Study of TAK-875 in Adults With Type 2 Diabetes and Cardiovascular Disease or Risk Factors for Cardiovascular Disease
Condition: Type 2 Diabetes; Cardiovascular Disease
MeSH terms: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: TAK-875; TAK-875 Placebo
Intervention description: TAK-875 tablets; TAK-875 placebo-matching tablets
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 3207.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      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.
    

Eligibility criteria:

        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.