Cardiovascular Disease, Type 2 Diabetes
Conditions
Keywords
Drug therapy
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.
Interventions
DRUGTAK-875
TAK-875 tablets
DRUGTAK-875 Placebo
TAK-875 placebo-matching tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite | 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. |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Croatia, Czechia, Estonia, France, Germany, Hong Kong, Hungary, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Peru, Philippines, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 469 investigative sites in 31 countries; 192 sites in North America, 175 in the Europe, Middle East, and Africa (EMEA) region (including Russia, Ukraine, Israel, and South Africa), 65 in the Asia Pacific region, and 37 in Latin/South America from 01 June 2012 to 05 May 2014.
Pre-assignment details
Participants with a historical diagnosis of type 2 diabetes mellitus (T2DM) and clinically-evident cardiovascular (CV) disease or multiple risk factors for CV events who were inadequately controlled while receiving the standard of care were enrolled in 1 of 2 treatment groups: placebo; fasiglifam 50 milligram (mg).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days. | 1,603 |
| Fasiglifam 50 mg Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days. | 1,604 |
| Total | 3,207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 20 | 18 |
| Overall Study | Lost to Follow-up | 10 | 10 |
| Overall Study | Other | 9 | 10 |
| Overall Study | Randomized, but not treated | 0 | 3 |
| Overall Study | Study Terminated by Sponsor | 1,543 | 1,548 |
| Overall Study | Withdrawal by Subject | 21 | 15 |
Baseline characteristics
| Characteristic | Placebo | Fasiglifam 50 mg | Total |
|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 9.03 | 63.4 years STANDARD_DEVIATION 9.2 | 63.7 years STANDARD_DEVIATION 9.12 |
| Age, Customized Greater than or equal to (>=) 65 years | 809 participants | 753 participants | 1562 participants |
| Age, Customized Less than (<) 65 years | 794 participants | 851 participants | 1645 participants |
| Body Mass Index (BMI) | 32.14 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.107 | 32.45 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 7.497 | 32.30 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.838 |
| Duration of Diabetes | 13.583 years STANDARD_DEVIATION 8.409 | 13.333 years STANDARD_DEVIATION 8.321 | 13.458 years STANDARD_DEVIATION 8.365 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 150 Participants | 119 Participants | 269 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 446 Participants | 477 Participants | 923 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1007 Participants | 1008 Participants | 2015 Participants |
| Glycosylated Hemoglobin (HbA1c) Category >=8.5% | 615 participants | 668 participants | 1283 participants |
| Glycosylated Hemoglobin (HbA1c) Category <8.5 percent (%) | 988 participants | 936 participants | 1924 participants |
| Height | 168.1 centimeter (cm) STANDARD_DEVIATION 9.84 | 167.6 centimeter (cm) STANDARD_DEVIATION 10.54 | 167.8 centimeter (cm) STANDARD_DEVIATION 10.2 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 47 participants | 41 participants | 88 participants |
| Race/Ethnicity, Customized Asian | 199 participants | 205 participants | 404 participants |
| Race/Ethnicity, Customized Black or African American | 79 participants | 95 participants | 174 participants |
| Race/Ethnicity, Customized Multiracial/More than 1 race | 7 participants | 10 participants | 17 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 6 participants | 7 participants | 13 participants |
| Race/Ethnicity, Customized White | 1265 participants | 1246 participants | 2511 participants |
| Region of Enrollment Argentina | 121 participants | 121 participants | 242 participants |
| Region of Enrollment Australia | 34 participants | 35 participants | 69 participants |
| Region of Enrollment Bulgaria | 21 participants | 22 participants | 43 participants |
| Region of Enrollment Canada | 104 participants | 107 participants | 211 participants |
| Region of Enrollment Croatia | 16 participants | 17 participants | 33 participants |
| Region of Enrollment Czech Republic | 56 participants | 56 participants | 112 participants |
| Region of Enrollment Estonia | 13 participants | 11 participants | 24 participants |
| Region of Enrollment France | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Germany | 30 participants | 30 participants | 60 participants |
| Region of Enrollment Hong Kong | 29 participants | 29 participants | 58 participants |
| Region of Enrollment Hungary | 74 participants | 72 participants | 146 participants |
| Region of Enrollment Israel | 25 participants | 26 participants | 51 participants |
| Region of Enrollment Italy | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Korea, Republic of | 29 participants | 27 participants | 56 participants |
| Region of Enrollment Latvia | 11 participants | 11 participants | 22 participants |
| Region of Enrollment Lithuania | 15 participants | 15 participants | 30 participants |
| Region of Enrollment Malaysia | 30 participants | 31 participants | 61 participants |
| Region of Enrollment Mexico | 26 participants | 26 participants | 52 participants |
| Region of Enrollment New Zealand | 20 participants | 20 participants | 40 participants |
| Region of Enrollment Peru | 18 participants | 17 participants | 35 participants |
| Region of Enrollment Philippines | 25 participants | 24 participants | 49 participants |
| Region of Enrollment Poland | 118 participants | 118 participants | 236 participants |
| Region of Enrollment Romania | 5 participants | 4 participants | 9 participants |
| Region of Enrollment Russian Federation | 25 participants | 23 participants | 48 participants |
| Region of Enrollment Slovakia | 31 participants | 31 participants | 62 participants |
| Region of Enrollment South Africa | 10 participants | 10 participants | 20 participants |
| Region of Enrollment Taiwan, Province of China | 31 participants | 31 participants | 62 participants |
| Region of Enrollment Thailand | 29 participants | 32 participants | 61 participants |
| Region of Enrollment Ukraine | 76 participants | 76 participants | 152 participants |
| Region of Enrollment United Kingdom | 16 participants | 16 participants | 32 participants |
| Region of Enrollment United States | 559 participants | 559 participants | 1118 participants |
| Sex: Female, Male Female | 543 Participants | 563 Participants | 1106 Participants |
| Sex: Female, Male Male | 1060 Participants | 1041 Participants | 2101 Participants |
| Smoking Classification Current smoker | 330 participants | 328 participants | 658 participants |
| Smoking Classification Ex-smoker | 606 participants | 608 participants | 1214 participants |
| Smoking Classification Never smoked | 667 participants | 668 participants | 1335 participants |
| Weight | 91.14 kilogram (kg) STANDARD_DEVIATION 19.832 | 91.40 kilogram (kg) STANDARD_DEVIATION 21.319 | 91.27 kilogram (kg) STANDARD_DEVIATION 20.586 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 427 / 1,603 | 415 / 1,601 |
| serious Total, serious adverse events | 197 / 1,603 | 201 / 1,601 |
Outcome results
Primary
Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite
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).
Time frame: Baseline up to end of study (up to Day 588)
Population: Full Analysis Set (FAS) included all randomized participants who had baseline and at least 1 post-baseline assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite | NA days |
| Fasiglifam 50 mg | Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite | NA days |
Secondary
Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite
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.
Time frame: Baseline up to end of study (up to Day 588)
Population: Full Analysis Set (FAS) included all randomized participants who had baseline and at least 1 post-baseline assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite | NA days |
| Fasiglifam 50 mg | Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite | NA days |