Efficacy and Safety of Alogliptin in Participants With Type 2 Diabetes

Study Overview
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Brief Summary
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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
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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.

Official Title
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An International, Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Determine the Efficacy and Safety of SYR-322 When Used in Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Alogliptin
* Drug: Placebo to alogliptin
* Drug: Metformin
* Drug: Pioglitazone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks. | Drug: Placebo to alogliptin<br>* Alogliptin placebo-matching tablets.<br>|
| Experimental: Alogliptin Monotherapy<br>Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks. | Drug: Alogliptin<br>* Alogliptin tablets<br>* Other names: SYR-322;|
| Other: Metformin<br>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. | Drug: Placebo to alogliptin<br>* Alogliptin placebo-matching tablets.<br>Drug: Metformin<br>* Stable metformin dose<br>* Other names: Glumetza;|
| Experimental: Metformin + Alogliptin Add-on Therapy<br>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. | Drug: Alogliptin<br>* Alogliptin tablets<br>* Other names: SYR-322;Drug: Metformin<br>* Stable metformin dose<br>* Other names: Glumetza;|
| Other: Pioglitazone<br>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. | Drug: Placebo to alogliptin<br>* Alogliptin placebo-matching tablets.<br>Drug: Pioglitazone<br>* Stable pioglitazone dose<br>* Other names: Actos;|
| Experimental: Pioglitazone + Alogliptin Add-on Therapy<br>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. | Drug: Alogliptin<br>* Alogliptin tablets<br>* Other names: SYR-322;Drug: Pioglitazone<br>* Stable pioglitazone dose<br>* Other names: Actos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Week 16. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Weeks 4, 8 and 12. | 
| 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. | Baseline and Weeks 4, 8, 12 and 16. | 
| 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). | Randomization to Week 16. | 
| 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. | Baseline and Weeks 8 and 16. | 
| 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. | Week 16 | 
| 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. | Week 16 | 
| 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. | Week 16 | 
| 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. | Baseline and Week 16 | 
| 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. | Baseline and Week 16 | 
| 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. | Baseline and Week 16. | 
| 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. | Baseline and Week 16. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Drug Therapy