Clinical trial NCT02036515: 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)
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
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: 2014-01-15
Enrollment: 464
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 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.

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 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

Primary outcomes:
measure: Change From Baseline in Hemoglobin A1C at Week 26
timeFrame: Baseline and Week 26
measure: Percentage of Participants Experiencing An Adverse Event (AE)
timeFrame: Up to Week 54
measure: Percentage of Participants Discontinuing Study Treatment Due to an AE
timeFrame: Up to Week 52
Secondary outcomes:
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
timeFrame: Baseline and Week 26
measure: Change From Baseline in Body Weight at Week 26
timeFrame: Baseline and Week 26
measure: Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 26
timeFrame: Week 26
measure: Change From Baseline in Sitting Systolic Blood Pressure at Week 26
timeFrame: Baseline and Week 26
measure: Change From Baseline in Hemoglobin A1C at Week 52
timeFrame: Baseline and Week 52
measure: Change From Baseline in FPG at Week 52
timeFrame: Baseline and Week 52
measure: Change From Baseline in Body Weight at Week 52
timeFrame: Baseline and Week 52
measure: Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52
timeFrame: Week 52
measure: Change From Baseline in Sitting Systolic Blood Pressure at Week 52
timeFrame: Baseline and Week 52
measure: Change From Baseline in Sitting Diastolic Blood Pressure at Week 26
timeFrame: Baseline and Week 26
measure: Change From Baseline in Sitting Diastolic Blood Pressure at Week 52
timeFrame: Baseline and Week 52
measure: Percentage of Participants Receiving Glycemic Rescue Medication by Week 26
timeFrame: Week 26
measure: Percentage of Participants Receiving Glycemic Rescue Medication by Week 52
timeFrame: Week 52
measure: Time to Initiation of Glycemic Rescue by Week 26
timeFrame: Up to Week 26 (plus 30 days for 1 placebo participant)
measure: Time to Initiation of Glycemic Rescue by Week 52
timeFrame: Up to week 52
measure: Baseline Homeostasis Model Assessment of β-cell Function (HOMA-%β) Value
timeFrame: Baseline
measure: Change From Baseline in HOMA-%β at Week 26
timeFrame: Baseline and Week 26
measure: Change From Baseline in HOMA-%β at Week 52
timeFrame: Baseline and Week 52
measure: Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score
timeFrame: Baseline
measure: Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26
timeFrame: Baseline and Week 26
measure: Change From Baseline in EQ-5D-3L Score at Week 52
timeFrame: Baseline and Week 52
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, Liao Y, Huyck S, Golm G, Terra SG, Mancuso JP, Engel SS, Lauring B. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab. 2018 Mar;20(3):530-540. doi: 10.1111/dom.13116. Epub 2017 Oct 23.
citation: Gallo S, Raji A, Calle RA, Pong A, Meyer C. The effects of ertugliflozin on beta-cell function: Pooled analysis from four phase 3 randomized controlled studies. Diabetes Obes Metab. 2020 Dec;22(12):2267-2275. doi: 10.1111/dom.14149. Epub 2020 Aug 27.
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: 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: Liu J, Pong A, Gallo S, Darekar A, Terra SG. Effect of ertugliflozin on blood pressure in patients with type 2 diabetes mellitus: a post hoc pooled analysis of randomized controlled trials. Cardiovasc Diabetol. 2019 May 7;18(1):59. doi: 10.1186/s12933-019-0856-7.