An Extension Study of PEAK Trial

Study Overview
=================
Brief Summary
-----------------
Double blind, three arm, comparative intervention trial for 24 weeks(PEAK study) with open label extension trial for 28 weeks followed by 2 year observational study.

Detailed Description
-----------------
PEAK trial is now undergoing (Multicenter, randomized, double blind, three-arm parallel group study to evaluate efficacy and safety of Alogliptin and Pioglitazone combination therapy on glucose control in type 2 diabetes subjects who have inadequate control with Metformin monotherapy in Korea, Takeda No. ALO-IIT-012). Duration of combination treatment is 24 week in the PEAK trial. Long-term efficacy and safety of alogliptin + pioglitazone + metformin combination therapy is not defined in Korea yet. Thus, extension of the PEAK trial for the longer treatment upto 1 year has been planned. PEAK trial will be followed by another 28 week open-label treatment of the same drug as initial randomization (total duration of treatment as randomized 52 week), and followed by 2 year of observation. During observation period, any antidiabetic medication can be added/changed when HbA1c of the subject is off target 7% with clinician's clinical decision. After 3 years of initial randomization, durability of glucose control will be assessed between 3 treatment group.

Official Title
-----------------
An Extension Study of Protocol ALO-IIT(PEAK Study) to Examine the Long-term Efficacy and Safety of Metformin + Alogliptin + Pioglitazone Triple Combination Therapy in the Korean Type 2 Diabetes Patients

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: alogliptin+pioglitazone
* Drug: alogliptin
* Drug: pioglitazone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Completed ALO-IIT-012(PEAK study), without major protocol deviations. Male, or female, 19 years to 75 years. Female with childbearing potential who has a negative urine pregnancy test result at study start and willing to continue practice appropriate birth control during the entire duration of study Subjects completed PEAK can be included within 30 days after End Of the Study Subjects completed PEAK can be included if their treatment is the same as randomized even after 30 days of End Of the Study. Exclusion Criteria: eGFR(Epidermal growth factor receptor) < 50mL/min AST(aspartate aminotransferase)/ALT(alanine aminotransaminase) >2.5 upper limit of normal Pregnant or lactating women Subject who the investigator deems inappropriate to participate in this study Patients with a history of bladder cancer or patients with active bladder cancer Patients with uninvestigated macroscopic hematuria Patients with cardiac failure or a history of cardiac failure (New York Heart Association [NYHA] Stages 3 to 4) Patients with genetic problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, since this study drug contains lactose

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: alogliptin+pioglitazone<br>A group who treat with alogliptin+pioglitazone: The Combination of Alogliptin 25 mg and pioglitazone 30 mg daily add on metformin for 28 week as extension and followed by 2 years of observation | Drug: alogliptin+pioglitazone<br>* alogliptin and pioglitazone add on metformin<br>* Other names: nesina, actos;|
| Active Comparator: alogliptin<br>A group who treat with alogliptin: Alogliptin 25 mg daily add on metformin for for 28 week as extension and followed by 2 years of observation | Drug: alogliptin<br>* nesina add on metformin<br>* Other names: nesina;|
| Active Comparator: pioglitazone<br>A group who treat with pioglitazone: Pioglitazone 30 mg daily add on metformin for for 28 week as extension and followed by 2 years of observation | Drug: pioglitazone<br>* actos add on metformin<br>* Other names: actos;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving HbA1c <7% after 36 month treatment | The proportion of subjects achieving HbA1c on target < 7.0% after 36 month. | 36 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving HbA1c <6.5% after 36 month treatment | The proportion of subjects achieving HbA1c on target < 6.5% after 36 month. | 36 Months after randomization | 
| Proportion of subjects achieving HbA1c <7% after 12 month treatment | The proportion of subjects achieving HbA1c on target < 7.0% after 12 month. | 12 Months after randomization | 
| Change in glycated hemoglobin(HbA1c) from baseline to 12 month | Change from baseline in HbA1c after 6 month of double blinded treatment followed by 6 month open treatment | baseline, 12 months | 
| Change in HOMA-IR(homeostasis model assessment of insulin resistance) from baseline to 36 month | Change from baseline in HOMA-IR(homeostasis model assessment of insulin resistance) after 12 month of randomized treatment followed by 24 month observation. | baseline, 36 months | 
| change of HOMA-beta(homeostasis model assessment of beta cell) from baseline to 36 month | Change from baseline in HOMA-beta(homeostasis model assessment of beta cell) after 12 month of randomized treatment followed by 24 month observation. | baseline, 36 months |