ACTOS

An Adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant whose parent or legal guardian had signed informed consent form to participate in a study; it did not necessarily have to have a causal relationship with this treatment or study participation. An AE could therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study participation whether or not it was considered related to the drug or study procedures. A TEAE was defined as any AE occurring after the start of TAK-536 administration, and until the end of follow-up period of 2 weeks.

The relatedness of TEAEs with resting 12-lead ECG was based upon investigator discretion.

The anthropometric measurements included weight, height and body mass index (BMI). The relatedness of TEAEs to anthropometric measurements was based upon investigator discretion.

The laboratory values outside the range (triglycerides greater than \[\>\] 2.5\*upper limit of normal \[ULN\], blood urea nitrogen \[BUN\] \>30 milligram per deciliter \[mg/dL\], estimated glomerular filtration rate \[eGFR\] less than \[\<\] 30 milliliter per minute per 1.73 square meter \[mL/min/1.73m\^2\], and glucose \<50 mg/dL were considered markedly abnormal for TEAEs. The relatedness of TEAEs to clinical laboratory parameters was based upon investigator discretion.

Vital signs included home sitting blood pressure (diastolic and systolic) and office sitting pulse rate (pulse rate per 1 minute). The pulse rate measured at the last measurement of the sitting blood pressure was used as the sitting pulse rate value. The relatedness of TEAEs to vital signs was based upon investigator discretion.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs or worsens after receiving study drug.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs or worsens after receiving study drug.

The laboratory values outside the range (Blood Urea Nitrogen (BUN) (mg/dL) \>30, Creatinine (mg/dL) \>2.0, eGFR (mL/min/1.73m\^2) \<30, Creatine Kinase (U/L) \>5×ULN) are considered markedly abnormal.

A standard 12-lead ECG was performed while the participant was at rest. Any abnormal ECG findings determined by the investigator to be clinically significant were reported as adverse events.

A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Vital signs included office standing blood pressure, office sitting pulse rate, office standing pulse rate, and home sitting blood pressure. Any abnormal vital signs findings determined by the investigator to be clinically significant were reported as adverse events.

AUC(0-24) is a measure of total plasma exposure to the drug from time 0 to 24 hours post-dose, calculated using the linear trapezoidal rule.

Cmax is the maximum observed plasma concentration (actual measurement value) of a drug after administration, obtained directly from the plasma concentration-time curve.

AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity, calculated as AUC(0-inf)=AUC(0-tlqc)+lqc/λz

Tmax is the time to reach Cmax (actual measurement value), equal to time (hours) to Cmax.

T1/2 is the terminal elimination half-life (time required for half of the drug to be eliminated from the plasma), calculated as T1/2=ln(2)/λz.

AUC(0-24) is a measure of total plasma exposure to the drug from time 0 to 24 hours post-dose, calculated using the linear trapezoidal rule.

Cmax is the maximum observed plasma concentration (actual measurement value) of a drug after administration, obtained directly from the plasma concentration-time curve.

AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity, calculated as AUC(0-inf)=AUC(0-tlqc)+lqc/λz.

Tmax is the time to reach Cmax (actual measurement value), equal to time (hours) to Cmax.

T1/2 is the terminal elimination half-life (time required for half of the drug to be eliminated from the plasma), calculated as T1/2=ln(2)/λz.

AUC(0-24) is a measure of total plasma exposure to the drug from time 0 to 24 hours post-dose, calculated using the linear trapezoidal rule.

Cmax is the maximum observed plasma concentration (actual measurement value) of a drug after administration, obtained directly from the plasma concentration-time curve.

AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity, calculated as AUC(0-inf)=AUC(0-tlqc)+lqc/λz.

Tmax is the time to reach Cmax (actual measurement value), equal to time (hours) to Cmax.

T1/2 is the terminal elimination half-life (time required for half of the drug to be eliminated from the plasma), calculated as T1/2=ln(2)/λz.

The cumulative urinary excretion ratio (% of dose \[TAK-536-equivalent\]) of TAK-536 will be calculated from the urinary concentration and volume of each participant.

The cumulative urinary excretion ratio (% of dose \[TAK-536-equivalent\]) of TAK-536 metabolite M-I will be calculated from the urinary concentration and volume of each participant.

The cumulative urinary excretion ratio (% of dose \[TAK-536-equivalent\]) of TAK-536 metabolite M-II will be calculated from the urinary concentration and volume of each participant.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. Treatment emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

Vital signs are defined as sitting blood pressure, sitting pulse rate and temperature.

A resting 12-lead ECG was recorded. The investigator or subinvestigator (or a qualified physician at the study site) interpreted the ECG results.

Laboratory test results are defined as serum chemistry, hematology and urinalysis.

The primary endpoint will be increased high density lipoprotein cholesterol and decreased triglycerides measured as the difference after 12 or 24 weeks of treatment from baseline levels. The data are expressed as the percent change from the baseline value and calculated using he equation: * Change=\[100%\*(Endpoint value - Baseline Value)/Baseline Value\]

The change between the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at final visit or week 24 and Glycosylated Hemoglobin collected at baseline.

The increase in High-Density Lipoprotein (HDL) Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.

The nominal change from baseline in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.

Presence and degree of airway hyperresponsiveness assessed by methacholine challenge test. PC20= Methacholine dose at wich the FEV1 deops by \> 20% from pre-methacholine baseline values.

1. Normal = normal plasma glucose and normal glucose tolerance (OGTT). 2. Impaired category includes all non-diabetic participants with either a) Impaired fasting glucose = fasting plasma glucose \>110 mg/dl and \<126 mg/dl; or b) Impaired glucose intolerance = 2-hour plasma glucose (OGTT) \>140 mg/dl and \<200 mg/dl. 3. Diabetes = fasting plasma glucose \>126 mg/dl 2-hour (OGTT) plasma glucose \>200 mg/dl.

1. Normal = normal plasma glucose and normal glucose tolerance (OGTT). 2. Impaired category includes all non-diabetic participants with either a) Impaired fasting glucose = fasting plasma glucose \>110 mg/dl and \<126 mg/dl; or b) Impaired glucose intolerance = 2-hour plasma glucose (OGTT) \>140 mg/dl and \<200 mg/dl. 3. Diabetes = fasting plasma glucose \>126 mg/dl 2-hour (OGTT) plasma glucose \>200 mg/dl.

Insulin Sensitivity = Index for Glycemia (ISI gly) = 2 / (\[INSp x GLYp\] + 1). GLYp = Glycemic 0-2 hr area = sum of normalized (based on institutional values) 0 \& 2 hr glucose. INSp = Insulinemic 0-2 hr area = sum of normalized (based on institutional values) 0 \& 2 hr insulin.

Insulin Sensitivity = Index for Glycemia (ISI gly) = 2 / (\[INSp x GLYp\] + 1). GLYp = Glycemic 0-2 hr area = sum of normalized (based on institutional values) 0 \& 2 hr glucose. INSp = Insulinemic 0-2 hr area = sum of normalized (based on institutional values) 0 \& 2 hr insulin.

Inventory of Depressive Symptoms-Clinician rated, 30 item (IDS-C30) score change from baseline to study endpoint. IDS-C30 total scores can range from 0 to 84, with higher scores indicating a worse outcome

The change between sitting trough clinic diastolic blood pressure measured at week 12 or final visit from diastolic blood pressure measured at baseline. Trough is a time point immediately before the next administration where drug blood concentration is lowest. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.