Clinical trial NCT02099110: Ertugliflozin and Sitagliptin Co-administration Factorial Study (VERTIS FACTORAL, MK-8835-005)
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
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: 2014-03-28
Enrollment: 1233
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 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.

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.

Eligibility 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

Primary outcomes:
measure: Change From Baseline in A1C at Week 26: Excluding Rescue Approach
timeFrame: Baseline and Week 26
measure: Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach
timeFrame: Up to 54 weeks
measure: Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach
timeFrame: Up to 52 weeks
Secondary outcomes:
measure: Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach
timeFrame: Baseline and Week 26
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach
timeFrame: Baseline and Week 26
measure: Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach
timeFrame: Week 26
measure: Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach
timeFrame: 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
measure: Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach
timeFrame: Baseline and Week 26
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Pratley RE, Eldor R, Raji A, Golm G, Huyck SB, Qiu Y, Sunga S, Johnson J, Terra SG, Mancuso JP, Engel SS, Lauring B. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes Metab. 2018 May;20(5):1111-1120. doi: 10.1111/dom.13194. Epub 2018 Jan 25.
citation: 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.
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.