Diabetes Mellitus, Type 2
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to determine the efficacy and safety of TAK-875, once daily (QD), plus metformin compared to glimepiride plus metformin in participants with type 2 diabetes mellitus (T2DM). The purpose of this study is to determine the efficacy and safety of TAK-875, once daily (QD), plus metformin compared to glimepiride plus metformin in participants with type 2 diabetes mellitus (T2DM).
Detailed description
Type 2 diabetes mellitus (T2DM) has increased dramatically throughout the world over the past decades despite the availability of several different treatment options. Current pharmacologic treatments include insulin, thiazolidinediones, sulfonylureas, metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) mimetics. A number of these treatments are associated with clinically important side effects such as low blood sugar (hypoglycemia), weight gainflud retention, exaggeration of pre-existent heart failure, and gastrointestinal side effects. These side effects and the disadvantages associated with many of the currently available antidiabetic agents can reduce compliance and limit their long-term use. Insulin is a hormone that is produced by the body to regulate blood sugar (glucose). In individuals with T2DM, the insulin produced by the body does not effectively control the amount of sugar in the bloodstream. If not properly managed, T2DM may cause elevated blood sugar levels (hyperglycemia) and ultimately result in serious health problems. In response to this problem, Takeda is developing TAK-875 (an investigational drug) as an addition to diet and exercise to improve blood sugar control in patients with T2DM. TAK-875 may affect the production of insulin and may improve how the body uses the sugar in the blood. The aim of this study is to find out if TAK-875, when taken for approximately 2 years in combination with current diabetes medicine (called metformin), is safe and effective at helping people with T2DM control their high blood sugar when compared to glimepiride (a type of medication called a sulfonylurea). The study is being done to find out if the combination of TAK-875 plus metformin works as well as the combination of glimepiride plus metformin. Approximately 2430 patients worldwide aged 18 or over with T2DM, will take part in this study and will be involved in the study for up to 110 or 120 weeks. TAK-875 is being developed at Takeda Global Research and Development, Inc. as an adjunct to diet and exercise to improve glycemic control in participants with T2DM. This study will investigate TAK-875 in participants with type 2 diabetes mellitus whose blood sugar level is inadequately controlled with metformin monotherapy. Due to potential concerns about liver safety, on balance, the benefits of treating patients with fasiglifam (TAK-875) do not outweigh the potential risks. For this reason, Takeda has decided voluntarily to terminate the development activities for fasiglifam.
Interventions
DRUGTAK-875
TAK-875 25 mg, tablets, orally, once daily and metformin ≥1500 mg or Maximum Tolerated Dose (MTD) for up to 104 weeks.
DRUGGlimepiride
Glimepiride 1 mg, tablets, orally, once daily (up-titrated to 2 mg after 1 week of treatment. Up-titrated to a maximum of 6 mg in 2 mg increments/down titrated if recurrent (or severe) hypoglycemia occurs) and metformin ≥1500 mg or MTD for up to 104 weeks.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. The participant is male or female and 18 years of age or older with a historical diagnosis of T2DM. 4. The participant meets one of the following criteria: 1. The participant has an HbA1c level ≥7.0 and \<10.0%, and has been on a stable daily dose of ≥1500 mg (or documented MTD) of metformin for at least 2 months prior to Screening. This participant will immediately enter the Placebo Run-in Period, or; 2. The participant has an HbA1c level ≥ 7.5 and \<10.5%, and has been on a stable daily dose of \<1500 mg of metformin without documented MTD for at least 2 months prior to Screening. After completing the Screening Visit, this participant will have their metformin dose immediately increased to ≥1500 mg (or MTD) for an 8-week Titration Period. Following this 8-week period, the participant must qualify for entry into the Placebo Run-in Period by completing the Week -3 procedures and having an HbA1c concentration ≥7.0 and \<10.0%. 5. The participant has had no treatment with antidiabetic agents other than metformin within 2 months prior to Screening (Exception: if a participant has received other antidiabetic therapy for ≤7 days within the 2 months prior to Screening). 6. The participant has a body mass index (BMI) of ≤45 kg/m2 at Screening. 7. Participants regularly using other, non-excluded medications, must be on a stable dose for at least 4 weeks prior to Screening. However, PRN (as needed) use of prescription or over-the-counter medications is allowed at the discretion of the investigator. 8. The participant is able and willing to monitor glucose with a home glucose monitor and consistently record his or her own blood glucose concentrations and complete participant diaries. Additional Inclusion Criteria Prior to Randomization 1. The participant has an HbA1c concentration ≥7.0% and \<10.0%, and a FPG ≤270 mg/dL (15.0 mmol/L) at the Week -1 Visit. (If the subject does not qualify for randomization based on these criteria, the assessment may be repeated weekly, for a maximum of 2 additional weeks). 2. The participant's compliance with the single-blind study medication during the Placebo Run-in Period is at least 75% and does not exceed 125% based on tablet/capsule counts performed by the study staff. 3. A female participant of childbearing potential must have a negative urine hCG pregnancy test at Baseline (Day 1) prior to Randomization and prior to administration of the first dose of double-blind study medication.
Exclusion criteria
1. The participant has received any investigational compound within 30 days prior to Screening or has received an investigational antidiabetic drug within the 3 months prior to Screening. 2. The participant has been randomized into a previous TAK-875 study 3. The participant is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress. 4. The participant donated or received any blood products within 12 weeks prior to Screening or is planning to donate blood during the study. 5. The participant has a hemoglobin ≤12 g/dL (≤120 gm/L) for males and ≤10 g/dL (≤100 gm/L) for females at Screening. 6. The participant has a systolic blood pressure ≥160 mm Hg or diastolic pressure ≥95 mm Hg at Screening (If the participant meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement). 7. The participant has history of cancer that has been in remission for \<5 years prior to Screening. A history of basal cell carcinoma or stage 1 squamous cell carcinoma of the skin is allowed. 8. The participant has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels \>2.0x upper limit of normal (ULN) at Screening. 9. The participant has a total bilirubin level greater than the ULN at Screening. Exception: if a participant has documented Gilbert's Syndrome the participant will be allowed with an elevated bilirubin level per the investigator's discretion. 10. The participant has a serum creatinine ≥1.5 mg/dL(males) and ≥1.4 mg/dL(females) and/or estimated glomerular filtration rate (GFR) \<60 mL/min/1.73m2 at Screening. 11. The participant has uncontrolled thyroid disease. 12. The participant has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening. 13. The participant has had gastric banding, or gastric bypass surgery within one year prior to Screening. 14. The participant has a known history of infection with human immunodeficiency virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV). 15. The participant had coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, unstable angina pectoris, clinically significant abnormal electrocardiogram (ECG), cerebrovascular accident or transient ischemic attack within 3 months prior to or at Screening. 16. The participant has a history of hypersensitivity, allergies, or has had an anaphylactic reaction(s) to any component of TAK-875, metformin, or glimepiride. 17. The participant has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse within 2 years prior to Screening. 18. The participant received excluded medications prior to Screening or is expected to receive excluded medication. 19. If female, the participant is pregnant (confirmed by laboratory testing, i.e., serum/urine human chorionic gonadotropin (hCG), in females of childbearing potential) or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period. 20. The participant is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available. 21. The participant has any other physical or psychiatric disease or condition that in the judgment of the investigator may affect life expectancy or may make it difficult to successfully manage and follow the participant according to the protocol. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at Weeks 78 and 104 | Baseline and Weeks 78 and 104 | The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) to be collected at Weeks 78 and 104 relative to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight at Weeks 78 and 104 | Baseline and Weeks 78 and 104 | The change between the body weight to be collected at Weeks 78 and 104 relative to baseline. |
| Change From Baseline in HbA1c at Weeks 26 and 52 | Baseline and Weeks 26 and 52 | The change in the value of HbA1c collected at Weeks 26 and 52 relative to baseline. |
| Percentage of Participants With Hypoglycemia | Day 1 up to Weeks 78 and 104 | Participants were provided diaries to document any hypoglycemic events that occurred between study visits. Any experience of hypoglycemic signs and symptoms (regardless of the blood glucose value by glucometer) or had a blood glucose value less than or equal to (\<=) 70 milligram per deciliter (mg/dL) (3.9 millimole per liter (mmol/L) by glucometer (regardless of symptoms) were to be recorded. |
| Percentage of Participants With HbA1c <7% for Participants Who Did Not Report Hypoglycemia | Weeks 26, 52, 78 and 104 | — |
| Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Baseline and Weeks 26, 52, 78 and 104 | The change between the fasting plasma glucose value to be collected at Weeks 26, 52, 78 and 104 relative to baseline. |
| Percentage of Participants With HbA1c <7% | Weeks 26, 52, 78 and 104 | — |
Countries
Argentina, Australia, Bulgaria, Canada, Colombia, Czechia, Estonia, Hong Kong, Israel, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Philippines, Poland, Romania, Russia, South Africa, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part at 291 sites in Argentina, Australia, Bulgaria, Canada, Colombia, Czech Republic, Estonia, Hong Kong, Israel, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Philippines, Poland, Romania, the Russian Federation, South Africa, Taiwan, Ukraine, the United Kingdom and the United States from 06 November 2011 to 24 April 2014.
Pre-assignment details
Participants with a historical diagnosis of type 2 diabetes mellitus who were inadequately controlled while receiving metformin alone were enrolled in 1 of 3 treatment groups as follows: glimepiride; TAK-875 25 milligram (mg); TAK-875 50 mg.
Participants by arm
| Arm | Count |
|---|---|
| Glimepiride TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia. | 824 |
| TAK-875 25 mg TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. | 817 |
| TAK-875 50 mg TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. | 813 |
| Total | 2,454 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 26 | 26 | 42 |
| Overall Study | Contraindications | 1 | 1 | 0 |
| Overall Study | Death | 2 | 1 | 0 |
| Overall Study | Hypoglycemic Event | 4 | 0 | 0 |
| Overall Study | Investigator Decision | 3 | 2 | 1 |
| Overall Study | Investigator's Discretion | 2 | 0 | 0 |
| Overall Study | Lack of Efficacy | 3 | 3 | 1 |
| Overall Study | Lost to Follow-up | 8 | 12 | 11 |
| Overall Study | Major Protocol Deviation | 3 | 7 | 1 |
| Overall Study | Non-Compliant With Study Drug | 0 | 1 | 1 |
| Overall Study | Other | 1 | 1 | 0 |
| Overall Study | Participant Moved Out of Area | 2 | 0 | 1 |
| Overall Study | Participant Moved Out of Country | 1 | 0 | 1 |
| Overall Study | Participant Started Taking Glipizide | 1 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 1 |
| Overall Study | Sponsor Decision | 0 | 1 | 3 |
| Overall Study | Study Termination | 730 | 729 | 713 |
| Overall Study | Withdrawal by Subject | 37 | 33 | 37 |
Baseline characteristics
| Characteristic | Total | Glimepiride | TAK-875 50 mg | TAK-875 25 mg |
|---|---|---|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 9.57 | 57.3 years STANDARD_DEVIATION 9.56 | 56.6 years STANDARD_DEVIATION 9.81 | 56.8 years STANDARD_DEVIATION 9.34 |
| Age, Customized >=65 years | 523 participants | 187 participants | 165 participants | 171 participants |
| Age, Customized Less than (<) 65 years | 1931 participants | 637 participants | 648 participants | 646 participants |
| Baseline Glycosylated Hemoglobin (HbA1c) Category >=8.5% | 691 participants | 238 participants | 221 participants | 232 participants |
| Baseline Glycosylated Hemoglobin (HbA1c) Category < 8.5 percent (%) | 1760 participants | 584 participants | 592 participants | 584 participants |
| Baseline Glycosylated Hemoglobin (HbA1c) Category Not Available | 3 participants | 2 participants | 0 participants | 1 participants |
| Body Mass Index (BMI) | 31.42 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.329 | 31.34 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.334 | 31.43 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.403 | 31.50 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.253 |
| Duration of Diabetes | 6.312 years STANDARD_DEVIATION 5.056 | 6.372 years STANDARD_DEVIATION 5.293 | 5.995 years STANDARD_DEVIATION 4.711 | 6.566 years STANDARD_DEVIATION 5.132 |
| Height | 166.6 centimeter (cm) STANDARD_DEVIATION 10.37 | 166.2 centimeter (cm) STANDARD_DEVIATION 10.66 | 167.3 centimeter (cm) STANDARD_DEVIATION 10.19 | 166.2 centimeter (cm) STANDARD_DEVIATION 10.23 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 40 participants | 8 participants | 12 participants | 20 participants |
| Race/Ethnicity, Customized Asian | 293 participants | 101 participants | 93 participants | 99 participants |
| Race/Ethnicity, Customized Black or African American | 209 participants | 62 participants | 77 participants | 70 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 204 participants | 68 participants | 70 participants | 66 participants |
| Race/Ethnicity, Customized Multiracial | 82 participants | 33 participants | 23 participants | 26 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 14 participants | 3 participants | 7 participants | 4 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 321 participants | 105 participants | 106 participants | 110 participants |
| Race/Ethnicity, Customized Not Available | 1929 participants | 651 participants | 637 participants | 641 participants |
| Race/Ethnicity, Customized White | 1816 participants | 617 participants | 601 participants | 598 participants |
| Region of Enrollment Argentina | 113 participants | 37 participants | 37 participants | 39 participants |
| Region of Enrollment Australia | 9 participants | 4 participants | 3 participants | 2 participants |
| Region of Enrollment Bulgaria | 51 participants | 17 participants | 16 participants | 18 participants |
| Region of Enrollment Canada | 121 participants | 42 participants | 39 participants | 40 participants |
| Region of Enrollment Colombia | 3 participants | 2 participants | 1 participants | 0 participants |
| Region of Enrollment Czech Republic | 93 participants | 31 participants | 31 participants | 31 participants |
| Region of Enrollment Estonia | 36 participants | 12 participants | 12 participants | 12 participants |
| Region of Enrollment Hong Kong | 29 participants | 9 participants | 10 participants | 10 participants |
| Region of Enrollment Israel | 150 participants | 50 participants | 50 participants | 50 participants |
| Region of Enrollment Latvia | 43 participants | 15 participants | 14 participants | 14 participants |
| Region of Enrollment Lithuania | 66 participants | 21 participants | 22 participants | 23 participants |
| Region of Enrollment Malaysia | 50 participants | 17 participants | 17 participants | 16 participants |
| Region of Enrollment Mexico | 43 participants | 14 participants | 15 participants | 14 participants |
| Region of Enrollment New Zealand | 44 participants | 15 participants | 15 participants | 14 participants |
| Region of Enrollment Philippines | 114 participants | 39 participants | 37 participants | 38 participants |
| Region of Enrollment Poland | 193 participants | 64 participants | 63 participants | 66 participants |
| Region of Enrollment Romania | 155 participants | 52 participants | 51 participants | 52 participants |
| Region of Enrollment Russian Federation | 78 participants | 26 participants | 26 participants | 26 participants |
| Region of Enrollment South Africa | 247 participants | 83 participants | 83 participants | 81 participants |
| Region of Enrollment Taiwan, Province Of China | 34 participants | 11 participants | 12 participants | 11 participants |
| Region of Enrollment Ukraine | 239 participants | 80 participants | 79 participants | 80 participants |
| Region of Enrollment United Kingdom | 51 participants | 18 participants | 17 participants | 16 participants |
| Region of Enrollment United States | 492 participants | 165 participants | 163 participants | 164 participants |
| Sex: Female, Male Female | 1212 Participants | 428 Participants | 362 Participants | 422 Participants |
| Sex: Female, Male Male | 1242 Participants | 396 Participants | 451 Participants | 395 Participants |
| Smoking Classification Current smoker | 383 participants | 114 participants | 126 participants | 143 participants |
| Smoking Classification Ex-smoker | 484 participants | 158 participants | 185 participants | 141 participants |
| Smoking Classification Never smoked | 1587 participants | 552 participants | 502 participants | 533 participants |
| Weight | 87.55 kilogram (kg) STANDARD_DEVIATION 18.501 | 86.95 kilogram (kg) STANDARD_DEVIATION 18.415 | 88.37 kilogram (kg) STANDARD_DEVIATION 18.796 | 87.35 kilogram (kg) STANDARD_DEVIATION 18.283 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 334 / 822 | 337 / 816 | 323 / 813 |
| serious Total, serious adverse events | 63 / 822 | 41 / 816 | 58 / 813 |
Outcome results
Primary
Change From Baseline in HbA1c at Weeks 78 and 104
The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) to be collected at Weeks 78 and 104 relative to baseline.
Time frame: Baseline and Weeks 78 and 104
Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glimepiride | Change From Baseline in HbA1c at Weeks 78 and 104 | Change at Week 78 | -0.80 percentage of glycosylated hemoglobin | Standard Error 0.957 |
| Glimepiride | Change From Baseline in HbA1c at Weeks 78 and 104 | Baseline | 8.00 percentage of glycosylated hemoglobin | Standard Error 0.814 |
| Glimepiride | Change From Baseline in HbA1c at Weeks 78 and 104 | Change at Week 104 | NA percentage of glycosylated hemoglobin | — |
| TAK-875 25 mg | Change From Baseline in HbA1c at Weeks 78 and 104 | Change at Week 78 | -0.82 percentage of glycosylated hemoglobin | Standard Error 0.865 |
| TAK-875 25 mg | Change From Baseline in HbA1c at Weeks 78 and 104 | Baseline | 8.01 percentage of glycosylated hemoglobin | Standard Error 0.777 |
| TAK-875 25 mg | Change From Baseline in HbA1c at Weeks 78 and 104 | Change at Week 104 | -1.03 percentage of glycosylated hemoglobin | Standard Error 1.159 |
| TAK-875 50 mg | Change From Baseline in HbA1c at Weeks 78 and 104 | Baseline | 7.99 percentage of glycosylated hemoglobin | Standard Error 0.792 |
| TAK-875 50 mg | Change From Baseline in HbA1c at Weeks 78 and 104 | Change at Week 104 | 0.03 percentage of glycosylated hemoglobin | Standard Error 0.603 |
| TAK-875 50 mg | Change From Baseline in HbA1c at Weeks 78 and 104 | Change at Week 78 | -0.98 percentage of glycosylated hemoglobin | Standard Error 0.834 |
Secondary
Change From Baseline in Body Weight at Weeks 78 and 104
The change between the body weight to be collected at Weeks 78 and 104 relative to baseline.
Time frame: Baseline and Weeks 78 and 104
Population: FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period. Data for body weight was not available at Week 104 due to early termination of the study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glimepiride | Change From Baseline in Body Weight at Weeks 78 and 104 | Baseline | 84.32 kg | Standard Error 0.981 |
| Glimepiride | Change From Baseline in Body Weight at Weeks 78 and 104 | Change at Week 78 | 1.24 kg | Standard Error 0.492 |
| TAK-875 25 mg | Change From Baseline in Body Weight at Weeks 78 and 104 | Baseline | 84.55 kg | Standard Error 1.003 |
| TAK-875 25 mg | Change From Baseline in Body Weight at Weeks 78 and 104 | Change at Week 78 | -0.07 kg | Standard Error 0.524 |
| TAK-875 50 mg | Change From Baseline in Body Weight at Weeks 78 and 104 | Baseline | 85.67 kg | Standard Error 0.995 |
| TAK-875 50 mg | Change From Baseline in Body Weight at Weeks 78 and 104 | Change at Week 78 | -0.21 kg | Standard Error 0.487 |
Comparison: Change at Week 78p-value: 0.06595% CI: [-2.7, 0.08]Mixed Model Repeated Measures
Comparison: Change at Week 78p-value: 0.03495% CI: [-2.78, -0.11]Mixed Model Repeated Measures
Secondary
Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104
The change between the fasting plasma glucose value to be collected at Weeks 26, 52, 78 and 104 relative to baseline.
Time frame: Baseline and Weeks 26, 52, 78 and 104
Population: FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glimepiride | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 78 | 0.0 milligram per deciliter (mg/dL) | Standard Error 41.87 |
| Glimepiride | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 52 | -19.8 milligram per deciliter (mg/dL) | Standard Error 40.81 |
| Glimepiride | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Baseline | 164.5 milligram per deciliter (mg/dL) | Standard Error 41.25 |
| Glimepiride | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 26 | -19.5 milligram per deciliter (mg/dL) | Standard Error 41.9 |
| Glimepiride | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 104 | NA milligram per deciliter (mg/dL) | — |
| TAK-875 25 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 52 | -19.3 milligram per deciliter (mg/dL) | Standard Error 36.85 |
| TAK-875 25 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Baseline | 165.2 milligram per deciliter (mg/dL) | Standard Error 38.45 |
| TAK-875 25 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 26 | -17.4 milligram per deciliter (mg/dL) | Standard Error 34.67 |
| TAK-875 25 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 78 | -17.6 milligram per deciliter (mg/dL) | Standard Error 30.03 |
| TAK-875 25 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 104 | -24.0 milligram per deciliter (mg/dL) | Standard Error 1.41 |
| TAK-875 50 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 104 | -32.0 milligram per deciliter (mg/dL) | Standard Error 17.58 |
| TAK-875 50 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 78 | -21.4 milligram per deciliter (mg/dL) | Standard Error 41.27 |
| TAK-875 50 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Baseline | 163.7 milligram per deciliter (mg/dL) | Standard Error 38.65 |
| TAK-875 50 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 52 | -23.7 milligram per deciliter (mg/dL) | Standard Error 33.78 |
| TAK-875 50 mg | Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 | Change at Week 26 | -23.0 milligram per deciliter (mg/dL) | Standard Error 31.99 |
Secondary
Change From Baseline in HbA1c at Weeks 26 and 52
The change in the value of HbA1c collected at Weeks 26 and 52 relative to baseline.
Time frame: Baseline and Weeks 26 and 52
Population: FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Glimepiride | Change From Baseline in HbA1c at Weeks 26 and 52 | Week 26 | -0.91 percentage of glycosylated hemoglobin | Standard Error 0.039 |
| Glimepiride | Change From Baseline in HbA1c at Weeks 26 and 52 | Week 52 | -0.78 percentage of glycosylated hemoglobin | Standard Error 0.043 |
| TAK-875 25 mg | Change From Baseline in HbA1c at Weeks 26 and 52 | Week 26 | -0.63 percentage of glycosylated hemoglobin | Standard Error 0.039 |
| TAK-875 25 mg | Change From Baseline in HbA1c at Weeks 26 and 52 | Week 52 | -0.65 percentage of glycosylated hemoglobin | Standard Error 0.044 |
| TAK-875 50 mg | Change From Baseline in HbA1c at Weeks 26 and 52 | Week 26 | -0.81 percentage of glycosylated hemoglobin | Standard Error 0.039 |
| TAK-875 50 mg | Change From Baseline in HbA1c at Weeks 26 and 52 | Week 52 | -0.81 percentage of glycosylated hemoglobin | Standard Error 0.043 |
Secondary
Percentage of Participants With HbA1c <7%
Time frame: Weeks 26, 52, 78 and 104
Population: FAS included all randomized subjects who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Glimepiride | Percentage of Participants With HbA1c <7% | Week 26 | 51.8 percentage of participants |
| Glimepiride | Percentage of Participants With HbA1c <7% | Week 78 | 45.2 percentage of participants |
| Glimepiride | Percentage of Participants With HbA1c <7% | Week 104 | NA percentage of participants |
| Glimepiride | Percentage of Participants With HbA1c <7% | Week 52 | 47.8 percentage of participants |
| TAK-875 25 mg | Percentage of Participants With HbA1c <7% | Week 26 | 38.3 percentage of participants |
| TAK-875 25 mg | Percentage of Participants With HbA1c <7% | Week 52 | 43.3 percentage of participants |
| TAK-875 25 mg | Percentage of Participants With HbA1c <7% | Week 78 | 37.7 percentage of participants |
| TAK-875 25 mg | Percentage of Participants With HbA1c <7% | Week 104 | 33.3 percentage of participants |
| TAK-875 50 mg | Percentage of Participants With HbA1c <7% | Week 78 | 54.5 percentage of participants |
| TAK-875 50 mg | Percentage of Participants With HbA1c <7% | Week 26 | 48.7 percentage of participants |
| TAK-875 50 mg | Percentage of Participants With HbA1c <7% | Week 52 | 54.5 percentage of participants |
| TAK-875 50 mg | Percentage of Participants With HbA1c <7% | Week 104 | 33.3 percentage of participants |
Secondary
Percentage of Participants With HbA1c <7% for Participants Who Did Not Report Hypoglycemia
Time frame: Weeks 26, 52, 78 and 104
Population: Data for this outcome measure was not analyzed as prespecified in the protocol.
Secondary
Percentage of Participants With Hypoglycemia
Participants were provided diaries to document any hypoglycemic events that occurred between study visits. Any experience of hypoglycemic signs and symptoms (regardless of the blood glucose value by glucometer) or had a blood glucose value less than or equal to (\<=) 70 milligram per deciliter (mg/dL) (3.9 millimole per liter (mmol/L) by glucometer (regardless of symptoms) were to be recorded.
Time frame: Day 1 up to Weeks 78 and 104
Population: Safety analysis set included all participants who received at least 1 dose of double-blind study medication. Participants were analyzed according to the study medication they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Glimepiride | Percentage of Participants With Hypoglycemia | Day 1 up to Week 78 | 30.2 percentage of participants |
| Glimepiride | Percentage of Participants With Hypoglycemia | Day 1 up to Week 104 | 30.2 percentage of participants |
| TAK-875 25 mg | Percentage of Participants With Hypoglycemia | Day 1 up to Week 78 | 5.4 percentage of participants |
| TAK-875 25 mg | Percentage of Participants With Hypoglycemia | Day 1 up to Week 104 | 5.4 percentage of participants |
| TAK-875 50 mg | Percentage of Participants With Hypoglycemia | Day 1 up to Week 78 | 5.3 percentage of participants |
| TAK-875 50 mg | Percentage of Participants With Hypoglycemia | Day 1 up to Week 104 | 5.3 percentage of participants |
Comparison: Day 1 up to Week 78: Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.p-value: <0.00195% CI: [0.09, 0.18]Regression, Logistic
Comparison: Day 1 up to Week 78: Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.p-value: <0.00195% CI: [0.09, 0.18]Regression, Logistic
Comparison: Day 1 up to Week 104: Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.p-value: <0.00195% CI: [0.09, 0.18]Regression, Logistic
Comparison: Day 1 up to Week 104: Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.p-value: <0.00195% CI: [0.09, 0.18]Regression, Logistic