Study of TAK-875 in Adults With Type 2 Diabetes and Cardiovascular Disease or Risk Factors for Cardiovascular Disease

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate Cardiovascular Outcomes of TAK-875, 50 mg in Addition to Standard of Care in Subjects With Type 2 Diabetes and With Cardiovascular Disease or Multiple Risk Factors for Cardiovascular Events

The purpose of this study is to demonstrate no excess risk of cardiovascular (CV) composite events exists following long term treatment with TAK-875 compared with placebo.

The drug being tested in this study is called TAK-875. TAK-875 is being tested to treat people who have diabetes. This study will look at the number of cardiovascular events (for example, heart attacks) of people who take TAK-875 in comparison to placebo in addition to standard care.

The study will enroll approximately 5000 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• TAK-875 50 mg.
• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient.

All participants will be asked to take one tablet at the same time each day throughout the study. All participants will be asked to record any time they have low blood sugar symptoms in a diary.

This multi-centre trial will be conducted worldwide, in approximately 700 sites. The overall time to participate in this study is 6 years. Participants will make up to approximately 24 visits to the clinic, with telephone visits conducted on an alternate 6 month schedule starting from Month 27.

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 patient is capable of understanding and complying with protocol requirements, including scheduled clinic appointments.

2. The patient or, when applicable, the patient'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. Has a diagnosis of type 2 diabetes mellitus.

4. Has an glycosylated hemoglobin (HbA1c) level between 7.0% and 10.5%, inclusive, at Screening. HbA1c testing may be repeated once during Screening.

5. Meets at least one (1) of the following three (3) High Risk Categories (a-c ):

   1. A documented history of myocardial infarction (MI) occurring no less than 2 months (60 days) and no greater than 24 months prior to Screening.

   2. Documented symptomatic peripheral arterial disease (PAD) (at least one (1) of the following three (3) criteria must be satisfied): i) Current intermittent claudication together with documented ankle-brachial index ≤0.85. ii) History of previous vascular intervention for intermittent claudication or resting limb ischemia (example: amputation for arterial disease, peripheral bypass, or history of angioplasty/stenting). iii) History of symptomatic carotid artery disease (requiring revascularization with carotid endarterectomy (CEA) or stenting).

   3. Documented cerebrovascular disease (at least one (1) of the following two (2) criteria must be satisfied): i) A history of transient ischemic attack (TIA) confirmed by a neurologist no greater than 24 months prior to screening and clinically and neurologically stable at randomization. ii) A history of ischemic stroke (IS) (with a Modified Rankin Scale Score ≤3 documented prior to Randomization) not less than 2 months (60 days) and no greater than 24 months prior to Screening, and clinically and neurologically stable at Randomization. The Modified Rankin Scale is located in appendix in protocol.

      Or meets at least one (1) of the following five (5) Intermediate Risk Categories (d-h):

   4. Stable angina with coronary disease documented by the presence of inducible ischemia or scar by stress myocardial perfusion imaging (MPI), echocardiogram or magnetic resonance imaging (MRI) in the past 24 months.

   5. Multi vessel coronary disease, based on coronary angiography, with or without angina, documented by >50% diameter stenosis in at least 2 of the 3 major coronary distributions.

   6. A history of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at least 2 months prior to Screening.

   7. The subject has diabetic nephropathy plus (2) of the clinical criteria listed below (i. to vi.). Diabetic nephropathy is defined as either urinary albumin excretion ≥ 30 µg/mg creatinine (3.4 mg/mmol creatinine) (based on a random spot collection) or urinary albumin excretion ≥ 30 mg/24h (based on a 24 h or timed collection). Results must be confirmed on at least two specimens collected within 12 months prior to Screening and no more than 6 months apart: i)Duration of diabetes ≥ 10 years on pharmacological treatment documented within medical records. ii) Confirmed systolic blood pressure (SBP) ≥150 mm Hg on 2 separate days during Screening despite treatment with at least 2 anti-hypertensive medications administered at doses considered optimal by local standard of care. iii) Presence of dyslipidemia as defined by any one (1) of the following confirmed at screening: A. Low density lipoprotein (LDL) > 100 mg/dl (2.59 mmol/L) while on statin therapy administered at maximum tolerated dose or optimal dose based on local standard of care for at least 4 weeks prior to screening. B. LDL > 130 mg/dL (3.37 mmol/L) when not on statin therapy. C. High density lipoprotein (HDL) < 40 mg/dL (1.04 mmol/L) in males or < 45 mg/dL (1.17 mmol/L) in females. D. Fasting Triglyceride >200 mg/dL(2.26 mmol/L). iv) Currently smoking >10 cigarettes per day at Screening. v) Male ≥65 years of age or female ≥70 years of age. vi) Highly selective C-reactive protein (hs-CRP) > 2.0 mg/L in the absence of intercurrent infection or acute process.

   h.) The subject meets at least five (5) of the following clinical criteria: i.) Duration of diabetes ≥10 years on pharmacological treatment documented within medical records. ii) Confirmed systolic blood pressure (SBP) ≥150 mm Hg on 2 separate days during Screening despite treatment with at least 2 anti-hypertensive medications administered at doses considered optimal by local standard of care. iii) Presence of dyslipidemia as defined by any one (1) of the following confirmed at screening: A. Low density lipoprotein (LDL) > 100 mg/dl (2.59 mmol/L) while on statin therapy administered at maximum tolerated dose or optimal dose based on local standard of care for at least 4 weeks prior to screening. B. LDL > 130 mg/dL (3.37 mmol/L) when not on statin therapy. C. High density lipoprotein (HDL) < 40 mg/dL (1.04 mmol/L) in males or < 45 mg/dL (1.17 mmol/L) in females. D. Fasting Triglyceride >200 mg/dL(2.26 mmol/L). iv) Currently smoking >10 cigarettes per day at Screening. v) Male ≥65 years of age or female ≥70 years of age. vi) Highly selective C-reactive protein (hs-CRP) > 2.0 mg/L in the absence of intercurrent infection or acute process.

6. Is able and willing to monitor glucose with a home glucose monitor and consistently record his or her own blood glucose concentrations in patient diaries.

7. A female of childbearing potential who is sexually active with a non-sterilized male partner agrees to routinely use adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose of study drug.

8. Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN) and if ALT or AST elevated above ULN, have chronic, well-compensated liver disease documented by usual clinical parameters.

Exclusion Criteria:

1. Has received any investigational medication within 30 days prior to Screening or any investigational antidiabetic medication or excluded medications within 3 months prior to Screening.
2. Has been randomized into a previous TAK-875 study.
3. 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 (eg, spouse, parent, biological or legally adopted child, or sibling) or may consent under duress
4. Is diagnosed with type 1 diabetes mellitus or latent autoimmune diabetes in adults.
5. Is hemodynamically unstable, including severe heart failure (New York Heart Association Class IV) at Screening.
6. Is hospitalized at the Screening Visit for the event associated with the CV inclusion criteria. (Patients who have been discharged from an acute hospital to a cardiac rehabilitation center or nursing home at the time of the Screening Visit or Randomization Visit are not excluded).
7. Has ALT and/or AST levels >3.0x ULN at Screening.
8. Has a total bilirubin level >ULN at Screening. Exception: if a patient has documented Gilbert's Syndrome, the patient will be allowed with an elevated bilirubin level per the investigator's discretion.
9. Has an glomerular filtration rate (estimated) (eGFR) ≤ 15 mL/min/1.73m2 based on Modification of Diet in Renal Disease (MDRD) calculation at Screening and is currently on dialysis or expected to start dialysis within the next 6 months.
10. Has uncontrolled thyroid disease, as determined by the investigator and/or clinical investigation.
11. Has a known history of infection with human immunodeficiency virus (HIV).
12. Has a known active infection with Hepatitis B virus (HBV), or Hepatitis C virus (HCV) requiring antiviral treatment.
13. Has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse within 2 years prior to Screening.
14. Has any major illness or condition that, in the investigator's opinion, prohibits the patient from participating in the study or meeting the planned visit schedule.
15. Has a history of hypersensitivity, allergies, or has had an anaphylactic reaction(s) to TAK-875.
16. If female, is pregnant (confirmed by laboratory testing, ie, serum or urine human chorionic gonadotropin (hCG), in females of childbearing potential) or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.
17. Is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.
18. Has a 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.