Clinical trial NCT04013581: 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
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Yonsei University
Sponsor class: OTHER
First posted: 2019-07-09
Enrollment: 121
Sex: ALL
Minimum age (years): 19
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, open label, randomized, parallel, multicenter clinical trial
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change of HbA1c
timeFrame: 12 weeks
measure: Change of HbA1c
timeFrame: 24 weeks
Secondary outcomes:
measure: glucose
timeFrame: 12 weeks
measure: glucose
timeFrame: 24 weeks
measure: Adverse events
timeFrame: 12 weeks
measure: Adverse events
timeFrame: 24 weeks
measure: Change of kidney function
timeFrame: 12 weeks
measure: Change of kidney function
timeFrame: 24 weeks
measure: Change of liver enzymes
timeFrame: 12 weeks
measure: Change of liver enzymes
timeFrame: 12 weeks
measure: Change of liver enzymes
timeFrame: 12 weeks
measure: Change of liver enzymes
timeFrame: 24 weeks
measure: Change of liver enzymes
timeFrame: 24 weeks
measure: Change of liver enzymes
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine
Study officials:
References: