Glycemic Control
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the efficacy of 2 doses of TAK-875 (25 mg and 50 mg), once daily (QD), plus metformin compared to placebo plus metformin and sitagliptin plus metformin on lowering blood sugar.
Detailed description
TAK-875 is being developed at Takeda Development Center, Inc. as an adjunct to diet and exercise to improve glycemic control in participants with Type 2 Diabetes Mellitus (T2DM) whose blood glucose level is inadequately controlled with metformin. This study will evaluate the efficacy of TAK-875 (25 mg and 50 mg) plus metformin compared to placebo plus metformin and sitagliptin plus metformin on glycemic control as measured by change from baseline in glycosylated hemoglobin (HbA1c) over a 24-week Treatment Period. Participants completing the 24-week Treatment Period may enter an optional 80-week extension period for a total of 104 weeks of treatment. Due to concerns about potential 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
Fasiglifam (TAK-875) tablets
DRUGSitagliptin
Sitagliptin tablets
DRUGPlacebo
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. The participant is male or female and 18 years of age or older with a historical diagnosis of type II diabetes mellitus. 2. The participant meets one of the following criteria: 1. The participant has an HbA1c level ≥7.5 and \<10.5%, and has been on a stable daily dose of ≥1500 mg (or documented maximum tolerated dose \[MTD\]) of metformin for at least 2 months prior to Screening. This participant will immediately enter the Placebo Run-in Period according to Study Schedule A, or; 2. The participant has an HbA1c level ≥7.5 and \<10.5%, and has been on a stable daily dose of \<1500 mg of metformin without documented MTD for at least 2 months prior to Screening. After completing the Screening Visit, this participant will have their metformin dose immediately increased to ≥1500 mg (or MTD) for an 8-week Titration Period according to Study Schedule B. Following this 8-week period, the participant must qualify for entry into the Placebo Run-in Period by completing the Week -3 procedures including having an HbA1c level ≥7.5 and \<10.5%. 3. The participant has had no treatment with antidiabetic agents other than metformin within 2 months prior to Screening (Exception: if a participant has received other antidiabetic therapy for ≤7 days within the 2 months prior to Screening). 4. The participant has a body mass index (BMI) ≤45 kg/m² at Screening. 5. Participants regularly using other, non-excluded medications, must be on a stable dose for at least 4 weeks prior to Screening. However, PRN (as needed) use of prescription or over-the-counter medications is allowed at the discretion of the investigator. 6. 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 subject diaries.
Exclusion criteria
1. The participant donated or received any blood products within 12 weeks prior to Screening or is planning to donate blood during the study. 2. Hemoglobin ≤12 g/dL (≤120 g/L) for males and ≤10 g/dL (≤100 g/L) for females at Screening Visit. 3. The participant has systolic blood pressure ≥160 mm Hg or diastolic pressure ≥95 mm Hg at Screening Visit. (If the participant meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement.) 4. The participant has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening. 5. The participant has had treatment for gastric banding or gastric bypass surgery within one year prior to Screening. 6. The participant had coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, unstable angina pectoris, clinically significant abnormal ECG, cerebrovascular accident or transient ischemic attack within 3 months prior to or at Screening.
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 was used for analysis with treatment, country, schedule, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of HbA1c <7% | 24 Weeks | Incidence (percentage) of participants with glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than 7% at Week 24. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Baseline and Week 24 | The change between FPG collected at week 24 relative to Baseline. A MMRM model was used for analysis with treatment, country, schedule, 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. |
Countries
Australia, Bulgaria, Croatia, Czechia, Hungary, Italy, Malaysia, Slovakia, South Korea, Thailand, United States
Participant flow
Recruitment details
Participants took part in the study at 168 investigative sites in Australia, Bulgaria, Croatia, Czech Republic, Hungary, Italy, Korea, Republic, Malaysia, Slovakia, Thailand and the United States from 05 April 2012 to 27 March 2014.
Pre-assignment details
Participants with a diagnosis of Type 2 Diabetes Mellitus were randomly enrolled in 1 of 4 treatment groups in a 1:2:2:2 ratio, once a day placebo, 100 mg sitagliptin, 25 mg fasiglifam or 50 mg fasiglifam in combination with metformin.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose. | 132 |
| Sitagliptin 100 mg Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose. | 260 |
| Fasiglifam 25 mg Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose. | 263 |
| Fasiglifam 50 mg Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose. | 261 |
| Total | 916 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 24-Week Treatment Period | Completion Status Unknown | 1 | 0 | 1 | 0 |
| 24-Week Treatment Period | Lack of Efficacy | 1 | 0 | 1 | 1 |
| 24-Week Treatment Period | Lost to Follow-up | 1 | 0 | 1 | 2 |
| 24-Week Treatment Period | Metformin/Sitagliptin Contraindication | 0 | 0 | 1 | 0 |
| 24-Week Treatment Period | Other | 1 | 0 | 1 | 0 |
| 24-Week Treatment Period | Pretreatment Event/Adverse Event | 1 | 4 | 4 | 4 |
| 24-Week Treatment Period | Randomized but Not Treated | 0 | 0 | 0 | 1 |
| 24-Week Treatment Period | Study Terminated by Sponsor | 50 | 104 | 104 | 105 |
| 24-Week Treatment Period | Voluntary Withdrawal | 6 | 3 | 3 | 8 |
| 80-Week Extension Period | Lost to Follow-up | 1 | 0 | 2 | 1 |
| 80-Week Extension Period | Pregnancy | 0 | 0 | 1 | 0 |
| 80-Week Extension Period | Pretreatment Event/Adverse Event | 0 | 0 | 1 | 2 |
| 80-Week Extension Period | Study Terminated by Sponsor | 65 | 137 | 132 | 132 |
| 80-Week Extension Period | Voluntary Withdrawal | 0 | 1 | 4 | 2 |
Baseline characteristics
| Characteristic | Total | Sitagliptin 100 mg | Fasiglifam 50 mg | Fasiglifam 25 mg | Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 56.0 years STANDARD_DEVIATION 9.6 | 55.8 years STANDARD_DEVIATION 9.84 | 56.0 years STANDARD_DEVIATION 9.37 | 56.3 years STANDARD_DEVIATION 9.58 | 55.6 years STANDARD_DEVIATION 9.72 |
| Age, Customized < 65 years | 757 participants | 214 participants | 220 participants | 216 participants | 107 participants |
| Age, Customized ≥ 65 years | 159 participants | 46 participants | 41 participants | 47 participants | 25 participants |
| BMI Category < 30 kg/m^2 | 352 participants | 106 participants | 101 participants | 92 participants | 53 participants |
| BMI Category ≥ 30 kg/m^2 | 562 participants | 154 participants | 159 participants | 170 participants | 79 participants |
| BMI Category Data Not Available | 2 participants | 0 participants | 1 participants | 1 participants | 0 participants |
| Body Mass Index (BMI) | 32.00 kg/m^2 STANDARD_DEVIATION 5.312 | 31.68 kg/m^2 STANDARD_DEVIATION 5.282 | 32.16 kg/m^2 STANDARD_DEVIATION 5.651 | 32.11 kg/m^2 STANDARD_DEVIATION 5.126 | 32.06 kg/m^2 STANDARD_DEVIATION 5.07 |
| Duration of Diabetes | 6.393 years STANDARD_DEVIATION 5.143 | 5.940 years STANDARD_DEVIATION 4.942 | 6.375 years STANDARD_DEVIATION 5.214 | 6.726 years STANDARD_DEVIATION 4.615 | 6.655 years STANDARD_DEVIATION 6.262 |
| Fasting Plasma Glucose | NA ng/dL | 175.6 ng/dL STANDARD_DEVIATION 37.67 | 180.0 ng/dL STANDARD_DEVIATION 37.98 | 179.0 ng/dL STANDARD_DEVIATION 33.52 | 178.4 ng/dL STANDARD_DEVIATION 36.94 |
| Glycosylated Hemoglobin (HbA1c) | NA percent | 8.35 percent STANDARD_DEVIATION 0.694 | 8.43 percent STANDARD_DEVIATION 0.765 | 8.41 percent STANDARD_DEVIATION 0.712 | 8.34 percent STANDARD_DEVIATION 0.739 |
| HbA1c Category < 8.5% | 538 participants | 156 participants | 148 participants | 154 participants | 80 participants |
| HbA1c Category ≥ 8.5% | 377 participants | 104 participants | 112 participants | 109 participants | 52 participants |
| HbA1c Category Data Not Available | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Height | 168.7 cm STANDARD_DEVIATION 10.34 | 169.4 cm STANDARD_DEVIATION 10.74 | 168.4 cm STANDARD_DEVIATION 9.85 | 168.5 cm STANDARD_DEVIATION 10.53 | 168.2 cm STANDARD_DEVIATION 10.08 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 participants | 0 participants | 3 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 96 participants | 30 participants | 26 participants | 28 participants | 12 participants |
| Race/Ethnicity, Customized Black or African American | 52 participants | 13 participants | 12 participants | 19 participants | 8 participants |
| Race/Ethnicity, Customized Data Not Available | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 98 participants | 29 participants | 28 participants | 28 participants | 13 participants |
| Race/Ethnicity, Customized Multiracial | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants | 0 participants | 2 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 195 participants | 59 participants | 55 participants | 53 participants | 28 participants |
| Race/Ethnicity, Customized Not Collected | 623 participants | 172 participants | 178 participants | 182 participants | 91 participants |
| Race/Ethnicity, Customized White | 759 participants | 216 participants | 217 participants | 214 participants | 112 participants |
| Region of Enrollment Australia | 18 participants | 5 participants | 5 participants | 5 participants | 3 participants |
| Region of Enrollment Bulgaria | 24 participants | 7 participants | 7 participants | 7 participants | 3 participants |
| Region of Enrollment Croatia | 24 participants | 6 participants | 6 participants | 8 participants | 4 participants |
| Region of Enrollment Czech Republic | 51 participants | 15 participants | 14 participants | 14 participants | 8 participants |
| Region of Enrollment Hungary | 206 participants | 56 participants | 60 participants | 61 participants | 29 participants |
| Region of Enrollment Italy | 9 participants | 3 participants | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Korea, Republic Of | 12 participants | 4 participants | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Malaysia | 25 participants | 8 participants | 8 participants | 7 participants | 2 participants |
| Region of Enrollment Slovakia | 231 participants | 66 participants | 66 participants | 65 participants | 34 participants |
| Region of Enrollment Thailand | 48 participants | 14 participants | 14 participants | 13 participants | 7 participants |
| Region of Enrollment United States | 268 participants | 76 participants | 77 participants | 76 participants | 39 participants |
| Sex: Female, Male Female | 422 Participants | 103 Participants | 126 Participants | 127 Participants | 66 Participants |
| Sex: Female, Male Male | 494 Participants | 157 Participants | 135 Participants | 136 Participants | 66 Participants |
| Weight | 91.42 kg STANDARD_DEVIATION 18.776 | 91.41 kg STANDARD_DEVIATION 19.664 | 91.53 kg STANDARD_DEVIATION 18.772 | 91.44 kg STANDARD_DEVIATION 17.859 | 91.15 kg STANDARD_DEVIATION 18.988 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 132 | 16 / 260 | 18 / 263 | 20 / 260 |
| serious Total, serious adverse events | 2 / 132 | 10 / 260 | 14 / 263 | 4 / 260 |
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 was used for analysis with treatment, country, schedule, 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.
Time frame: Baseline and Week 24
Population: Full Analysis Set included all randomized participants who received at least 1 dose of study drug analyzed according to the treatment group to which they were randomized. A participant was included in the analyses when there was both a Baseline and at least 1 Post-baseline value at Week 24.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.19 Percent | Standard Error 0.098 |
| Sitagliptin 100 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -1.07 Percent | Standard Error 0.074 |
| Fasiglifam 25 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.75 Percent | Standard Error 0.073 |
| Fasiglifam 50 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -1.01 Percent | Standard Error 0.074 |
p-value: <0.00195% CI: [-0.77, -0.34]Mixed model for repeated measurements
p-value: <0.00195% CI: [0.15, 0.49]Mixed model for repeated measurements
p-value: <0.00195% CI: [-1.03, -0.6]Mixed model for repeated measurements
p-value: 0.52495% CI: [-0.12, 0.23]Mixed model for repeated measurements
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
The change between FPG collected at week 24 relative to Baseline. A MMRM model was used for analysis with treatment, country, schedule, 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.
Time frame: Baseline and Week 24
Population: Full Analysis Set included all randomized participants who received at least 1 dose of study drug analyzed according to the treatment group to which they were randomized. A participant was included in the analyses when there was both a Baseline and at least 1 Post-baseline value at Week 24.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | -1.6 mg/dL | Standard Error 4.07 |
| Sitagliptin 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | -21.7 mg/dL | Standard Error 3.13 |
| Fasiglifam 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | -26.9 mg/dL | Standard Error 3.13 |
| Fasiglifam 50 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | -32.9 mg/dL | Standard Error 3.18 |
p-value: <0.00195% CI: [-33.8, -16.6]Mixed model for repeated measurements
p-value: 0.14295% CI: [-12, 1.7]Mixed model for repeated measurements
p-value: <0.00195% CI: [-39.9, -22.6]Mixed model for repeated measurements
p-value: 0.00295% CI: [-18.1, -4.2]Mixed model for repeated measurements
Secondary
Incidence of HbA1c <7%
Incidence (percentage) of participants with glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than 7% at Week 24.
Time frame: 24 Weeks
Population: Full Analysis Set included all randomized participants who received at least 1 dose of study drug analyzed according to the treatment group to which they were randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence of HbA1c <7% | 14.9 percentage of participants |
| Sitagliptin 100 mg | Incidence of HbA1c <7% | 42.8 percentage of participants |
| Fasiglifam 25 mg | Incidence of HbA1c <7% | 24.3 percentage of participants |
| Fasiglifam 50 mg | Incidence of HbA1c <7% | 37.0 percentage of participants |
p-value: <0.00195% CI: [0.23, 0.67]Regression, Logistic
p-value: 0.0595% CI: [1, 5.08]Regression, Logistic
p-value: <0.00195% CI: [2.24, 11.42]Regression, Logistic
p-value: 0.49395% CI: [0.5, 1.39]Regression, Logistic