Diabetes Mellitus, Type 2
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to determine the efficacy and safety of TAK-875 (fasiglifam), once daily (QD), in participants with type 2 diabetes mellitus (T2DM).
Detailed description
TAK-875 is being developed at Takeda Development Center, Inc. as an adjunct to diet and exercise to improve glycemic control in patients with T2DM. This study will investigate TAK-875 in participants with type 2 diabetes mellitus who have been treated with only diet and exercise for at least 12 weeks prior to Screening, who have taken ≤7 days of any antidiabetic agent within the 12 weeks prior to Screening, and whose glycemic control is inadequate.
Interventions
DRUGPlacebo
Fasiglifam placebo-matching tablets
DRUGFasiglifam
Fasiglifam 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 participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant'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. The participant is male or female and 18 years of age or older with a historical diagnosis of T2DM. 4. The participant has been treated with only diet and exercise for at least 12 weeks prior to Screening and has an HbA1c concentration between 7.0 % and 10.5%, inclusive, at Screening. 5. The participant has received ≤7 days of any antidiabetic agent within 12 weeks prior to Screening. 6. The participant has a body mass index (BMI) ≤45 kg/m\^2 at Screening. 7. Participants regularly using other, non-excluded medications must be on a stable dose for at least 4 weeks prior to Screening. However, as needed (PRN) use of prescription or over-the-counter medication is allowed at the discretion of the investigator. 8. The participant is able and willing to monitor glucose with a home glucose monitor and consistently record his or her own blood glucose concentrations and complete participant diaries. 9. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of the informed consent throughout the duration of the study and for 30 days after the last dose of study drug. Additional Inclusion Criteria prior to Randomization 1. The participant has an HbA1c concentration between 7.0 and 10.5%, inclusive, and a fasting plasma glucose (FPG) ≤270 mg/dL (≤15.0 mmol/L) at Week -1 Visit. (If the participant does not qualify for randomization based on these criteria, the assessments may be repeated weekly, for a maximum of 2 additional weeks). 2. The participant's overall compliance with single-blind study medication during the Placebo Run-in Period is at least 75% and does not exceed 125% based on tablet counts performed by the study staff. 3. A female participant of childbearing potential must have a negative urine hCG pregnancy test at Baseline (Visit 4) prior to Randomization and prior to administration of the first dose of double-blind study medication
Exclusion criteria
1. The participant has received any investigational compound within 30 days prior to Screening or has received an investigational antidiabetic drug within 3 months prior to Screening. 2. The participant has been randomized in a previous TAK-875 study. 3. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, or sibling; biological or legally adopted) or may consent under duress. 4. The participant donated or received any blood products within 12 weeks prior to Screening or is planning to donate blood during the study. 5. The participant has a hemoglobin ≤12 g/dL (≤120 gm/L) for males and ≤10 g/dL (≤100 gm/L) for females at Screening. 6. The participant has a systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥95 mm Hg at Screening (If the participant meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement and decision will be made based on the second measurement). 7. The participant 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. 8. The participant has an alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels \>2.0x the upper limit of normal (ULN) at Screening. 9. The participant has a total bilirubin level greater than the ULN at Screening. Exception: if a participant has documented Gilbert's Syndrome, the participant will be allowed with an elevated bilirubin level per the investigator's discretion. 10. The participant has a serum creatinine ≥1.5 mg/dL(≥133 µmol/L) \[males\] and ≥1.4 mg/dL (≥124 µmol/L) \[females\] and/or estimated glomerular filtration rate (GFR) \<60 mL/min/1.73m\^2 at Screening. 11. The participant has uncontrolled thyroid disease. 12. The participant has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening. 13. The participant has had gastric banding or gastric bypass surgery within one year prior to Screening. 14. The participant has a known history of infection with human immunodeficiency virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV). 15. The participant had coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, unstable angina pectoris, clinically significant abnormal electrocardiogram (ECG), cerebrovascular accident or transient ischemic attack within 3 months prior or at Screening. 16. The participant has a history of hypersensitivity, allergies, or has had an anaphylactic reaction(s) to any component of TAK-875. 17. The participant has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse within 2 years prior to Screening. 18. The participant received excluded medications prior to Screening or is expected to receive excluded medication. 19. If female, the participant is pregnant (confirmed by laboratory testing, i.e., serum human chorionic gonadotropin (hCG), in females of childbearing potential) or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period. 20. The participant is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available. 21. The participant has any other physical or psychiatric disease or condition that in the judgment of the investigator may affect life expectancy or may make it difficult to successfully manage and follow the participant according to the protocol. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Baseline and Week 24 | The change in 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 Week 24 relative to Baseline. A mixed model repeated measures (MMRM) model with treatment, country, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of HbA1c <7% | Week 24 | The incidence (percentage of participants with) HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of less than seven percent for target glycemic control at Week 24. |
| Change From Baseline in Fasting Plasma Glucose | Baseline and Week 24 | The change between the fasting plasma glucose value collected at Week 24 relative to Baseline measured in milligrams per deciliter (mg/dL). A MMRM model with treatment, country, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure was used for analysis. |
| Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Meal Tolerance Test (MTT) | Baseline and Week 24 | The change between the value of glucose after a meal, measured by the meal tolerance test collected at Week 24 relative to Baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and 2 hours after the start of the meal measured in millimoles per liter (mmol/L). An Analysis of Covariance (ANCOVA) model with treatment and country as fixed factors and Baseline value as covariate was used for analysis. |
Countries
Argentina, Bulgaria, Guatemala, Hungary, Mexico, Slovakia, Ukraine, United States
Participant flow
Recruitment details
Participants took part in the study at 109 investigative sites in United States, Bulgaria, Argentina, Ukraine, Guatemala, Slovakia, Mexico and Hungary from 02 November 2011 to 30 July 2013.
Pre-assignment details
Participants with a diagnosis of Type 2 Diabetes Mellitis were enrolled equally in 1 of 3 treatment groups, once a day placebo, 25 mg fasiglifam or 50 mg fasiglifam.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Fasiglifam placebo-matching tablets, orally, once daily for up to 24 weeks. | 143 |
| Fasiglifam 25 mg Fasiglifam 25 mg, tablets, orally, once daily for up to 24 weeks. | 137 |
| Fasiglifam 50 mg Fasiglifam 50 mg, tablets, orally, once daily for up to 24 weeks. | 141 |
| Total | 421 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 | 3 |
| Overall Study | Other Reasons | 2 | 1 | 3 |
| Overall Study | Pretreatment Event/Adverse Event | 1 | 4 | 1 |
| Overall Study | Voluntary Withdrawal | 5 | 3 | 7 |
Baseline characteristics
| Characteristic | Total | Placebo | Fasiglifam 25 mg | Fasiglifam 50 mg |
|---|---|---|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 10.82 | 53.1 years STANDARD_DEVIATION 10.61 | 53.2 years STANDARD_DEVIATION 11.31 | 54.2 years STANDARD_DEVIATION 10.57 |
| Age, Customized < 65 years | 352 participants | 124 participants | 114 participants | 114 participants |
| Age, Customized ≥ 65 years | 69 participants | 19 participants | 23 participants | 27 participants |
| Baseline BMI Group < 30 kg/m^2 | 159 participants | 54 participants | 49 participants | 56 participants |
| Baseline BMI Group ≥ 30 kg/m^2 | 262 participants | 89 participants | 88 participants | 85 participants |
| Baseline Body Mass Index (BMI) | 32.29 kg/m^2 STANDARD_DEVIATION 5.443 | 32.33 kg/m^2 STANDARD_DEVIATION 5.714 | 32.50 kg/m^2 STANDARD_DEVIATION 5.256 | 32.05 kg/m^2 STANDARD_DEVIATION 5.369 |
| Baseline HbA1c Category < 8.5% | 295 participants | 102 participants | 91 participants | 102 participants |
| Baseline HbA1c Category ≥ 8.5 % | 126 participants | 41 participants | 46 participants | 39 participants |
| Duration of Diabetes | 3.345 years STANDARD_DEVIATION 3.773 | 3.048 years STANDARD_DEVIATION 3.164 | 3.290 years STANDARD_DEVIATION 3.447 | 3.700 years STANDARD_DEVIATION 4.56 |
| Height | 166.1 cm STANDARD_DEVIATION 10.96 | 166.3 cm STANDARD_DEVIATION 10.63 | 165.3 cm STANDARD_DEVIATION 11.17 | 166.7 cm STANDARD_DEVIATION 11.11 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 50 participants | 19 participants | 15 participants | 16 participants |
| Race/Ethnicity, Customized Asian | 9 participants | 5 participants | 4 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 26 participants | 8 participants | 6 participants | 12 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 69 participants | 22 participants | 25 participants | 22 participants |
| Race/Ethnicity, Customized Multiracial | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 116 participants | 39 participants | 36 participants | 41 participants |
| Race/Ethnicity, Customized Not Applicable | 236 participants | 82 participants | 76 participants | 78 participants |
| Race/Ethnicity, Customized White | 335 participants | 110 participants | 112 participants | 113 participants |
| Region of Enrollment Argentina | 30 participants | 10 participants | 10 participants | 10 participants |
| Region of Enrollment Bulgaria | 24 participants | 8 participants | 7 participants | 9 participants |
| Region of Enrollment Guatemala | 42 participants | 15 participants | 14 participants | 13 participants |
| Region of Enrollment Hungary | 23 participants | 8 participants | 7 participants | 8 participants |
| Region of Enrollment Mexico | 18 participants | 6 participants | 5 participants | 7 participants |
| Region of Enrollment Slovakia | 72 participants | 24 participants | 24 participants | 24 participants |
| Region of Enrollment Ukraine | 28 participants | 11 participants | 9 participants | 8 participants |
| Region of Enrollment United States | 184 participants | 61 participants | 61 participants | 62 participants |
| Sex: Female, Male Female | 206 Participants | 68 Participants | 65 Participants | 73 Participants |
| Sex: Female, Male Male | 215 Participants | 75 Participants | 72 Participants | 68 Participants |
| Smoking Classification Current smoker | 61 participants | 21 participants | 17 participants | 23 participants |
| Smoking Classification Ex-smoker | 66 participants | 23 participants | 22 participants | 21 participants |
| Smoking Classification Never smoked | 294 participants | 99 participants | 98 participants | 97 participants |
| Weight | 89.45 kg STANDARD_DEVIATION 18.66 | 89.66 kg STANDARD_DEVIATION 18.858 | 89.24 kg STANDARD_DEVIATION 18.541 | 89.43 kg STANDARD_DEVIATION 18.706 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 143 | 6 / 137 | 7 / 141 |
| serious Total, serious adverse events | 3 / 143 | 3 / 137 | 3 / 141 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c)
The change in 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 Week 24 relative to Baseline. A mixed model repeated measures (MMRM) model with treatment, country, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure was used for analysis.
Time frame: Baseline and Week 24
Population: Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available for analysis. Only participants with Baseline and at least 1 post-Baseline value are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.17 percent | Standard Error 0.09 |
| Fasiglifam 25 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.65 percent | Standard Error 0.087 |
| Fasiglifam 50 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.93 percent | Standard Error 0.087 |
p-value: <0.00195% CI: [-0.72, -0.24]Mixed model for repeated measurements
p-value: <0.00195% CI: [-1, -0.52]Mixed model for repeated measurements
Secondary
Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Meal Tolerance Test (MTT)
The change between the value of glucose after a meal, measured by the meal tolerance test collected at Week 24 relative to Baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and 2 hours after the start of the meal measured in millimoles per liter (mmol/L). An Analysis of Covariance (ANCOVA) model with treatment and country as fixed factors and Baseline value as covariate was used for analysis.
Time frame: Baseline and Week 24
Population: Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available for analysis. Only participants with Baseline and at least 1 post-Baseline value are included. MTT were only done at sites that had MTT capabilities.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Meal Tolerance Test (MTT) | -0.6 mmol/L | Standard Error 12.47 |
| Fasiglifam 25 mg | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Meal Tolerance Test (MTT) | -29.4 mmol/L | Standard Error 11.82 |
| Fasiglifam 50 mg | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Meal Tolerance Test (MTT) | -30.6 mmol/L | Standard Error 12.5 |
p-value: 0.195% CI: [-63.2, 5.7]ANCOVA
p-value: 0.09695% CI: [-65.5, 5.5]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose
The change between the fasting plasma glucose value collected at Week 24 relative to Baseline measured in milligrams per deciliter (mg/dL). A MMRM model with treatment, country, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure was used for analysis.
Time frame: Baseline and Week 24
Population: Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available for analysis. Only participants with Baseline and at least 1 post-Baseline value are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose | 1.4 mg/dL | Standard Error 3.45 |
| Fasiglifam 25 mg | Change From Baseline in Fasting Plasma Glucose | -12.3 mg/dL | Standard Error 3.29 |
| Fasiglifam 50 mg | Change From Baseline in Fasting Plasma Glucose | -20.9 mg/dL | Standard Error 3.26 |
p-value: 0.00395% CI: [-22.7, -4.6]Mixed model for repeated measurements
p-value: <0.00195% CI: [-31.4, -13.2]Mixed model for repeated measurements
Secondary
Incidence of HbA1c <7%
The incidence (percentage of participants with) HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of less than seven percent for target glycemic control at Week 24.
Time frame: Week 24
Population: Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available for analysis. Only participants with Baseline and at least 1 post-Baseline value are included. Last Observation Carried Forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of HbA1c <7% | 24.1 percentage of participants |
| Fasiglifam 25 mg | Incidence of HbA1c <7% | 36.0 percentage of participants |
| Fasiglifam 50 mg | Incidence of HbA1c <7% | 50.4 percentage of participants |
p-value: 0.0195% CI: [1.2, 3.79]Regression, Logistic
p-value: <0.00195% CI: [2.48, 7.82]Regression, Logistic