Efficacy and Safety of TAK-875 Compared to Glimepiride When Used With Metformin in Participants With Type 2 Diabetes

A Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-875 25 mg and 50 mg Compared to Glimepiride When Used in Combination With Metformin in Subjects With Type 2 Diabetes

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).

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.

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 Exclusion Criteria Prior to Randomization

1. The participant has received excluded medications listed in the protocol during the Placebo Run-in Period (topical and inhaled corticosteroids are allowed).
2. The participant has a systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥95 mm Hg at Baseline (Day 1) (If the subject meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement and decision will be made based on the second measurement).
3. The participant has a serum creatinine ≥1.5 mg/dL(≥133µmol/L) [males] and ≥1.4 mg/dL (≥124 µmol/L) [females] and/or estimated glomerular filtration rate (GFR) <60 mL/min/1.73m2 at Visit 3 (Schedule B subjects only).