284. doi: 10.1080/03007995.2020.1760228. Epub 2020 May 13.
citation: Liu J, Tarasenko L, Pong A, Huyck S, Patel S, Hickman A, Mancuso JP, Ellison MC, Gantz I, Terra SG. Efficacy and safety of ertugliflozin in Hispanic/Latino patients with type 2 diabetes mellitus. Curr Med Res Opin. 2020 Jul;36(7):1097-1106. doi: 10.1080/03007995.2020.1760227. Epub 2020 May 13.
citation: Cherney DZI, Heerspink HJL, Frederich R, Maldonado M, Liu J, Pong A, Xu ZJ, Patel S, Hickman A, Mancuso JP, Gantz I, Terra SG. Effects of ertugliflozin on renal function over 104 weeks of treatment: a post hoc analysis of two randomised controlled trials. Diabetologia. 2020 Jun;63(6):1128-1140. doi: 10.1007/s00125-020-05133-4. Epub 2020 Mar 31.
citation: Liu J, Patel S, Cater NB, Wu L, Huyck S, Terra SG, Hickman A, Darekar A, Pong A, Gantz I. Efficacy and safety of ertugliflozin in East/Southeast Asian patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2020 Apr;22(4):574-582. doi: 10.1111/dom.13931. Epub 2020 Jan 3.
citation: Hollander P, Liu J, Hill J, Johnson J, Jiang ZW, Golm G, Huyck S, Terra SG, Mancuso JP, Engel SS, Lauring B. Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. Diabetes Ther. 2018 Feb;9(1):193-207. doi: 10.1007/s13300-017-0354-4. Epub 2017 Dec 27.