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出境医 / 临床实验 / 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 Antidiabeti

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 Antidiabeti

Study Description
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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: TZD group Drug: SGLT-2 group Phase 4

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 121 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, open label, randomized, parallel, multicenter clinical trial
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
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
Actual Study Start Date : August 5, 2019
Actual Primary Completion Date : May 13, 2020
Actual Study Completion Date : May 28, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: TZD group
Pioglitazone added to Metformin, DPP-4 inhibitors, Sulfonylurea
 Drug: TZD group
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
Other Name: Acpio
Active Comparator: SGLT-2 inhibitor group
Empagliflozin added to Metformin, DPP-4 inhibitors, Sulfonylurea
 Drug: SGLT-2 group
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
Other Name: Jardiance
Outcome Measures
Primary Outcome Measures :
  1. Change of HbA1c [ Time Frame: 12 weeks ]
  2. Change of HbA1c [ Time Frame: 24 weeks ]
    Mean difference of HbA1c after 24 week-treatment


Secondary Outcome Measures :
  1. glucose [ Time Frame: 12 weeks ]
    Percentage of patients who achieve target HbA1c (≤7% level)

  2. glucose [ Time Frame: 24 weeks ]
    Mean difference of fasting blood glucose after 24 week-treatment

  3. Adverse events [ Time Frame: 12 weeks ]
    Incidence of adverse events during treatment period

  4. Adverse events [ Time Frame: 24 weeks ]
    Incidence of adverse events during treatment period

  5. Change of kidney function [ Time Frame: 12 weeks ]
    Mean change of BUN and serum creatinine

  6. Change of kidney function [ Time Frame: 24 weeks ]
    Mean change of BUN and serum creatinine

  7. Change of liver enzymes [ Time Frame: 12 weeks ]
    Mean change of AST(Asparate aminotransferase)

  8. Change of liver enzymes [ Time Frame: 12 weeks ]
    Mean change of ALT(Alanine aminotransferase)

  9. Change of liver enzymes [ Time Frame: 12 weeks ]
    Mean change of Total bilirubin

  10. Change of liver enzymes [ Time Frame: 24 weeks ]
    Mean change of AST

  11. Change of liver enzymes [ Time Frame: 24 weeks ]
    Mean change of ALT

  12. Change of liver enzymes [ Time Frame: 24 weeks ]
    Mean change of Total bilirubin


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   19 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations

Locations
Layout table for location information
Korea, Republic of
Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine
Seoul, Korea, Republic of
Sponsors and Collaborators
Yonsei University
Tracking Information
First Submitted Date  ICMJE July 2, 2019
First Posted Date  ICMJE July 9, 2019
Last Update Posted Date May 4, 2021
Actual Study Start Date  ICMJE August 5, 2019
Actual Primary Completion Date May 13, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2019)
  • Change of HbA1c [ Time Frame: 12 weeks ]
  • Change of HbA1c [ Time Frame: 24 weeks ]
    Mean difference of HbA1c after 24 week-treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2019)
  • glucose [ Time Frame: 12 weeks ]
    Percentage of patients who achieve target HbA1c (≤7% level)
  • glucose [ Time Frame: 24 weeks ]
    Mean difference of fasting blood glucose after 24 week-treatment
  • Adverse events [ Time Frame: 12 weeks ]
    Incidence of adverse events during treatment period
  • Adverse events [ Time Frame: 24 weeks ]
    Incidence of adverse events during treatment period
  • Change of kidney function [ Time Frame: 12 weeks ]
    Mean change of BUN and serum creatinine
  • Change of kidney function [ Time Frame: 24 weeks ]
    Mean change of BUN and serum creatinine
  • Change of liver enzymes [ Time Frame: 12 weeks ]
    Mean change of AST(Asparate aminotransferase)
  • Change of liver enzymes [ Time Frame: 12 weeks ]
    Mean change of ALT(Alanine aminotransferase)
  • Change of liver enzymes [ Time Frame: 12 weeks ]
    Mean change of Total bilirubin
  • Change of liver enzymes [ Time Frame: 24 weeks ]
    Mean change of AST
  • Change of liver enzymes [ Time Frame: 24 weeks ]
    Mean change of ALT
  • Change of liver enzymes [ Time Frame: 24 weeks ]
    Mean change of Total bilirubin
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Prospective, open label, randomized, parallel, multicenter clinical trial
Masking: None (Open Label)
Masking Description:
Open label
Primary Purpose: Treatment
Condition  ICMJE Type 2 Diabetes Mellitus
Intervention  ICMJE
  • Drug: TZD group
    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
    Other Name: Acpio
  • Drug: SGLT-2 group
    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
    Other Name: Jardiance
Study Arms  ICMJE
  • Experimental: TZD group
    Pioglitazone added to Metformin, DPP-4 inhibitors, Sulfonylurea
    Intervention: Drug: TZD group
  • Active Comparator: SGLT-2 inhibitor group
    Empagliflozin added to Metformin, DPP-4 inhibitors, Sulfonylurea
    Intervention: Drug: SGLT-2 group
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 28, 2020) 		121
Original Estimated Enrollment  ICMJE
 (submitted: July 3, 2019) 		120
Actual Study Completion Date  ICMJE May 28, 2020
Actual Primary Completion Date May 13, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04013581
Other Study ID Numbers  ICMJE 4-2019-0393
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Yonsei University
Study Sponsor  ICMJE Yonsei University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Yonsei University
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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