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.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 621
- 主要终点
- Change From Baseline in A1C at Week 26 (Excluding Rescue Approach)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Ertuglifozin 5 mg
Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Ertugliflozin 5 mg (Drug)
Ertuglifozin 5 mg
Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Placebo to Ertugliflozin (Drug)
Ertuglifozin 5 mg
Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Glimepiride (Other)
Ertuglifozin 5 mg
Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Placebo to Glimepiride (Drug)
Ertuglifozin 5 mg
Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Basal Insulin (Biological)
Ertuglifozin 5 mg
Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Metformin (Drug)
Ertugliflozin 15 mg
Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Ertugliflozin 15 mg (Drug)
Ertugliflozin 15 mg
Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Glimepiride (Other)
Ertugliflozin 15 mg
Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Placebo to Glimepiride (Drug)
Ertugliflozin 15 mg
Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Basal Insulin (Biological)
Ertugliflozin 15 mg
Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Metformin (Drug)
Placebo/Glimepiride
Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Placebo to Ertugliflozin (Drug)
Placebo/Glimepiride
Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Glimepiride (Other)
Placebo/Glimepiride
Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Basal Insulin (Biological)
Placebo/Glimepiride
Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.
干预措施: Metformin (Drug)
结局指标
主要结局
Change From Baseline in A1C at Week 26 (Excluding Rescue Approach)
时间窗: Baseline and Week 26
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 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)
时间窗: Up to Week 106
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. Per protocol, participants who met pre-specified glycemic criteria were rescued with open-label glimepiride or basal insulin according to Investigator judgment.
Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)
时间窗: Up to Week 104
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. Per protocol, participants who met pre-specified glycemic criteria were rescued with open-label glimepiride or basal insulin according to Investigator judgment.
次要结局
- Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)(Baseline and Week 26)
- Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach)(Baseline and Week 26)
- Percentage of Participants With an A1C of <7% (53 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach)(Week 26)
- Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)(Baseline and Week 26)
- Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 26(Up to Week 26)
- Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)(Baseline and Week 26)
- Percentage of Participants With an A1C of <6.5% (48 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach)(Week 26)
- Time to Glycemic Rescue Therapy at Week 26(Week 26)
- Change From Baseline in A1C at Week 52 (Excluding Rescue Approach)(Baseline and Week 52)
- Change From Baseline in Fasting Plasma Glucose at Week 52 (Excluding Rescue Therapy)(Baseline and Week 52)
- Percentage of Participants With an A1C of <7% (53 mmol/Mol) at Week 52 (Excluding Rescue Approach)(Week 52)
- Percentage of Participants With an A1C of <6.5% (48 mmol/Mol) at Week 52 (Excluding Rescue Approach)(Week 52)
- Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 52(Up to Week 52)
- Change From Baseline in Body Weight at Week 52 (Excluding Rescue Approach)(Baseline and Week 52)
- Change From Baseline in Sitting Systolic Blood Pressure at Week 52 (Excluding Rescue Approach)(Baseline and Week 52)
- Percentage of Participants With an A1C of <6.5% (48 mmol/Mol) at Week 104 (Excluding Rescue Approach)(Week 104)
- Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 104(Up to Week 104)
- Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 (Excluding Rescue Approach)(Baseline and Week 52)
- Change From Baseline in A1C at Week 104 (Excluding Rescue Approach)(Baseline and Week 104)
- Change From Baseline in Fasting Plasma Glucose at Week 104 (Excluding Rescue Approach)(Baseline and Week 104)
- Percentage of Participants With an A1C of <7% (53 mmol/Mol) at Week 104 (Excluding Rescue Approach)(Week 104)
- Change From Baseline in Body Weight at Week 104 (Excluding Rescue Approach)(Baseline and Week 104)
- Change From Baseline in Sitting Systolic Blood Pressure at Week 104 (Excluding Rescue Approach)(Baseline and Week 104)
- Change From Baseline in Sitting Diastolic Blood Pressure at Week 104 (Excluding Rescue Approach)(Baseline and Week 104)
- Ertugliflozin Plasma Concentrations (ng/mL): Summary Statistics Over Time (Excluding Rescue Approach)(Pre-dose and/or 60 minutes post-dose on Weeks 6, 12, 18, and 30)
- 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)(Baseline and Week 26)
- Percent Change From Baseline in BMD at Week 26 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 26)
- Percent Change From Baseline in BMD at Week 26 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 26)
- Percent Change From Baseline in BMD at Week 26 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 26)
- Percent Change From Baseline in Bone Biomarker Carboxy-Terminal Cross-Linking Telopeptides of Type I Collagen (CTX) at Week 26 (Excluding Bone Rescue Approach)(Baseline and Week 26)
- Percent Change From Baseline in Bone Biomarker Procollagen Type I N-terminal Propeptide (P1NP) at Week 26 (Excluding Bone Rescue Approach)(Baseline and Week 26)
- Percent Change From Baseline in Bone Biomarker Parathyroid Hormone (PTH) at Week 26 (Excluding Bone Rescue Approach)(Baseline and Week 26)
- 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)(Baseline and Week 52)
- Percent Change From Baseline in BMD at Week 52 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 52)
- Percent Change From Baseline in BMD at Week 52 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 52)
- Percent Change From Baseline in BMD at Week 52 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 52)
- Percent Change From Baseline in Bone Biomarker CTX at Week 52 (Excluding Bone Rescue Approach)(Baseline and Week 52)
- Percent Change From Baseline in Bone Biomarker P1NP at Week 52 (Excluding Bone Rescue Approach)(Baseline and Week 52)
- Percent Change From Baseline in Bone Biomarker PTH at Week 52 (Excluding Bone Rescue Approach)(Baseline and Week 52)
- 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)(Baseline and Week 104)
- Percent Change From Baseline in BMD at Week 104 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 104)
- Percent Change From Baseline in BMD at Week 104 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 104)
- Percent Change From BMD at Week 104 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)(Baseline and Week 104)
- Percent Change From Baseline in Bone Biomarker CTX at Week 104 (Excluding Bone Rescue Approach)(Baseline and Week 104)
- Percent Change From Baseline in Bone Biomarker P1NP at Week 104 (Excluding Bone Rescue Approach)(Baseline and Week 104)
- Percent Change From Baseline in Bone Biomarker PTH at Week 104 (Excluding Bone Rescue Approach)(Baseline and Week 104)