Type 2 Diabetes Mellitus
Conditions
Keywords
Acarbose, ACADEMIC
Brief summary
Primary objective To evaluate the efficacy of Acarbose add-on therapy on glucose control in subjects with type 2 diabetes inadequately controlled with Metformin and Sitagliptin combination therapy. The effect of acarbose, an alpha glucosidase inhibitor as a third-line therapeutic medication in subject who are inadequately controlled with metformin and DPP4 inhibitor will be evaluated with multicenter, randomized, 24-week, double blinded, placebo-controlled study in Korea.
Detailed description
Eligible subjects will be assigned among 3 groups randomly at a ration of 2:2:1 to the following groups and primary efficacy variable analyzed at week 16. group 1 : acarbose placebo + metformin + sitagliptin (with switching placebo to acarbose qt week 16) group 2 : acarbose + metformin + sitagliptin group 3 : acarbose + metformin placebo + sitagliptin (with switching placebo to metformin at week 16) After 16 week of treatment, all subjects in 3 groups will be treated as triple combination of acarbose + metformin + sitagliptin, and diabetes related variables be collected and analyzed. 1. Primary Endpoint Changes in HbA1c (hemoglobin A1c) at 16 week from baseline between group1 vs grou2 2. Secondary Endpoints (1) Changes of HbA1c at 24 week between 3 groups (2) Changed of post-prandial blood glucose at 2 hour (ppg2h) at 16, 24 week for exploratory purpose, following data will be collected and analyzed 1. continuous glucose monitoring system (CGMS) data among selected subjects in 3 groups 2. mixed meal tolerance test in only available institution. (glucose, insulin, GLP-1, GIP, glucagon ) among selected subjects in group 1 and group 2 3. oxidative stress markers (8-OHdG, nitrotyrosin, CML) 4. self monitoring of blood glucose
Interventions
DRUGAcarbose
Acarbose 50mg b.i.d at first, at the 2nd week 50mg t.i.d and the 4th week, 100mg tid.
DRUGPlacebo acarbose
acarbose placebo
metformin placebo
Sponsors
Bayer
The Catholic University of Korea
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
placebo medication
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects with type-II diabetes mellitus; 2. Subjects aged between 20 and 80; 3. Subjects whose HbA1c ratio is between 7.0% and 10.0%; 4. Subjects who took Metformin and Sitagliptin for at least 12 weeks; 5. Subjects who were given the explanation about this clinical study and signed the consent form.
Exclusion criteria
1. Subjects who have taken drugs that are likely to affect blood glucose or who need to take such drugs, e.g., glucocorticoid; 2. Subjects with severe renal diseases (men: Scr\>1.5 / women: Scr\>1.4); 3. Subjects with severe liver diseases or whose AST and ALT are at least 2.5 times higher than the upper limits of normal (ULN); 4. Subjects having the case history of lactic acidosis; 5. Subjects who have the case history of myocardial infarction or unstable angina or who underwent the coronary artery bypass graft 6 months before the screening test or who have arrhythmia to be treated; 6. Subjects with congestive heart failures to be treated; 7. Subjects who fall into New York Heart Association (NYHA) class III or IV; 8. Subjects having the case history of acute or chronic metabolic acidosis including ketoacidosis; 9. Subjects who have been pregnant or who are in the period of lactation; 10. Subjects diagnosed with malignant tumors within 5 years; 11. Subjects who are hypersensitive to Metformin, Sitagliptin and Acarbose or their ingredients; 12. Subjects with inflammatory bowel diseases or intestinal ulcers or enterostenosis (includes Subjects who are vulnerable to enterostenosis) or chronic enteric diseases related to digestion and absorption or whose symptoms are likely to worsen due to intestinal gas; 13. Subjects who participated in other clinical studies as Subjects within 60 days before this study (or before taking the investigational drugs); 14. Subjects judged unfit for this study by investigators.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change of Glycated Hemoglogin(HbA1c) From Baseline to 16 Weeks of Treatment | baseline, 16 weeks | The change of glycated hemoglogin(HbA1c) from baseline to 16 weeks of treatment between Placebo + Metformin+Sitagliptin and Metformin + Sitagliptin + Acarbose group |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Glucose During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | Visit 2(baseline) and Visit 5(16W) | Change of AUC(area under the curve) of glucose at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin) |
| Change in Active GLP-1 at 0 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2) | baseline, 16 week | Change of active GLP-1 at 0 minute during mixed meal test at 16 week from baseline between 2 groups(group1, group2) |
| Change in Active GLP-1 at 120 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2) | baseline, 16 week | Change of active GLP-1 at 120 minute during mixed meal test at 16 week from baseline between 2 groups(group1, group2) |
| Changes in Glucagon During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | Visit 2(baseline) and Visit 5(16W) | Change of AUC(area under the curve) of glucagon at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin) |
| The Change of HbA1c From Baseline to 24 Weeks of Treatment | baseline, 24 weeks | The change of glycated hemoglogin(HbA1c) from baseline to 24 weeks of treatment between 3 groups |
| The Change of PPG2hr From Baseline to 24 Weeks of Treatment | baseline, 24 weeks | The change of PPG2hr (post prandia blood glucose 2hr from baseline to 24 weeks of treatment between 3 groups |
| Changes in Insulin During Mixed Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | Visit 2(baseline) and Visit 5(16W) | Change of AUC(area under the curve) of insulin at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in MAGE of Glucose During CGMS Between 2 Group(Group 1 vs Group 2), | Visit 2(baseline) and Visit 5(16W) | Change of mean amplitude of glycemic excursion of CGMS(continuous glucose monitoring system) data at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin) |
| Changes in Mean Glucose During CGMS Between 3 Group | Visit 2(baseline) and Visit 5(16W) | Change of mean glucose of CGMS(continuous glucose monitoring system) data at 16 week from baseline between 3 groups |
| Changes in Variation of Glucose During CGMS Between 3 Group | Visit 2(baseline) and Visit 5(16W) | Change of standard deviation of CGMS(continuous glucose monitoring system) data at 16 week from baseline between 3 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin vs placebo + acarbose + sitagliptin) |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acarbose Placebo, Metformin, Sitagliptin The dose of Acarbose should be 50mg b.i.d, 50mg t.i.d and 100mg t.i.d at the 18th week, the 20th week and the 24th week respectively. The Acarbose placebo should be changed into real Acarbose from the 16th week.
Acarbose: The dose of Acarbose or its placebo should be 50mg b.i.d at first. At the 2nd week and the 4th week, it should be 50mg t.i.d and 100mg t.i.d respectively | 65 |
| Sitagliptin, Metformin, Acarbose The group's drugs not include placebo. (Metformin, Sitagliptin, Acarbose)
Acarbose: The dose of Acarbose or its placebo should be 50mg b.i.d at first. At the 2nd week and the 4th week, it should be 50mg t.i.d and 100mg t.i.d respectively | 66 |
| Metformin Placebo, Sitagliptin, Acarbose The Metformin placebo should be changed into real Metformin from the 16th week.
Acarbose: The dose of Acarbose or its placebo should be 50mg b.i.d at first. At the 2nd week and the 4th week, it should be 50mg t.i.d and 100mg t.i.d respectively | 34 |
| Total | 165 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 |
| Overall Study | other cause | 4 | 5 | 8 |
| Overall Study | Withdrawal by Subject | 7 | 8 | 3 |
Baseline characteristics
| Characteristic | Acarbose Placebo, Metformin, Sitagliptin | Sitagliptin, Metformin, Acarbose | Metformin Placebo, Sitagliptin, Acarbose | Total |
|---|---|---|---|---|
| Age, Continuous | 56.55 years STANDARD_DEVIATION 10.51 | 60.89 years STANDARD_DEVIATION 8.8 | 60.15 years STANDARD_DEVIATION 9.92 | 59.03 years STANDARD_DEVIATION 9.88 |
| Region of Enrollment South Korea | 65 participants | 66 participants | 34 participants | 165 participants |
| Sex: Female, Male Female | 30 Participants | 43 Participants | 14 Participants | 87 Participants |
| Sex: Female, Male Male | 35 Participants | 23 Participants | 20 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 66 | 0 / 34 |
| other Total, other adverse events | 14 / 65 | 19 / 66 | 11 / 34 |
| serious Total, serious adverse events | 2 / 65 | 1 / 66 | 0 / 34 |
Outcome results
Primary
The Change of Glycated Hemoglogin(HbA1c) From Baseline to 16 Weeks of Treatment
The change of glycated hemoglogin(HbA1c) from baseline to 16 weeks of treatment between Placebo + Metformin+Sitagliptin and Metformin + Sitagliptin + Acarbose group
Time frame: baseline, 16 weeks
Population: ITT: intention to treatment, All subject randomized to each treatment group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | The Change of Glycated Hemoglogin(HbA1c) From Baseline to 16 Weeks of Treatment | -0.09 % of HbA1c | Standard Error 0.1 |
| Sitagliptin+Metformin+Acarbose | The Change of Glycated Hemoglogin(HbA1c) From Baseline to 16 Weeks of Treatment | -0.44 % of HbA1c | Standard Error 0.08 |
| Placebo+Sitagliptin+Acarbose | The Change of Glycated Hemoglogin(HbA1c) From Baseline to 16 Weeks of Treatment | 0.84 % of HbA1c | Standard Error 0.21 |
Comparison: primary outcome efficacy will be evaluated between group 1(placebo + metfromin + sitagliptin) and 2 (sitagliptine + metformin + acarbose)p-value: 0.0036ANCOVA
Secondary
Change in Active GLP-1 at 0 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2)
Change of active GLP-1 at 0 minute during mixed meal test at 16 week from baseline between 2 groups(group1, group2)
Time frame: baseline, 16 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Change in Active GLP-1 at 0 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2) | -8.55 pg/ml | Standard Deviation 19.01 |
| Sitagliptin+Metformin+Acarbose | Change in Active GLP-1 at 0 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2) | -9.33 pg/ml | Standard Deviation 31.12 |
p-value: 0.9217ANCOVA
Secondary
Change in Active GLP-1 at 120 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2)
Change of active GLP-1 at 120 minute during mixed meal test at 16 week from baseline between 2 groups(group1, group2)
Time frame: baseline, 16 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Change in Active GLP-1 at 120 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2) | -32.92 pg/ml | Standard Deviation 21.78 |
| Sitagliptin+Metformin+Acarbose | Change in Active GLP-1 at 120 Minute During Mixed Meal Test Between 2 Groups (Group 1, group2) | -23.36 pg/ml | Standard Deviation 33.43 |
p-value: 0.16ANCOVA
Secondary
Changes in Glucagon During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2),
Change of AUC(area under the curve) of glucagon at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin)
Time frame: Visit 2(baseline) and Visit 5(16W)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Changes in Glucagon During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | -79.22 min pg/mL | Standard Deviation 833.59 |
| Sitagliptin+Metformin+Acarbose | Changes in Glucagon During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | -1411.79 min pg/mL | Standard Deviation 1049.41 |
p-value: 0.004ANCOVA
Secondary
Changes in Glucose During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2),
Change of AUC(area under the curve) of glucose at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin)
Time frame: Visit 2(baseline) and Visit 5(16W)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Changes in Glucose During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | 28.85 mg min/dL | Standard Deviation 2168.64 |
| Sitagliptin+Metformin+Acarbose | Changes in Glucose During Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | -743.08 mg min/dL | Standard Deviation 1278.28 |
p-value: 0.0356ANCOVA
Secondary
Changes in Insulin During Mixed Meal Tolerance Test Between 2 Group(Group 1 vs Group 2),
Change of AUC(area under the curve) of insulin at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin)
Time frame: Visit 2(baseline) and Visit 5(16W)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Changes in Insulin During Mixed Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | 647.65 pg min/mL | Standard Deviation 3854.75 |
| Sitagliptin+Metformin+Acarbose | Changes in Insulin During Mixed Meal Tolerance Test Between 2 Group(Group 1 vs Group 2), | 221.42 pg min/mL | Standard Deviation 8339.6 |
p-value: 0.8258ANCOVA
Secondary
The Change of HbA1c From Baseline to 24 Weeks of Treatment
The change of glycated hemoglogin(HbA1c) from baseline to 24 weeks of treatment between 3 groups
Time frame: baseline, 24 weeks
Population: ITT: intention to treatment, All subject randomized to each treatment group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | The Change of HbA1c From Baseline to 24 Weeks of Treatment | -0.34 % of HbA1c | Standard Deviation 0.82 |
| Sitagliptin+Metformin+Acarbose | The Change of HbA1c From Baseline to 24 Weeks of Treatment | -0.47 % of HbA1c | Standard Deviation 0.78 |
| Placebo+Sitagliptin+Acarbose | The Change of HbA1c From Baseline to 24 Weeks of Treatment | 0.23 % of HbA1c | Standard Deviation 1.32 |
p-value: <0.0001ANCOVA
Secondary
The Change of PPG2hr From Baseline to 24 Weeks of Treatment
The change of PPG2hr (post prandia blood glucose 2hr from baseline to 24 weeks of treatment between 3 groups
Time frame: baseline, 24 weeks
Population: ITT: intention to treatment, All subject randomized to each treatment group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | The Change of PPG2hr From Baseline to 24 Weeks of Treatment | -1.73 mmol/L | Standard Deviation 3.38 |
| Sitagliptin+Metformin+Acarbose | The Change of PPG2hr From Baseline to 24 Weeks of Treatment | -1.76 mmol/L | Standard Deviation 3.53 |
| Placebo+Sitagliptin+Acarbose | The Change of PPG2hr From Baseline to 24 Weeks of Treatment | 0.06 mmol/L | Standard Deviation 4.53 |
p-value: 0.0185ANCOVA
Other Pre-specified
Changes in MAGE of Glucose During CGMS Between 2 Group(Group 1 vs Group 2),
Change of mean amplitude of glycemic excursion of CGMS(continuous glucose monitoring system) data at 16 week from baseline between 2 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin)
Time frame: Visit 2(baseline) and Visit 5(16W)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Changes in MAGE of Glucose During CGMS Between 2 Group(Group 1 vs Group 2), | -8.79 mg/dL | Standard Deviation 15.01 |
| Sitagliptin+Metformin+Acarbose | Changes in MAGE of Glucose During CGMS Between 2 Group(Group 1 vs Group 2), | -18.5 mg/dL | Standard Deviation 13.23 |
| Placebo+Sitagliptin+Acarbose | Changes in MAGE of Glucose During CGMS Between 2 Group(Group 1 vs Group 2), | 2.72 mg/dL | Standard Deviation 2.72 |
p-value: 0.7563ANCOVA
Other Pre-specified
Changes in Mean Glucose During CGMS Between 3 Group
Change of mean glucose of CGMS(continuous glucose monitoring system) data at 16 week from baseline between 3 groups
Time frame: Visit 2(baseline) and Visit 5(16W)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Changes in Mean Glucose During CGMS Between 3 Group | -0.91 mmol/L | Standard Deviation 0.81 |
| Sitagliptin+Metformin+Acarbose | Changes in Mean Glucose During CGMS Between 3 Group | -1.16 mmol/L | Standard Deviation 0.49 |
| Placebo+Sitagliptin+Acarbose | Changes in Mean Glucose During CGMS Between 3 Group | 3.22 mmol/L | Standard Deviation 1.25 |
p-value: 0.292ANCOVA
Other Pre-specified
Changes in Variation of Glucose During CGMS Between 3 Group
Change of standard deviation of CGMS(continuous glucose monitoring system) data at 16 week from baseline between 3 groups (placebo+metformin + sitagliptin vs acarbose + metformin + sitagliptin vs placebo + acarbose + sitagliptin)
Time frame: Visit 2(baseline) and Visit 5(16W)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin+Sitagliptin | Changes in Variation of Glucose During CGMS Between 3 Group | -0.33 mmol/L | Standard Deviation 1 |
| Sitagliptin+Metformin+Acarbose | Changes in Variation of Glucose During CGMS Between 3 Group | -0.65 mmol/L | Standard Deviation 0.8 |
| Placebo+Sitagliptin+Acarbose | Changes in Variation of Glucose During CGMS Between 3 Group | 0.03 mmol/L | Standard Deviation 0.29 |
p-value: 0.314ANCOVA