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

Tracking Information
First Submitted Date ICMJE	May 29, 2012
First Posted Date ICMJE	June 1, 2012
Results First Submitted Date	July 24, 2015
Results First Posted Date	August 21, 2015
Last Update Posted Date	October 19, 2015
Study Start Date ICMJE	June 2012
Actual Primary Completion Date	May 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: July 24, 2015)	Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite [ Time Frame: Baseline up to end of study (up to Day 588) ]; The time from randomization to the first occurrences of any event in the primary MACE composite was evaluated using Kaplan-Meier analysis. The primary MACE composite comprised cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for unstable angina (with or without revascularization).
Original Primary Outcome Measures ICMJE; (submitted: May 31, 2012)	Time to the first occurrence of any component of the primary major adverse cardiovascular event (MACE) composite [ Time Frame: 6 years. ]; The time to the first occurrence of any component of the primary MACE composite, including: Cardiovascular death; Nonfatal Myocardial infarction; Nonfatal stroke; Hospitalization for unstable angina (with or without revascularization)
Change History	Complete list of historical versions of study NCT01609582 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: July 24, 2015)	Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite [ Time Frame: Baseline up to end of study (up to Day 588) ]; The time from randomization to the first occurrences of any event in the secondary MACE composite was evaluated using Kaplan-Meier analysis. The secondary MACE composite comprised CV death, nonfatal MI, and nonfatal stroke.
Original Secondary Outcome Measures ICMJE; (submitted: May 31, 2012)	The time to first occurrence of any component of the secondary major adverse cardiovascular event MACE composite [ Time Frame: 6 years. ]; The time to first occurrence of any component of the secondary MACE composite, including: CV death; Nonfatal myocardial infarction; Nonfatal stroke
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Study of TAK-875 in Adults With Type 2 Diabetes and Cardiovascular Disease or Risk Factors for Cardiovascular Disease
Official Title ICMJE	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
Brief 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.
Detailed Description	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.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Type 2 Diabetes; Cardiovascular Disease
Intervention ICMJE	Drug: TAK-875 TAK-875 tablets; Drug: TAK-875 Placebo TAK-875 placebo-matching tablets
Study Arms	Experimental: TAK-875 50 mg TAK-875 50 mg tablets, orally, once daily for up to 6 years. Intervention: Drug: TAK-875; Placebo Comparator: Placebo TAK-875 placebo-matching tablets, orally, once daily for up to 6 years. Intervention: Drug: TAK-875 Placebo
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Terminated
Actual Enrollment ICMJE; (submitted: January 24, 2014)	3207
Original Estimated Enrollment ICMJE; (submitted: May 31, 2012)	5000
Actual Study Completion Date	May 2014
Actual Primary Completion Date	May 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: In the opinion of the investigator, the patient is capable of understanding and complying with protocol requirements, including scheduled clinic appointments.; 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.; Has a diagnosis of type 2 diabetes mellitus.; Has an glycosylated hemoglobin (HbA1c) level between 7.0% and 10.5%, inclusive, at Screening. HbA1c testing may be repeated once during Screening.; Meets at least one (1) of the following three (3) High Risk Categories (a-c ): A documented history of myocardial infarction (MI) occurring no less than 2 months (60 days) and no greater than 24 months prior to Screening. 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). 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): 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. 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. A history of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at least 2 months prior to Screening. 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.; 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.; 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.; 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: 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.; Has been randomized into a previous TAK-875 study.; 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; Is diagnosed with type 1 diabetes mellitus or latent autoimmune diabetes in adults.; Is hemodynamically unstable, including severe heart failure (New York Heart Association Class IV) at Screening.; 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).; Has ALT and/or AST levels >3.0x ULN at Screening.; 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.; 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.; Has uncontrolled thyroid disease, as determined by the investigator and/or clinical investigation.; Has a known history of infection with human immunodeficiency virus (HIV).; Has a known active infection with Hepatitis B virus (HBV), or Hepatitis C virus (HCV) requiring antiviral treatment.; Has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse within 2 years prior to Screening.; 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.; Has a history of hypersensitivity, allergies, or has had an anaphylactic reaction(s) to TAK-875.; 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.; Is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.; 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.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Argentina, Australia, Brazil, Bulgaria, Canada, Croatia, Czech Republic, Estonia, France, Germany, Hong Kong, Hungary, Israel, Italy, Korea, Republic of, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Peru, Philippines, Poland, Romania, Russian Federation, Slovakia, South Africa, Taiwan, Thailand, Ukraine, United Kingdom, United States
Removed Location Countries	Guatemala
Administrative Information
NCT Number ICMJE	NCT01609582
Other Study ID Numbers ICMJE	TAK-875_306; 2011-001732-37 ( EudraCT Number ); U1111-1129-7824 ( Registry Identifier: WHO ); TAK-875_306CTIL ( Registry Identifier: Israel MOH ); DOH-27-0313-4117 ( Registry Identifier: SANCTR ); 12/SC/0504 ( Registry Identifier: NRES ); NMRR-12-433-12087 ( Registry Identifier: NMRR (Malaysia) ); PHRR130916-000119 ( Registry Identifier: PHRR (Philippines) ); 1015031332 ( Registry Identifier: TCTIN )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Takeda
Study Sponsor ICMJE	Takeda
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Sr. Medical Director Clinical Science Takeda
PRS Account	Takeda
Verification Date	October 2015
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP