Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus - Type 2, Diabetes Mellitus, Drug Therapy
Brief summary
The purpose of this study was evaluate the efficacy and safety of alogliptin, once dairy (QD) combined with metformin taken twice daily (BID) or three times daily (TID) 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 metformin in type 2 diabetic patients who have uncontrolled blood glucose despite treatment with metformin as well as diet and exercise therapies.
Interventions
Alogliptin 12.5 mg, tablets, orally, once daily and metformin 250 mg, tablets, orally, twice or three times daily for up 12 weeks.
DRUGMetformin
Metformin 250 mg, tablets, orally, twice or three times daily and alogliptin placebo-matching 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
26 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
1. Had been taking metformin at a stable dose regimen (500 mg/day twice daily after meal or 750 mg/day three times daily after meal) for at least 12 weeks prior to the initiation of the treatment period (Week 0). 2. Had an glycosylated hemoglobin (HbA1c) of 6.5% or more and below 10.0% at 8 weeks after the initiation of the observation period (Week -4). 3. Had an HbA1c difference between 4 weeks after the initiation of the observation period (Week -8) and 8 weeks after the initiation of the observation period (Week -4) being within 10.0%\* of the value at 4 weeks after the initiation of the observation period (Week -8) (\*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 other diabetic medications than metformin within 12 weeks before the initiation of the treatment period (Week 0). 2. With a history or symptoms of lactic acidosis.
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 or final visit 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 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 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 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 at 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 baseline. |
Participant flow
Recruitment details
Participants enrolled at 30 investigative sites in Japan from 22 August 2008 to 28 April 2009.
Pre-assignment details
Participants with a historical diagnosis of type 2 diabetes mellitus with uncontrolled blood glucose despite treatment with metformin as well as diet and exercise were enrolled in one of 3, once-daily (QD), twice daily (BID) or three times daily (TID) treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Alogliptin 12.5 mg QD and Metformin 500mg BID or 750mg TID Alogliptin 12.5 mg, tablets, orally, once daily and metformin 250 mg, tablets, orally, twice or three times daily for up 12 weeks. | 92 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID Alogliptin 25 mg, tablets, orally, once daily and metformin 250 mg, tablets, orally, twice or three times daily for up 12 weeks. | 96 |
| Metformin 500mg BID or 750mg TID Metformin 250 mg, tablets, orally, twice or three times daily and alogliptin placebo-matching tablets, orally, once daily for up 12 weeks. | 100 |
| Total | 288 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 |
| Overall Study | Schedule Conflict | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Alogliptin 12.5 mg QD and Metformin 500mg BID or 750mg TID | Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Metformin 500mg BID or 750mg TID | Total |
|---|---|---|---|---|
| Age Continuous | 53.4 years STANDARD_DEVIATION 8.8 | 52.3 years STANDARD_DEVIATION 8.02 | 52.1 years STANDARD_DEVIATION 8.05 | 52.6 years STANDARD_DEVIATION 8.28 |
| Sex: Female, Male Female | 32 Participants | 30 Participants | 28 Participants | 90 Participants |
| Sex: Female, Male Male | 60 Participants | 66 Participants | 72 Participants | 198 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 | 32 / 92 | 37 / 96 | 29 / 100 |
| serious Total, serious adverse events | 0 / 92 | 2 / 96 | 0 / 100 |
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 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 Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 12). | -0.54 percentage of Glycosylated Hemoglobin | Standard Deviation 0.562 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 12). | -0.64 percentage of Glycosylated Hemoglobin | Standard Deviation 0.488 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 12). | 0.21 percentage of Glycosylated Hemoglobin | Standard Deviation 0.641 |
95% CI: [-0.923, -0.579]
95% CI: [-1.019, -0.697]
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 at 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 Metformin 500mg BID or 750mg TID | Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12). | 61.7 mg/dL | Standard Deviation 43.42 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12). | 64.2 mg/dL | Standard Deviation 34.76 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12). | 70.6 mg/dL | Standard Deviation 35.31 |
95% CI: [-20.14, 2.37]
95% CI: [-16.34, 3.52]
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 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 Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 12). | -19.0 mg/dL | Standard Deviation 23.23 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 12). | -23.1 mg/dL | Standard Deviation 27.84 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 12). | -0.8 mg/dL | Standard Deviation 32.2 |
95% CI: [-26.32, -10.16]
95% CI: [-30.87, -13.88]
Secondary
Change From Baseline in Fasting Plasma Glucose (Week 2).
The change between the value of fasting plasma glucose collected at week 2 and 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 Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 2). | -19.2 mg/dL | Standard Deviation 21.1 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 2). | -23.2 mg/dL | Standard Deviation 24.17 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 2). | 0.0 mg/dL | Standard Deviation 26.37 |
95% CI: [-26.12, -12.4]
95% CI: [-30.43, -16.12]
Secondary
Change From Baseline in Fasting Plasma Glucose (Week 4).
The change between the value of fasting plasma glucose collected at week 4 and 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 Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 4). | -19.8 mg/dL | Standard Deviation 25.28 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 4). | -23.5 mg/dL | Standard Deviation 26.05 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 4). | -2.2 mg/dL | Standard Deviation 23.37 |
95% CI: [-24.54, -10.66]
95% CI: [-28.32, -14.39]
Secondary
Change From Baseline in Fasting Plasma Glucose (Week 8).
The change between the value of fasting plasma glucose collected at week 8 and 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 Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 8). | -22.0 mg/dL | Standard Deviation 23.05 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 8). | -21.3 mg/dL | Standard Deviation 25.3 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Fasting Plasma Glucose (Week 8). | -3.1 mg/dL | Standard Deviation 26.23 |
95% CI: [-25.95, -11.79]
95% CI: [-25.43, -10.9]
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 Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 2). | -0.13 percentage of Glycosylated Hemoglobin | Standard Deviation 0.196 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 2). | -0.13 percentage of Glycosylated Hemoglobin | Standard Deviation 0.15 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 2). | 0.06 percentage of Glycosylated Hemoglobin | Standard Deviation 0.197 |
95% CI: [-0.247, -0.135]
95% CI: [-0.242, -0.143]
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 Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 4). | -0.29 percentage of Glycosylated Hemoglobin | Standard Deviation 0.279 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 4). | -0.31 percentage of Glycosylated Hemoglobin | Standard Deviation 0.268 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 4). | 0.09 percentage of Glycosylated Hemoglobin | Standard Deviation 0.302 |
95% CI: [-0.469, -0.303]
95% CI: [-0.484, -0.323]
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 Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 8). | -0.49 percentage of Glycosylated Hemoglobin | Standard Deviation 0.488 |
| Alogliptin 25mg QD and Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 8). | -0.56 percentage of Glycosylated Hemoglobin | Standard Deviation 0.404 |
| Metformin 500mg BID or 750mg TID | Change From Baseline in Glycosylated Hemoglobin (Week 8). | 0.13 percentage of Glycosylated Hemoglobin | Standard Deviation 0.465 |
95% CI: [-0.757, -0.486]
95% CI: [-0.814, -0.569]