Quadruple Oral Combination Therapy for Type 2 Diabetes Mellitus : Glycemic Control by Thiazolidinedione (TZD) or Sodium Glucose Co-transporter 2 (SGLT-2) Inhibitor as an add-on Therapy in Type 2 Diabetes Mellitus After Failure of an Oral Triple Antidiabetic Regimen

Study Overview
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Brief Summary
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In the treatment of type 2 diabetes (T2D), the number of patients requiring combination therapy of oral antidiabetic agents (OADs) is more than 70%. Especially in Korea, the tendency to avoid insulin therapy is relatively higher than other countries, therefore, the need for combination therapy of OADs is quite high. However, according to the current guidelines, clinicians are recommended to prescribe three or fewer OADs as the combination therapy for T2D. Recently, various OADs have been developed, and it is expected that quadruple combination therapy of OADs would be quite effective to lower blood glucose levels. In the present study, the investigators designed the study to compare the efficacy and safety of quadruple combination therapy; thiazolidinedione (TZD) vs. SGLT-2 inhibitor as an add-on therapy to triple combination therapy (Metformin, Sulfonylurea, Dipeptidyl peptidase-4(DPP-4) inhibitors). Quadruple combination therapy group with the SGLT-2 inhibitor will be considered as active control group, because it have shown non-inferior glycemic efficacy to the conventional insulin conversion therapy in a previous clinical study. Patients who could not achieve the target blood glucose level (7% <HbA1c ≤ 10%) under the triple combination therapy (Metformin, Sulfonylurea, DPP-4 inhibitors) for more than 12 weeks will be enrolled in this prospective, open-label, randomized, parallel comparison, multicenter clinical trial. Subjects in each group (60 patients/group) will be treated with TZD-containing quadruple therapy or SGLT-2 inhibitor-containing quadruple therapy for 24 weeks. The investigators will evaluate the glycemic efficacy and safety of each group. Primary outcome is the 24 week-change of HbA1c from baseline levels.

Official Title
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Quadruple Oral Combination Therapy for Type 2 Diabetes Mellitus : Glycemic Control by Thiazolidinedione (TZD) or Sodium Glucose Co-transporter 2 (SGLT-2) Inhibitor as an add-on Therapy in Type 2 Diabetes Mellitus After Failure of an Oral Triple Antidiabetic Regimen

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: TZD group
* Drug: SGLT-2 group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. 19 ≤ age ≤ 80, male or female 2. Type 2 diabetes patients who have taken triple combination therapy of OADs as followed : Metformin (≥1000 mg/day), Sulfonylurea (Glimepiride ≥ 4 mg/day or Gliclazide ≥ 60 mg/day), DPP-4 inhibitor (Full dose) for over 12 weeks 3. At screening, 7% < HbA1c ≤ 10% 4. Patients who refused insulin therapy. 5. Subjects who understood the contents of the clinical trial and are cooperative in the trial progress, and are considered to be able to participate until the end of the trial. 6. Patients who have voluntarily agreed in writing to participate in the clinical trial after hearing the explanation of the trial. Exclusion Criteria: 1. Type 1 diabetes, gestational diabetes, and other types of diabetes than type 2 diabetes mellitus. 2. Patients who have the history of allergy of hypersensitivity for the medication of the clinical trial. 3. Patients who have the history of taking TZDs or SGLT-2 inhibitors within a year prior to screening visit, or have the history of discontinuation of them due to severe side effects. 4. Patients who have the history of acute or chronic metabolic acidosis including diabetic ketoacidosis (with or without coma), or any kinds of ketosis within 12 weeks prior to screening visit. 5. Patients who have genetic metabolic diseases, such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption 6. Patients who have the history of taking steroids for more than 2 weeks, within 8 weeks prior to screening visit. 7. Patients who have the history of malignancy within 5 years prior to screening visit (In case of bladder cancer, subjects will be excluded regardless of the time of diagnosis) 8. Patients who have the history of coronary artery bypass surgery or percutaneous coronary intervention, or suffered from heart failure (NYHA class III, IV) 9. Patients who have the history of uncontrolled arrhythmia, unstable angina, myocardial infarction, stroke, transient ischemic attacks, and cerebral vascular disease within 24 weeks prior to the screening date. 10. Patients of chronic renal failure, chronic kidney disease stage 3 5 (estimated glomerular filtration rate calculated vial CKD-EPI <60 mL/min/1.73m2) or on dialysis therapy. 11. Elevated liver enzymes (AST, ALT, ALP ≥ 2.5*upper limit of normal (ULN) or Total bilirubin ≥ 2.5*ULN) or Child-Pugh class B or C (for the patients of liver cirrhosis) 12. Subjects who are pregnant or lactating 13. Perioperative patients, patients with severe infections or severe trauma 14. Patients with unexamined gross hematuria 15. Any other subjects who is determined to be ineligible for the clinical trials by researchers.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 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
Interventional Model Description: Prospective, open label, randomized, parallel, multicenter clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TZD group<br>Pioglitazone added to Metformin, DPP-4 inhibitors, Sulfonylurea | Drug: TZD group<br>* Pioglitazone 15mg (Acpio®, once daily, regardless of meal time, for 24 weeks) will be added for T2DM(type 2 diabetes mellitus) patients who had inadequate glycemic control (7% <HbA1c ≤ 10%) with triple therapy (metformin, DPP-4 inhibitors, sulfonylurea). At visit 3 (after 12 week-treatment), patients whose HbA1c level is more than 7.0% will be prescribed increased dosage of pioglitazone : from 15mg to 30mg<br>* Other names: Acpio;|
| Active Comparator: SGLT-2 inhibitor group<br>Empagliflozin added to Metformin, DPP-4 inhibitors, Sulfonylurea | Drug: SGLT-2 group<br>* Empagliflozin 10mg (Jardiance®, once daily, regardless of meal time, for 24 weeks) will be added for T2DM patients who had inadequate glycemic control (7% <HbA1c ≤ 10%) with triple therapy (metformin, DPP-4 inhibitors, sulfonylurea). At visit 3 (after 12 week-treatment), patients whose HbA1c level is more than 7.0% will be prescribed increased dosage of empagliflozin : from 10mg to 25mg<br>* Other names: Jardiance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of HbA1c |  | 12 weeks | 
| Change of HbA1c | Mean difference of HbA1c after 24 week-treatment | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| glucose | Percentage of patients who achieve target HbA1c (≤7% level) | 12 weeks | 
| glucose | Mean difference of fasting blood glucose after 24 week-treatment | 24 weeks | 
| Adverse events | Incidence of adverse events during treatment period | 12 weeks | 
| Adverse events | Incidence of adverse events during treatment period | 24 weeks | 
| Change of kidney function | Mean change of BUN and serum creatinine | 12 weeks | 
| Change of kidney function | Mean change of BUN and serum creatinine | 24 weeks | 
| Change of liver enzymes | Mean change of AST(Asparate aminotransferase) | 12 weeks | 
| Change of liver enzymes | Mean change of ALT(Alanine aminotransferase) | 12 weeks | 
| Change of liver enzymes | Mean change of Total bilirubin | 12 weeks | 
| Change of liver enzymes | Mean change of AST | 24 weeks | 
| Change of liver enzymes | Mean change of ALT | 24 weeks | 
| Change of liver enzymes | Mean change of Total bilirubin | 24 weeks |