Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus - Type2, Diabetes Mellitus, Drug Therapy
Brief summary
The purpose of this study was to evaluate the efficacy and safety of alogliptin, once daily (QD) combined with a thiazolidine taken QD in type 2 diabetic patients with uncontrolled blood glucose.
Detailed description
Both insulin hyposecretion and insulin-resistance are considered to be involved in the development of type 2 diabetes mellitus. Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV (DPP-IV) enzyme. DPP-IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of DPP-IV will improve glycemic control in patients with type 2 diabetes. The present study was planned to evaluate the efficacy and safety of alogliptin as an add-on to pioglitazone in type 2 diabetic patients with uncontrolled blood glucose despite treatment with pioglitazone as well as diet and exercise therapies.
Interventions
Alogliptin 12.5mg, tablets, orally, once daily and Pioglitazone 15 or 30 mg, tablets orally once daily for up 12 weeks.
DRUGPioglitazone
Pioglitazone 15 or 30 mg, tablets orally once daily for up 12 weeks.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
33 Years to 88 Years
Healthy volunteers
No
Inclusion criteria
1. Had been taking pioglitazone at a stable dose (15 mg/day or 30 mg/day) for at least 16 weeks prior to the start of the treatment period (Week 0). 2. Had glycosylated hemoglobin (HbA1c) of 6.5% or more and below 10.0% at 14 weeks after the start of the observation period (Week -2). 3. Had HbA1c difference within 10.0%\* at 10 weeks after the start of the observation period (Week -6) and 14 weeks after the start of the observation period (Week -2) from 10 weeks after the start of the observation period (Week -6) (\*rounded off to the first decimal place). 4. Was receiving specific diet and exercise (if any) therapies during the observation period.
Exclusion criteria
1. Had taken a diabetic medications other than pioglitazone within 16 weeks before the start of the treatment period (Week 0). 2. Had a history or symptoms of cardiac failure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (Week 12). | Baseline and Week 12. | 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 12 and glycosylated hemoglobin collected at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (Week 4). | Baseline and Week 4. | 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 4 and glycosylated hemoglobin collected at baseline. |
| Change From Baseline in Glycosylated Hemoglobin (Week 8). | Baseline and Week 8. | 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 8 and glycosylated hemoglobin collected at baseline. |
| Change From Baseline in Fasting Plasma Glucose (Week 2). | Baseline and Week 2. | The change between the value of fasting plasma glucose collected at week 2 and glycosylated hemoglobin collected at baseline. |
| Change From Baseline in Glycosylated Hemoglobin (Week 2). | Baseline and Week 2. | 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 2 and glycosylated hemoglobin collected at baseline. |
| Change From Baseline in Fasting Plasma Glucose (Week 8). | Baseline and Week 8. | The change between the value of fasting plasma glucose collected at week 8 and glycosylated hemoglobin collected at baseline. |
| Change From Baseline in Fasting Plasma Glucose (Week 12). | Baseline and Week 12. | The change between the value of fasting plasma glucose collected at week 12 or final visit and glycosylated hemoglobin collected at baseline. |
| Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12). | Baseline and Week 12. | The change between the value of blood glucose measured by the meal tolerance test collected at week 12 or final visit and blood glucose measured by the meal tolerance test collected at baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and 2 hours after the start of the meal. |
| Change From Baseline in Fasting Plasma Glucose (Week 4). | Baseline and Week 4. | The change between the value of fasting plasma glucose collected at week 4 and glycosylated hemoglobin collected at baseline. |
Participant flow
Recruitment details
Participants enrolled at 33 investigative sites in Japan from 22 November 2007 to 22 October 2008.
Pre-assignment details
Participants with historical diagnosis of type 2 diabetes with uncontrolled blood glucose despite treatment with pioglitazone as well as diet and exercise therapies were enrolled in one of 3, once-daily (QD) treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD Alogliptin 12.5mg, tablets, orally, once daily and Pioglitazone 15 or 30 mg, tablets orally once daily for up 12 weeks. | 111 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD Alogliptin 25 mg, tablets, orally, once daily and Pioglitazone 15 or 30 mg, tablets orally once daily for up 12 weeks. | 113 |
| Pioglitazone 15 mg or 30 mg QD Pioglitazone 15 or 30 mg, tablets orally once daily for up 12 weeks. | 115 |
| Total | 339 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 5 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
| Overall Study | Principal Investigator Discretion | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Pioglitazone 15 mg or 30 mg QD | Total |
|---|---|---|---|---|
| Age, Customized ≤ 64 years | 77 participants | 70 participants | 77 participants | 224 participants |
| Age, Customized ≥ 65 years | 34 participants | 43 participants | 38 participants | 115 participants |
| Sex: Female, Male Female | 44 Participants | 43 Participants | 39 Participants | 126 Participants |
| Sex: Female, Male Male | 67 Participants | 70 Participants | 76 Participants | 213 Participants |
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 | 5 / 111 | 17 / 113 | 13 / 115 |
| serious Total, serious adverse events | 1 / 111 | 2 / 113 | 5 / 115 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (Week 12).
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 12 and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 12.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 12). | -0.91 percentage of Glycosylated Hemoglobin | Standard Deviation 0.441 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 12). | -0.97 percentage of Glycosylated Hemoglobin | Standard Deviation 0.517 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 12). | -0.19 percentage of Glycosylated Hemoglobin | Standard Deviation 0.552 |
95% CI: [-0.848, -0.586]
95% CI: [-0.913, -0.634]
Secondary
Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12).
The change between the value of blood glucose measured by the meal tolerance test collected at week 12 or final visit and blood glucose measured by the meal tolerance test collected at baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and 2 hours after the start of the meal.
Time frame: Baseline and Week 12.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12). | 58.3 mg/dL | Standard Deviation 28.75 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12). | 49.4 mg/dL | Standard Deviation 29.27 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12). | 70.6 mg/dL | Standard Deviation 39.58 |
95% CI: [-21.51, -3.1]
95% CI: [-30.43, -11.95]
Secondary
Change From Baseline in Fasting Plasma Glucose (Week 12).
The change between the value of fasting plasma glucose collected at week 12 or final visit and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 12.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Fasting Plasma Glucose (Week 12). | -14.9 mg/dL | Standard Deviation 18.42 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 12). | -18.9 mg/dL | Standard Deviation 20.96 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 12). | -2.4 mg/dL | Standard Deviation 26.84 |
95% CI: [-18.51, -6.4]
95% CI: [-22.78, -10.19]
Secondary
Change From Baseline in Fasting Plasma Glucose (Week 2).
The change between the value of fasting plasma glucose collected at week 2 and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 2.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Fasting Plasma Glucose (Week 2). | -12.8 mg/dL | Standard Deviation 14.68 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 2). | -17.0 mg/dL | Standard Deviation 18.36 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 2). | -3.9 mg/dL | Standard Deviation 18.25 |
95% CI: [-13.2, -4.47]
95% CI: [-17.86, -8.26]
Secondary
Change From Baseline in Fasting Plasma Glucose (Week 4).
The change between the value of fasting plasma glucose collected at week 4 and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 4.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Fasting Plasma Glucose (Week 4). | -14.4 mg/dL | Standard Deviation 18.45 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 4). | -17.9 mg/dL | Standard Deviation 20.16 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 4). | -3.1 mg/dL | Standard Deviation 19.54 |
95% CI: [-16.22, -6.25]
95% CI: [-20, -9.63]
Secondary
Change From Baseline in Fasting Plasma Glucose (Week 8).
The change between the value of fasting plasma glucose collected at week 8 and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 8.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Fasting Plasma Glucose (Week 8). | -17.1 mg/dL | Standard Deviation 16.96 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 8). | -21.3 mg/dL | Standard Deviation 20.2 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Fasting Plasma Glucose (Week 8). | -4.2 mg/dL | Standard Deviation 22.29 |
95% CI: [-18.09, -7.68]
95% CI: [-22.64, -11.53]
Secondary
Change From Baseline in Glycosylated Hemoglobin (Week 2).
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 2 and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 2.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 2). | -0.22 percentage of Glycosylated Hemoglobin | Standard Deviation 0.15 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 2). | -0.22 percentage of Glycosylated Hemoglobin | Standard Deviation 0.154 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 2). | -0.04 percentage of Glycosylated Hemoglobin | Standard Deviation 0.186 |
95% CI: [-0.224, -0.135]
95% CI: [-0.225, -0.135]
Secondary
Change From Baseline in Glycosylated Hemoglobin (Week 4).
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 4 and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 4.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 4). | -0.47 percentage of Glycosylated Hemoglobin | Standard Deviation 0.236 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 4). | -0.46 percentage of Glycosylated Hemoglobin | Standard Deviation 0.254 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 4). | -0.10 percentage of Glycosylated Hemoglobin | Standard Deviation 0.301 |
95% CI: [-0.434, -0.292]
95% CI: [-0.432, -0.287]
Secondary
Change From Baseline in Glycosylated Hemoglobin (Week 8).
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 8 and glycosylated hemoglobin collected at baseline.
Time frame: Baseline and Week 8.
Population: Analysis based on last observation carried forward, where the last postbaseline double-blind observed value is carried forward and used for all subsequent scheduled time points where data is missing. Values are from the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alogliptin 12.5 mg QD and Pioglitazone 15 or 30mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 8). | -0.76 percentage of Glycosylated Hemoglobin | Standard Deviation 0.353 |
| Alogliptin 25 mg QD and Pioglitazone 15 or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 8). | -0.81 percentage of Glycosylated Hemoglobin | Standard Deviation 0.398 |
| Pioglitazone 15 mg or 30 mg QD | Change From Baseline in Glycosylated Hemoglobin (Week 8). | -0.17 percentage of Glycosylated Hemoglobin | Standard Deviation 0.433 |
95% CI: [-0.692, -0.484]
95% CI: [-0.743, -0.526]