Efficacy and Safety of TAK-875 Compared to Glimepiride When Used With Metformin in Participants With Type 2 Diabetes
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: TAK-875; TAK-875; Glimepiride
Intervention description: TAK-875 25 mg, tablets, orally, once daily and metformin ≥1500 mg or Maximum Tolerated Dose (MTD) for up to 104 weeks.; TAK-875 50 mg, tablets, orally, once daily and metformin ≥1500 mg or MTD for up to 104 weeks.; 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.
Intervention MeSH terms: Glimepiride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 2454.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug Therapy

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).
    

Eligibility criteria:

        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).