Diabetes Mellitus, Type 2
Conditions
Keywords
Type 2 Diabetes Mellitus, Drug Therapy
Brief summary
The purpose of the study is to determine the efficacy of alogliptin compared to placebo when given alone or as add-on therapy to metformin or add-on to pioglitazone (with or without metformin).
Detailed description
Diabetes is a chronic illness associated with microvascular complications such as nephropathy (kidney disease), retinopathy (eye damage) and neuropathy (nervous system damage). Diabetes is also associated with macrovascular complications including cardiovascular disease (heart disease), stroke and peripheral vascular disease (narrowing or blockage of blood vessels). These complications are associated with reduced quality of life and increased morbidity and mortality. Takeda is developing SYR-322 (alogliptin) for improvement of glycemic control in patients with Type 2 diabetes mellitus. Evaluations of alogliptin and its clinical efficacy have been conducted in multiple countries including the United States and Japan. This study will be conducted as a multi-center clinical trial in order to validate the efficacy and safety of alogliptin on type 2 diabetes population within Asia. Participants who qualified for the study were stratified into 1 of the 3 therapy groups based upon their background antidiabetic therapy before being randomized 1:1 to receive either alogliptin 25 mg once daily or matching placebo once daily. * Monotherapy group - patients who had been treated with diet and exercise for at least 2 months prior to screening. * Add-on to metformin therapy group - patients who had been treated with metformin for at least 3 months and at a stable dose (≥1000 mg/day) for at least 8 weeks prior to screening. * Add-on to pioglitazone therapy group - patients who had been treated with a stable dose of pioglitazone alone or in combination with metformin at a stable dose for at least 8 weeks prior to screening.
Interventions
DRUGAlogliptin
Alogliptin tablets
Alogliptin placebo-matching tablets.
DRUGMetformin
Stable metformin dose
DRUGPioglitazone
Stable pioglitazone dose
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Has a historical diagnosis of Type 2 Diabetes Mellitus. * Has a body mass index between acceptable range. * Is experiencing inadequate glycemic control. * Body weight keeps constant. * Females of childbearing potential and males who are sexually active agree to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after last dose.
Exclusion criteria
* Has participated in another clinical study within the past 90 days or has received any investigational compound within 30 days prior to randomization. * Has a systolic blood pressure beyond the acceptable range at Screening visit. * Has New York Heart Association Class III or IV heart failure regardless of therapy. * Has any major illness or debility that in the investigator's opinion prohibits the subject from completing the study. * Has a history of hypersensitivity or allergies to any DPP-4 inhibitor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Baseline and Week 16. | The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Week 16. Least squares means are derived from an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline HbA1c as a covariate for the monotherapy, baseline HbA1c with baseline metformin dose as covariates for the metformin therapy, baseline HbA1c with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose Over Time | Baseline and Weeks 4, 8, 12 and 16. | The change from Baseline in fasting plasma glucose (FPG) at Weeks 4, 8, 12 and 16. Least squares means are derived from an ANCOVA model with treatment as a fixed effect, and baseline FPG as a covariate for the monotherapy, baseline FPG with baseline metformin dose as covariates for the metformin therapy, baseline FPG with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy. |
| Percentage of Participants With Marked Hyperglycemia | Randomization to Week 16. | Marked Hyperglycemia was defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L). |
| Change From Baseline in Body Weight | Baseline and Weeks 8 and 16. | The change between body weight measured at Baseline and body weight measured at Weeks 8 and 16. The least squares means are derived from an ANCOVA model with treatment as a fixed effect, and baseline body weight as a covariate for the monotherapy, baseline body weight with baseline metformin dose as covariates for the add-on to metformin therapy, baseline body weight with baseline metformin therapy status and baseline pioglitazone dose as covariates for the add-on to pioglitazone therapy. |
| Percentage of Participants With HbA1c ≤6.5% at Week 16 | Week 16 | Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 6.5% at Week 16. |
| Percentage of Participants With HbA1c ≤7.0% at Week 16 | Week 16 | Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 7.0% at Week 16. |
| Change From Baseline in HbA1c Over Time | Baseline and Weeks 4, 8 and 12. | The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at Weeks 4, 8 and 12. Least squares means are derived from an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline HbA1c as a covariate for the monotherapy, baseline HbA1c with baseline metformin dose as covariates for the metformin therapy, baseline HbA1c with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy. |
| Percentage of Participants With a Decrease in HbA1c ≥ 0.5% | Baseline and Week 16 | Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 0.5% at Week 16. |
| Percentage of Participants With a Decrease in HbA1c ≥1.0% | Baseline and Week 16 | Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.0% at Week 16. |
| Percentage of Participants With a Decrease in HbA1c ≥1.5% | Baseline and Week 16. | Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.5% at Week 16. |
| Percentage of Participants With a Decrease in HbA1c ≥2.0% | Baseline and Week 16. | Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 2.0% at Week 16. |
| Percentage of Participants With HbA1c ≤7.5% at Week 16 | Week 16 | Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 7.5% at Week 16. |
Countries
China, Hong Kong, Taiwan
Participant flow
Recruitment details
Participants took part in the study at 30 investigative sites in China, Taiwan province and Hong Kong from 23 December 2010 to 19 December 2011.
Pre-assignment details
Participants with a historical diagnosis of Type 2 diabetes mellitus who were experiencing inadequate glycemic control were stratified into 1 of the 3 therapy groups based upon their background antidiabetic therapy before being randomized 1:1 to receive either alogliptin 25 mg once daily or matching placebo once daily.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks | 93 |
| Alogliptin Monotherapy Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks. | 92 |
| Metformin Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks. | 98 |
| Metformin + Alogliptin Add-on Therapy Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks. | 99 |
| Pioglitazone Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks. | 63 |
| Pioglitazone + Alogliptin Add-on Therapy Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks. | 61 |
| Total | 506 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 0 | 2 | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 | 1 | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 | 0 | 0 | 1 |
| Overall Study | Major Protocol Deviation | 2 | 1 | 3 | 0 | 2 | 1 |
| Overall Study | Other | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 2 | 4 | 3 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Alogliptin Monotherapy | Metformin | Metformin + Alogliptin Add-on Therapy | Placebo | Pioglitazone | Pioglitazone + Alogliptin Add-on Therapy |
|---|---|---|---|---|---|---|---|
| Age Continuous | 52.6 years STANDARD_DEVIATION 9.71 | 51.6 years STANDARD_DEVIATION 10.41 | 53.2 years STANDARD_DEVIATION 9.46 | 53.0 years STANDARD_DEVIATION 9.88 | 53.1 years STANDARD_DEVIATION 8.88 | 51.8 years STANDARD_DEVIATION 10.37 | 52.6 years STANDARD_DEVIATION 9.44 |
| Age, Customized ≥65 years | 66 participants | 12 participants | 12 participants | 14 participants | 12 participants | 7 participants | 9 participants |
| Age, Customized <65 Years | 440 participants | 80 participants | 86 participants | 85 participants | 81 participants | 56 participants | 52 participants |
| Body Mass Index (BMI) | 25.73 kg/m^2 STANDARD_DEVIATION 3.042 | 25.79 kg/m^2 STANDARD_DEVIATION 3.086 | 25.54 kg/m^2 STANDARD_DEVIATION 2.876 | 25.75 kg/m^2 STANDARD_DEVIATION 3.122 | 25.86 kg/m^2 STANDARD_DEVIATION 3.002 | 26.13 kg/m^2 STANDARD_DEVIATION 3.031 | 25.32 kg/m^2 STANDARD_DEVIATION 3.223 |
| Diabetes duration | 4.11 years STANDARD_DEVIATION 4.215 | 1.86 years STANDARD_DEVIATION 2.369 | 5.33 years STANDARD_DEVIATION 3.873 | 5.38 years STANDARD_DEVIATION 4.335 | 2.12 years STANDARD_DEVIATION 2.845 | 4.85 years STANDARD_DEVIATION 4.724 | 5.80 years STANDARD_DEVIATION 5.3 |
| HbA1c <8.0% | 270 participants | 48 participants | 54 participants | 55 participants | 47 participants | 34 participants | 32 participants |
| HbA1c ≥8.0% | 236 participants | 44 participants | 44 participants | 44 participants | 46 participants | 29 participants | 29 participants |
| Height | 165.2 cm STANDARD_DEVIATION 8.31 | 165.9 cm STANDARD_DEVIATION 8.61 | 164.8 cm STANDARD_DEVIATION 8.47 | 165.7 cm STANDARD_DEVIATION 9.06 | 165.4 cm STANDARD_DEVIATION 7.19 | 166.2 cm STANDARD_DEVIATION 8.87 | 163.0 cm STANDARD_DEVIATION 7.06 |
| Race/Ethnicity, Customized | 506 participants | 92 participants | 98 participants | 99 participants | 93 participants | 63 participants | 61 participants |
| Region of Enrollment China | 491 participants | 90 participants | 94 participants | 92 participants | 91 participants | 63 participants | 61 participants |
| Region of Enrollment Hong Kong | 9 participants | 2 participants | 2 participants | 4 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment Taiwan | 6 participants | 0 participants | 2 participants | 3 participants | 1 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 231 Participants | 37 Participants | 50 Participants | 48 Participants | 39 Participants | 24 Participants | 33 Participants |
| Sex: Female, Male Male | 275 Participants | 55 Participants | 48 Participants | 51 Participants | 54 Participants | 39 Participants | 28 Participants |
| Stable Daily Dose of Metformin | 1426.6 mg STANDARD_DEVIATION 450.9 | NA mg | 1484.2 mg STANDARD_DEVIATION 451.09 | 1472.2 mg STANDARD_DEVIATION 417.31 | NA mg | 1355.0 mg STANDARD_DEVIATION 431.8 | 1295.0 mg STANDARD_DEVIATION 506.82 |
| Stable Daily Dose of Pioglitazone | 21.0 mg STANDARD_DEVIATION 9.55 | NA mg | NA mg | NA mg | NA mg | 21.9 mg STANDARD_DEVIATION 11.37 | 20.2 mg STANDARD_DEVIATION 7.19 |
| Weight | 70.55 kg STANDARD_DEVIATION 11.856 | 71.16 kg STANDARD_DEVIATION 11.065 | 69.67 kg STANDARD_DEVIATION 11.792 | 71.20 kg STANDARD_DEVIATION 13.473 | 70.86 kg STANDARD_DEVIATION 10.464 | 72.44 kg STANDARD_DEVIATION 11.989 | 67.59 kg STANDARD_DEVIATION 11.989 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 92 | 12 / 92 | 8 / 98 | 7 / 99 | 14 / 63 | 18 / 61 |
| serious Total, serious adverse events | 2 / 92 | 2 / 92 | 3 / 98 | 0 / 99 | 0 / 63 | 1 / 61 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c)
The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Week 16. Least squares means are derived from an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline HbA1c as a covariate for the monotherapy, baseline HbA1c with baseline metformin dose as covariates for the metformin therapy, baseline HbA1c with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy.
Time frame: Baseline and Week 16.
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.42 percentage glycosylated hemoglobin | Standard Error 0.074 |
| Alogliptin Monotherapy | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.99 percentage glycosylated hemoglobin | Standard Error 0.074 |
| Metformin | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.22 percentage glycosylated hemoglobin | Standard Error 0.065 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.91 percentage glycosylated hemoglobin | Standard Error 0.065 |
| Pioglitazone | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.25 percentage glycosylated hemoglobin | Standard Error 0.097 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | -0.76 percentage glycosylated hemoglobin | Standard Error 0.101 |
Comparison: The analysis was conducted at the 2-sided 5% significance level without a multiplicity adjustment.p-value: <0.00195% CI: [-0.78, -0.37]ANCOVA
Comparison: The analysis was conducted at the 2-sided 5% significance level without a multiplicity adjustment.p-value: <0.00195% CI: [-0.87, -0.51]ANCOVA
Comparison: The analysis was conducted at the 2-sided 5% significance level without a multiplicity adjustment.p-value: <0.00195% CI: [-0.75, -0.28]ANCOVA
Secondary
Change From Baseline in Body Weight
The change between body weight measured at Baseline and body weight measured at Weeks 8 and 16. The least squares means are derived from an ANCOVA model with treatment as a fixed effect, and baseline body weight as a covariate for the monotherapy, baseline body weight with baseline metformin dose as covariates for the add-on to metformin therapy, baseline body weight with baseline metformin therapy status and baseline pioglitazone dose as covariates for the add-on to pioglitazone therapy.
Time frame: Baseline and Weeks 8 and 16.
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline weight assessment. Last observation carried forward was utilized.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | Week 16 (n=88, 87, 94, 96, 63, 59) | -1.55 kg | Standard Error 0.244 |
| Placebo | Change From Baseline in Body Weight | Week 8 (n=87, 86, 94, 96, 63, 59) | -1.04 kg | Standard Error 0.21 |
| Alogliptin Monotherapy | Change From Baseline in Body Weight | Week 8 (n=87, 86, 94, 96, 63, 59) | -0.71 kg | Standard Error 0.211 |
| Alogliptin Monotherapy | Change From Baseline in Body Weight | Week 16 (n=88, 87, 94, 96, 63, 59) | -0.89 kg | Standard Error 0.245 |
| Metformin | Change From Baseline in Body Weight | Week 8 (n=87, 86, 94, 96, 63, 59) | -0.82 kg | Standard Error 0.17 |
| Metformin | Change From Baseline in Body Weight | Week 16 (n=88, 87, 94, 96, 63, 59) | -1.06 kg | Standard Error 0.219 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in Body Weight | Week 8 (n=87, 86, 94, 96, 63, 59) | -0.43 kg | Standard Error 0.168 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in Body Weight | Week 16 (n=88, 87, 94, 96, 63, 59) | -0.76 kg | Standard Error 0.217 |
| Pioglitazone | Change From Baseline in Body Weight | Week 8 (n=87, 86, 94, 96, 63, 59) | -0.74 kg | Standard Error 0.286 |
| Pioglitazone | Change From Baseline in Body Weight | Week 16 (n=88, 87, 94, 96, 63, 59) | -0.68 kg | Standard Error 0.364 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in Body Weight | Week 16 (n=88, 87, 94, 96, 63, 59) | -0.10 kg | Standard Error 0.388 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in Body Weight | Week 8 (n=87, 86, 94, 96, 63, 59) | -0.15 kg | Standard Error 0.304 |
Secondary
Change From Baseline in Fasting Plasma Glucose Over Time
The change from Baseline in fasting plasma glucose (FPG) at Weeks 4, 8, 12 and 16. Least squares means are derived from an ANCOVA model with treatment as a fixed effect, and baseline FPG as a covariate for the monotherapy, baseline FPG with baseline metformin dose as covariates for the metformin therapy, baseline FPG with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy.
Time frame: Baseline and Weeks 4, 8, 12 and 16.
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline FPG assessment. Last observation carried forward was utilized.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=89, 89, 97, 97, 63, 60) | -0.330 mmol/L | Standard Error 0.1224 |
| Placebo | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=89, 89, 97, 97, 63, 60) | -0.317 mmol/L | Standard Error 0.1556 |
| Placebo | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=89, 89, 97, 97, 63, 60) | -0.411 mmol/L | Standard Error 0.1515 |
| Placebo | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=89, 87, 97, 97, 63, 60) | -0.331 mmol/L | Standard Error 0.1221 |
| Alogliptin Monotherapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=89, 89, 97, 97, 63, 60) | -1.123 mmol/L | Standard Error 0.1515 |
| Alogliptin Monotherapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=89, 87, 97, 97, 63, 60) | -0.719 mmol/L | Standard Error 0.1235 |
| Alogliptin Monotherapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=89, 89, 97, 97, 63, 60) | -1.243 mmol/L | Standard Error 0.1556 |
| Alogliptin Monotherapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=89, 89, 97, 97, 63, 60) | -1.015 mmol/L | Standard Error 0.1224 |
| Metformin | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=89, 89, 97, 97, 63, 60) | -0.235 mmol/L | Standard Error 0.1397 |
| Metformin | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=89, 87, 97, 97, 63, 60) | -0.251 mmol/L | Standard Error 0.1454 |
| Metformin | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=89, 89, 97, 97, 63, 60) | -0.335 mmol/L | Standard Error 0.16 |
| Metformin | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=89, 89, 97, 97, 63, 60) | -0.512 mmol/L | Standard Error 0.1565 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=89, 87, 97, 97, 63, 60) | -0.985 mmol/L | Standard Error 0.1454 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=89, 89, 97, 97, 63, 60) | -1.265 mmol/L | Standard Error 0.1397 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=89, 89, 97, 97, 63, 60) | -1.270 mmol/L | Standard Error 0.16 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=89, 89, 97, 97, 63, 60) | -1.240 mmol/L | Standard Error 0.1565 |
| Pioglitazone | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=89, 89, 97, 97, 63, 60) | -0.187 mmol/L | Standard Error 0.2484 |
| Pioglitazone | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=89, 89, 97, 97, 63, 60) | -0.114 mmol/L | Standard Error 0.2579 |
| Pioglitazone | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=89, 87, 97, 97, 63, 60) | 0.284 mmol/L | Standard Error 0.2505 |
| Pioglitazone | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=89, 89, 97, 97, 63, 60) | -0.038 mmol/L | Standard Error 0.2503 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=89, 89, 97, 97, 63, 60) | -0.924 mmol/L | Standard Error 0.26 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=89, 89, 97, 97, 63, 60) | -1.070 mmol/L | Standard Error 0.2679 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=89, 87, 97, 97, 63, 60) | -0.985 mmol/L | Standard Error 0.2603 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=89, 89, 97, 97, 63, 60) | -1.177 mmol/L | Standard Error 0.2581 |
Secondary
Change From Baseline in HbA1c Over Time
The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at Weeks 4, 8 and 12. Least squares means are derived from an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline HbA1c as a covariate for the monotherapy, baseline HbA1c with baseline metformin dose as covariates for the metformin therapy, baseline HbA1c with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy.
Time frame: Baseline and Weeks 4, 8 and 12.
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in HbA1c Over Time | Week 8 (n=90, 90, 97, 98, 63, 60) | -0.39 percentage glycosylated hemoglobin | Standard Error 0.068 |
| Placebo | Change From Baseline in HbA1c Over Time | Week 4 (n=90, 88, 97, 98, 63, 60) | -0.24 percentage glycosylated hemoglobin | Standard Error 0.059 |
| Placebo | Change From Baseline in HbA1c Over Time | Week 12 (n=90, 90, 97, 98, 63, 60) | -0.41 percentage glycosylated hemoglobin | Standard Error 0.078 |
| Alogliptin Monotherapy | Change From Baseline in HbA1c Over Time | Week 8 (n=90, 90, 97, 98, 63, 60) | -0.86 percentage glycosylated hemoglobin | Standard Error 0.068 |
| Alogliptin Monotherapy | Change From Baseline in HbA1c Over Time | Week 4 (n=90, 88, 97, 98, 63, 60) | -0.56 percentage glycosylated hemoglobin | Standard Error 0.059 |
| Alogliptin Monotherapy | Change From Baseline in HbA1c Over Time | Week 12 (n=90, 90, 97, 98, 63, 60) | -0.99 percentage glycosylated hemoglobin | Standard Error 0.078 |
| Metformin | Change From Baseline in HbA1c Over Time | Week 8 (n=90, 90, 97, 98, 63, 60) | -0.15 percentage glycosylated hemoglobin | Standard Error 0.057 |
| Metformin | Change From Baseline in HbA1c Over Time | Week 4 (n=90, 88, 97, 98, 63, 60) | -0.15 percentage glycosylated hemoglobin | Standard Error 0.036 |
| Metformin | Change From Baseline in HbA1c Over Time | Week 12 (n=90, 90, 97, 98, 63, 60) | -0.24 percentage glycosylated hemoglobin | Standard Error 0.069 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in HbA1c Over Time | Week 8 (n=90, 90, 97, 98, 63, 60) | -0.66 percentage glycosylated hemoglobin | Standard Error 0.057 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in HbA1c Over Time | Week 4 (n=90, 88, 97, 98, 63, 60) | -0.43 percentage glycosylated hemoglobin | Standard Error 0.036 |
| Metformin + Alogliptin Add-on Therapy | Change From Baseline in HbA1c Over Time | Week 12 (n=90, 90, 97, 98, 63, 60) | -0.86 percentage glycosylated hemoglobin | Standard Error 0.068 |
| Pioglitazone | Change From Baseline in HbA1c Over Time | Week 8 (n=90, 90, 97, 98, 63, 60) | -0.31 percentage glycosylated hemoglobin | Standard Error 0.094 |
| Pioglitazone | Change From Baseline in HbA1c Over Time | Week 4 (n=90, 88, 97, 98, 63, 60) | -0.09 percentage glycosylated hemoglobin | Standard Error 0.064 |
| Pioglitazone | Change From Baseline in HbA1c Over Time | Week 12 (n=90, 90, 97, 98, 63, 60) | -0.25 percentage glycosylated hemoglobin | Standard Error 0.102 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in HbA1c Over Time | Week 4 (n=90, 88, 97, 98, 63, 60) | -0.44 percentage glycosylated hemoglobin | Standard Error 0.066 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in HbA1c Over Time | Week 12 (n=90, 90, 97, 98, 63, 60) | -0.77 percentage glycosylated hemoglobin | Standard Error 0.106 |
| Pioglitazone + Alogliptin Add-on Therapy | Change From Baseline in HbA1c Over Time | Week 8 (n=90, 90, 97, 98, 63, 60) | -0.70 percentage glycosylated hemoglobin | Standard Error 0.098 |
Secondary
Percentage of Participants With a Decrease in HbA1c ≥ 0.5%
Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 0.5% at Week 16.
Time frame: Baseline and Week 16
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Decrease in HbA1c ≥ 0.5% | 41.1 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With a Decrease in HbA1c ≥ 0.5% | 84.4 percentage of participants |
| Metformin | Percentage of Participants With a Decrease in HbA1c ≥ 0.5% | 37.1 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥ 0.5% | 70.4 percentage of participants |
| Pioglitazone | Percentage of Participants With a Decrease in HbA1c ≥ 0.5% | 42.9 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥ 0.5% | 76.7 percentage of participants |
Secondary
Percentage of Participants With a Decrease in HbA1c ≥1.0%
Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.0% at Week 16.
Time frame: Baseline and Week 16
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Decrease in HbA1c ≥1.0% | 20.0 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With a Decrease in HbA1c ≥1.0% | 50.0 percentage of participants |
| Metformin | Percentage of Participants With a Decrease in HbA1c ≥1.0% | 9.3 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥1.0% | 45.9 percentage of participants |
| Pioglitazone | Percentage of Participants With a Decrease in HbA1c ≥1.0% | 19.0 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥1.0% | 46.7 percentage of participants |
Secondary
Percentage of Participants With a Decrease in HbA1c ≥1.5%
Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.5% at Week 16.
Time frame: Baseline and Week 16.
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Decrease in HbA1c ≥1.5% | 7.8 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With a Decrease in HbA1c ≥1.5% | 23.3 percentage of participants |
| Metformin | Percentage of Participants With a Decrease in HbA1c ≥1.5% | 1.0 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥1.5% | 22.4 percentage of participants |
| Pioglitazone | Percentage of Participants With a Decrease in HbA1c ≥1.5% | 7.9 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥1.5% | 8.3 percentage of participants |
Secondary
Percentage of Participants With a Decrease in HbA1c ≥2.0%
Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 2.0% at Week 16.
Time frame: Baseline and Week 16.
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Decrease in HbA1c ≥2.0% | 2.2 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With a Decrease in HbA1c ≥2.0% | 8.9 percentage of participants |
| Metformin | Percentage of Participants With a Decrease in HbA1c ≥2.0% | 0.0 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥2.0% | 9.2 percentage of participants |
| Pioglitazone | Percentage of Participants With a Decrease in HbA1c ≥2.0% | 1.6 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With a Decrease in HbA1c ≥2.0% | 3.3 percentage of participants |
Secondary
Percentage of Participants With HbA1c ≤6.5% at Week 16
Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 6.5% at Week 16.
Time frame: Week 16
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With HbA1c ≤6.5% at Week 16 | 12.2 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With HbA1c ≤6.5% at Week 16 | 36.7 percentage of participants |
| Metformin | Percentage of Participants With HbA1c ≤6.5% at Week 16 | 4.1 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With HbA1c ≤6.5% at Week 16 | 21.4 percentage of participants |
| Pioglitazone | Percentage of Participants With HbA1c ≤6.5% at Week 16 | 9.5 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With HbA1c ≤6.5% at Week 16 | 30.0 percentage of participants |
Secondary
Percentage of Participants With HbA1c ≤7.0% at Week 16
Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 7.0% at Week 16.
Time frame: Week 16
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With HbA1c ≤7.0% at Week 16 | 30.0 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With HbA1c ≤7.0% at Week 16 | 63.3 percentage of participants |
| Metformin | Percentage of Participants With HbA1c ≤7.0% at Week 16 | 25.8 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With HbA1c ≤7.0% at Week 16 | 55.1 percentage of participants |
| Pioglitazone | Percentage of Participants With HbA1c ≤7.0% at Week 16 | 31.7 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With HbA1c ≤7.0% at Week 16 | 61.7 percentage of participants |
Secondary
Percentage of Participants With HbA1c ≤7.5% at Week 16
Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 7.5% at Week 16.
Time frame: Week 16
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With HbA1c ≤7.5% at Week 16 | 53.3 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With HbA1c ≤7.5% at Week 16 | 81.1 percentage of participants |
| Metformin | Percentage of Participants With HbA1c ≤7.5% at Week 16 | 50.5 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With HbA1c ≤7.5% at Week 16 | 80.6 percentage of participants |
| Pioglitazone | Percentage of Participants With HbA1c ≤7.5% at Week 16 | 47.6 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With HbA1c ≤7.5% at Week 16 | 85.0 percentage of participants |
Secondary
Percentage of Participants With Marked Hyperglycemia
Marked Hyperglycemia was defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L).
Time frame: Randomization to Week 16.
Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Marked Hyperglycemia | 16.9 percentage of participants |
| Alogliptin Monotherapy | Percentage of Participants With Marked Hyperglycemia | 4.5 percentage of participants |
| Metformin | Percentage of Participants With Marked Hyperglycemia | 25.8 percentage of participants |
| Metformin + Alogliptin Add-on Therapy | Percentage of Participants With Marked Hyperglycemia | 13.4 percentage of participants |
| Pioglitazone | Percentage of Participants With Marked Hyperglycemia | 23.8 percentage of participants |
| Pioglitazone + Alogliptin Add-on Therapy | Percentage of Participants With Marked Hyperglycemia | 8.3 percentage of participants |