Clinical trial NCT02033889: A Study To Evaluate The Efficacy And Safety Of Ertugliflozin In Participants With Type 2 Diabetes Mellitus And Inadequate Glycemic Control On Metformin Monotherapy (MK-8835-007).
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 26-Week Multicenter Study With a 78-Week Extension To Evaluate The Efficacy And Safety Of Ertugliflozin In Subjects With Type 2 Diabetes Mellitus And 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: 2014-01-13
Enrollment: 621
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 an efficacy and safety study of ertugliflozin in participants with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on metformin monotherapy. The primary study hypothesis is that at Week 26, the mean reduction from baseline in hemoglobin A1c (HbA1c) for ertugliflozin is greater than that for placebo.

Detailed description: The trial includes a 13-15 week run-in period prior to randomization, and a 26-week, double-blind, placebo-controlled treatment period followed by a 78-week double-blind, extension period.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of T2DM in accordance to American Diabetes Association guidelines
* Participants must be receiving metformin monotherapy for less than 8 weeks prior to study participation or require change in their diabetes regimen to remain eligible to participate in the trial (including discontinuing anti-hyperglycemic agent \[AHA\] therapy) and must have a hemoglobin A1c of 7.0 to 10.5% (53-91 mmol/mol) after at least 8 weeks on a regimen of metformin monotherapy

Exclusion Criteria:

* 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 clinically significant electrocardiogram abnormality
* 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
* A known hypersensitivity or intolerance to any sodium-glucose co-transporter 2 (SGLT2) inhibitor or glimepiride
* On a blood pressure or lipid altering medication that have not been on a stable dose for at least 4 weeks prior to study participation
* A surgical procedure within 6 weeks prior to study participation or planned major surgery during the trial
* 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
* Pregnant or breast-feeding, or is expecting to conceive during the trial, including 14 days following the last dose of study drug

Primary outcomes:
measure: Change From Baseline in A1C at Week 26 (Excluding Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)
timeFrame: Up to Week 106
measure: Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)
timeFrame: Up to Week 104
Secondary outcomes:
measure: Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)
timeFrame: Baseline and Week 26
measure: Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percentage of Participants With an A1C of <7% (53 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach)
timeFrame: Week 26
measure: Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)
timeFrame: Baseline and Week 26
measure: Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percentage of Participants With an A1C of <6.5% (48 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach)
timeFrame: Week 26
measure: Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 26
timeFrame: Up to Week 26
measure: Time to Glycemic Rescue Therapy at Week 26
timeFrame: Week 26
measure: Change From Baseline in A1C at Week 52 (Excluding Rescue Approach)
timeFrame: Baseline and Week 52
measure: Change From Baseline in Fasting Plasma Glucose at Week 52 (Excluding Rescue Therapy)
timeFrame: Baseline and Week 52
measure: Percentage of Participants With an A1C of <7% (53 mmol/Mol) at Week 52 (Excluding Rescue Approach)
timeFrame: Week 52
measure: Percentage of Participants With an A1C of <6.5% (48 mmol/Mol) at Week 52 (Excluding Rescue Approach)
timeFrame: Week 52
measure: Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 52
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 at Week 52 (Excluding Rescue Approach)
timeFrame: Baseline and Week 52
measure: Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 (Excluding Rescue Approach)
timeFrame: Baseline and Week 52
measure: Change From Baseline in A1C at Week 104 (Excluding Rescue Approach)
timeFrame: Baseline and Week 104
measure: Change From Baseline in Fasting Plasma Glucose at Week 104 (Excluding Rescue Approach)
timeFrame: Baseline and Week 104
measure: Percentage of Participants With an A1C of <7% (53 mmol/Mol) at Week 104 (Excluding Rescue Approach)
timeFrame: Week 104
measure: Percentage of Participants With an A1C of <6.5% (48 mmol/Mol) at Week 104 (Excluding Rescue Approach)
timeFrame: Week 104
measure: Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 104
timeFrame: Up to Week 104
measure: Change From Baseline in Body Weight at Week 104 (Excluding Rescue Approach)
timeFrame: Baseline and Week 104
measure: Change From Baseline in Sitting Systolic Blood Pressure at Week 104 (Excluding Rescue Approach)
timeFrame: Baseline and Week 104
measure: Change From Baseline in Sitting Diastolic Blood Pressure at Week 104 (Excluding Rescue Approach)
timeFrame: Baseline and Week 104
measure: Ertugliflozin Plasma Concentrations (ng/mL): Summary Statistics Over Time (Excluding Rescue Approach)
timeFrame: Pre-dose and/or 60 minutes post-dose on Weeks 6, 12, 18, and 30
measure: Percent Change From Baseline in BMD at Week 26 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percent Change From Baseline in BMD at Week 26 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percent Change From Baseline in BMD at Week 26 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percent Change From Baseline in BMD at Week 26 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percent Change From Baseline in Bone Biomarker Carboxy-Terminal Cross-Linking Telopeptides of Type I Collagen (CTX) at Week 26 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percent Change From Baseline in Bone Biomarker Procollagen Type I N-terminal Propeptide (P1NP) at Week 26 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percent Change From Baseline in Bone Biomarker Parathyroid Hormone (PTH) at Week 26 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 26
measure: Percent Change From Baseline in BMD at Week 52 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in BMD at Week 52 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in BMD at Week 52 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in BMD at Week 52 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Bone Biomarker CTX at Week 52 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Bone Biomarker P1NP at Week 52 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in Bone Biomarker PTH at Week 52 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 52
measure: Percent Change From Baseline in BMD at Week 104 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 104
measure: Percent Change From Baseline in BMD at Week 104 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 104
measure: Percent Change From Baseline in BMD at Week 104 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 104
measure: Percent Change From BMD at Week 104 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 104
measure: Percent Change From Baseline in Bone Biomarker CTX at Week 104 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 104
measure: Percent Change From Baseline in Bone Biomarker P1NP at Week 104 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 104
measure: Percent Change From Baseline in Bone Biomarker PTH at Week 104 (Excluding Bone Rescue Approach)
timeFrame: Baseline and Week 104
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Rosenstock J, Frias J, Pall D, Charbonnel B, Pascu R, Saur D, Darekar A, Huyck S, Shi H, Lauring B, Terra SG. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab. 2018 Mar;20(3):520-529. doi: 10.1111/dom.13103. Epub 2017 Oct 2.
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, 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: 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.
citation: Gallo S, Charbonnel B, Goldman A, Shi H, Huyck S, Darekar A, Lauring B, Terra SG. Long-term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104-week VERTIS MET trial. Diabetes Obes Metab. 2019 Apr;21(4):1027-1036. doi: 10.1111/dom.13631. Epub 2019 Feb 14.