A Study to Evaluate the Efficacy and Safety of Pioglitazone 15mg or 30mg Add-on in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin and Dapagliflozin

Study Overview
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Brief Summary
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase III Study to Evaluate the Efficacy and Safety of Pioglitazone 15mg or Pioglitazone 30mg Add-on in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin and Dapagliflozin

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase III Study to Evaluate the Efficacy and Safety of Pioglitazone 15mg or Pioglitazone 30mg Add-on in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin and Dapagliflozin

Conditions
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Type2 Diabetes

Intervention / Treatment
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* Drug: Metformin≥1000mg
* Drug: Pioglitazone 15mg
* Drug: Pioglitazone 30 mg
* Drug: Pioglitazone 15mg Placebo
* Drug: Pioglitazone 30mg Placebo
* Drug: Dapagliflozin 10mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Those who voluntarily signed the informed consent to participate in this study. Adults aged 19 years or older. Those diagnosed with type 2 diabetes mellitus. Subjects taking constant doses of ≥1000mg of Metformin and 10 mg of Dapagliflozin for more than 8 weeks at Visit 1 (regardless of dosage forms (immediate-release and sustained-release) and single agent or combination drug.) Subjects with 7% ≤ HbA1c ≤ 10.5% at Visit 1 and Visit 2 Subjects able to understand the study, comply with study procedures, and attend all scheduled visits. Exclusion Criteria: Uncontrolled hyperglycemia at Visit 1 or Visit 2 (subjects with FPG > 270 mg/dL as a result of the test conducted by the study institution.) Medication compliance is <70% or >120% for each BR3003D, BR3003C, BR3003A-2, and BR3003B-2 during the Run-in period at Visit 2. Patients with other types of diabetes instead of type 2 diabetes (e.g., type 1 diabetes, secondary diabetes, or congenital renal glycosuria). Patients with uncontrolled, severe diabetic complications (e.g., proliferative diabetic retinopathy uncontrolled despite medication and severe diabetic neuropathy) Those who suffered from acute or chronic metabolic acidosis within 3 months as of Visit 1, including lactic acidosis and diabetic ketoacidosis. Those with > 40 kg/m2 of BMI measured at Visit 1. Those with uncontrolled hypertension at Visit 1 or Visit 2 (SBP > 180 mmHg or DBP > 110 mmHg). Those diagnosed with cardiovascular diseases (myocardial infarction, stroke, unstable angina, and transient ischemic attack (TIA)) or undergo revascularization within 3 months as of Visit 1 Those with heart failure (NYHA class II IV) or who had suffered from heart failure. Those who suffered from gastrointestinal diseases that may affect the absorption, distribution, metabolism, and excretion of investigational products or had underwent surgery; Those who underwent surgery requiring general anesthesia within 4 weeks as of Visit 1 or who are scheduled to receive such surgery within 4 weeks after the study ends Those with a history of malignant tumor within 5 years as of Visit 1 Those who have a clinically significant liver disease Those who have a clinically significant renal disease Those with clinically significant hematuria detected at Visit 1 or Visit 2 Those with chronic diseases requiring the continued use of systemic steroid or immunosuppressants (oral administration, injection, or inhalation). Patients with pituitary insufficiency or adrenal insufficiency. Those with clinically significant severe infection or trauma based on an investigator's judgement. Patients with AIDS. Patients with acute or chronic diseases that may cause histotoxic hypoxia such as respiratory failure and shock. Those who need treatment due to dehydration caused by persistent diarrhea and vomiting or at a risk of fluid volume depletion. Those who have been administered with the following drugs or expected to require the continued administration during the study period: Those administered with systemic steroid agents (Prednisolone, >30 mg/day) within 2 weeks as of Visit 1. Those being administered with thyroid medications and whose dose has been modified within 6 weeks as of Visit 1 (however, dose reduction is accepted.) Those being administered with diuretics and whose dose has been modified within 8 weeks as of Visit 1 however, dose reduction is accepted.) Those who have been administered with antidiabetics other than Metformin and Dapagliflozin within 8 weeks as of Visit 1. Those who have been administered with obesity drugs (e.g., phentermine, phendimetrazine, diethylpropion, and mazindol) within 12 weeks as of Visit 1. Those who need to take prohibited concomitant medications stated here during the study period. Those with history of alcohol or drug abuse within 1 year as of Visit 1. Those who had allergic reaction to main ingredients or components of the investigational products. Those who had genetic disorders such as galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption. Females who are pregnant or breastfeeding. Patients planning to become pregnant or of childbearing potential, but not using any recognized contraceptive method Those who are currently participating in other ongoing clinical studies or those who have taken the investigational products from other clinical studies within 12 weeks as of Visit 1 Those who are judged unsuitable for the study by a principal investigator or investigators.

Ages Eligible for Study
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Minimum Age: 19 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin≥1000mg + Dapagliflozin 10mg + Pioglitazone 15mg + Pioglitazone 30mg Placebo<br>Metformin≥1000mg Dapagliflozin 10mg Pioglitazone 15mg Pioglitazone 30mg placebo | Drug: Metformin≥1000mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003D;Drug: Pioglitazone 15mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003A-1;Drug: Pioglitazone 30mg Placebo<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003B-2;Drug: Dapagliflozin 10mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003C;|
| Experimental: Metformin≥1000mg + Dapagliflozin 10mg + Pioglitazone 30mg +Pioglitazone 15mg Placebo<br>Metformin≥1000mg Dapagliflozin 10mg Pioglitazone 30mg Pioglitazone 15mg placebo | Drug: Metformin≥1000mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003D;Drug: Pioglitazone 30 mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003B-1;Drug: Pioglitazone 15mg Placebo<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003A-2;Drug: Dapagliflozin 10mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003C;|
| Active Comparator: Metformin≥1000mg + Dapagliflozin 10mg + Pioglitazone 15mg Placebo+ Pioglitazone 30mg Placebo<br>Metformin≥1000mg Dapagliflozin 10mg Pioglitazone 15mg placebo Pioglitazone 30mg placebo | Drug: Metformin≥1000mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003D;Drug: Pioglitazone 15mg Placebo<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003A-2;Drug: Pioglitazone 30mg Placebo<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003B-2;Drug: Dapagliflozin 10mg<br>* Subjects take the investigational products once a day for 24 weeks.<br>* Other names: BR3003C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in HbA1c | Changes in HbA1c at the 24th week after the administration of investigational products from the baseline | 24th week |