Type 2 Diabetes Mellitus
Conditions
Keywords
Beta cell function, Type 2 diabetes, Combination treatment
Brief summary
It has been shown in previous study that progressive glycemic deterioration was associated with progressive loss of b-cell function, measured by the decrease in plasma insulin levels, irrespective of the therapy used (diet, sulfonylureas or metformin).There is growing evidence that thiazolidinediones could have a positive action on the b-cell function. But it has not yet been demonstrated that they could protect from a deterioration in insulin secretion in the long term. So, it appears interesting to study the long term evolution of the b-cell function and the possible protection with rosiglitazone in patients with type 2 diabetes showing evidence of loss of b-cell function with metformin alone.
Interventions
DRUGrosiglitazone-metformin
DRUGMetformin
DRUGmetformin+ gliclazide
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Males and females 40 to 75 years of age (inclusive at the time of screening) * Type 2 diabetes mellitus as defined by the WHO criteria, diagnosed for at least 1 year * Subjects receiving 1.5 to 3g of metformin alone at a constant dose for at least 8 weeks prior to visit 1 * Patients with 6.5% \< HbA1c \> 8% at visit 1 and visit 2 * 25 \< BMI \< 35
Exclusion criteria
* Patient with type 1 diabetes * Treatment with other hypoglycaemic agents than metformin in the last 3 months * FPG \>200 mg/dL at visit 2 * Hypersensitivity to the studied treatments (rosiglitazone, metformin chlorhydrate, gliclazide) * Congestive heart failure (NYHA class I to IV), unstable or severe angina, recent myocardial infarction * Respiratory insufficiency * Subjects who have required the use of insulin for glycaemic control in the past 6 months prior to visit 1 (except during pregnancy or acute episodes such as hospitalization, trauma or infection) or subjects with a history of metabolic acidosis including diabetic ketoacidosis * Anemia defined by haemoglobin concentration \<11.0 g/dL for males and \<10.0 g/dL for females * Renal disease or renal dysfunction, e.g. as suggested by serum creatinine levels ≥135.0 µmol/L in males and ≥110.0 µmol/L in females and/or creatinine clearance \<40 mL/min * Presence of clinically significant hepatic disease, with ALT, AST, total bilirubin, alkaline phosphatase \>2.5 times the upper limit of the normal reference range * Subjects with chronic diseases requiring periodic ot intermittent treatment with oral or IV corticosteroids * Subjects receiving danazol, miconazole or phenylbutazone * Active alcohol, drug or medication abuse within the last 6 months or any condition that would indicate the likelihood of poor subject compliance * Women who are lactating, pregnant or planning to become pregnant * Any clinically significant abnormality identified at screening which, in the investigator's judgement, makes the subject unsuitable for inclusion in the study * Use of any other investigational agent within 30 days or 5 half-lives (whichever is longer) prior to visit 1 * Subjects who receive or anticipate receiving radiocontrast dye during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Baseline and Month 36 | Change from baseline in the insulin secretory capacity was measured by the assesment of blood insulin concentrations (conc.) using the hyperglycaemic clamp (HC) technique, per intravenous glucose perfusion by a catheter. Change from baseline for insulin conc peaks (highest conc level) was calculated as the Month 36 value minus the baseline value. Insulin secretion was assessed by calculating AUC during the first 10 minutes of HC (incremental and total AUC0-10 min) and the AUC after the first 10 minutes of the HC (10-180min). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Baseline and Month 18 | Change from baseline was calculated as the Month 18 value minus the baseline value. Insulin secretion capacity is measured in blood (blood level of insulin) and is a response of the pancreatic beta-cells to hyperglycemia induced by a glucose IV bolus, then infusion. Hyperglycemic clamp (HC) is a reference technique to evaluate the initial and the secondary phases of insulin secretion. |
| Mean Change From Baseline in HbA1c at Month 36 | Baseline and Month 36 | Change from baseline was calculated as the Month 36 value minus the baseline value. HbA1c levels were measured by blood draw. |
| Mean Change From Baseline in FBG at Month 36 | Baseline and Month 36 | Change from baseline was calculated as the Month 36 value minus the baseline value. FBG levels were measured by blood draw. |
| Median Change From Baseline in Insulin Resistance Index (HOMA-IR) After a 36-month Treatment | Baseline and Month 36 | — |
| Median Change From Baseline in the Ratio M/I After a 36-month Treatment | Baseline and Month 36 | — |
| Mean Change From Baseline in CPP Total and Incremental AUC T0-T30 After a 36-month Treatment | Baseline and Month 36 | — |
| Mean Change From Baseline in CPP Concentration Peak and Incremental Concentration Peak T0-T30 After a 36-month Treatment | Baseline and Month 36 | — |
| Mean Change From Baseline in Insulin Sensitivity Index at Months 18 and 36 | Baseline and Months 18 and 36 | Change from baseline was calculated as the Month 18 and 36 values minus the baseline value. Insulin sensitivity is measured as the quantity of glucose metabolized per unit of plasma insulin concentration. |
| Median Change From Baseline in Beta Cell Function Index (HOMA-beta) After a 36-month Treatment | Baseline and Month 36 | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rosiglitazone + Metformin 4 mg/2 g/Day Initial dose of rosiglitazone + metformin of 4 milligrams (mg)/2 grams (g)/day; allowed adjustment of up to 8 mg/2 g/day after 8 weeks | 43 |
| Gliclazide + Metformin 80 mg/2 g/Day Initial dose of gliclazide + metformin 80 mg/2 g/day; allowed adjustment of up to 160 mg/2 g/day after 4 weeks, up to 240 mg/2 g/day after 8 weeks, up to 320 mg/2 g/day after 3 months | 41 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Lack of Efficacy | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Participant Living too Far from Hospital | 0 | 1 |
| Overall Study | Patient's Willing | 3 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Stopping Criterion Met | 0 | 1 |
Baseline characteristics
| Characteristic | Gliclazide + Metformin 80 mg/2 g/Day | Total | Rosiglitazone + Metformin 4 mg/2 g/Day |
|---|---|---|---|
| Age Continuous | 58.1 years STANDARD_DEVIATION 8 | 58.2 years STANDARD_DEVIATION 8.2 | 58.3 years STANDARD_DEVIATION 8.4 |
| Body Mass Index (BMI) <25 | 0 kilograms per square meter (kg/m2) | 3 kilograms per square meter (kg/m2) | 3 kilograms per square meter (kg/m2) |
| Body Mass Index (BMI) 25-30 | 20 kilograms per square meter (kg/m2) | 41 kilograms per square meter (kg/m2) | 21 kilograms per square meter (kg/m2) |
| Body Mass Index (BMI) >30 | 21 kilograms per square meter (kg/m2) | 40 kilograms per square meter (kg/m2) | 19 kilograms per square meter (kg/m2) |
| FBG | 8.28 Millimoles/Liter (mmol/L) STANDARD_DEVIATION 1.11 | 8.70 Millimoles/Liter (mmol/L) STANDARD_DEVIATION 1.5 | 9.10 Millimoles/Liter (mmol/L) STANDARD_DEVIATION 1.72 |
| HbA1c | 7.3 percentage STANDARD_DEVIATION 0.55 | 7.4 percentage STANDARD_DEVIATION 0.57 | 7.5 percentage STANDARD_DEVIATION 0.55 |
| Sex: Female, Male Female | 16 Participants | 27 Participants | 11 Participants |
| Sex: Female, Male Male | 25 Participants | 57 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 43 | 29 / 41 |
| serious Total, serious adverse events | 8 / 43 | 12 / 41 |
Outcome results
Primary
Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment
Change from baseline in the insulin secretory capacity was measured by the assesment of blood insulin concentrations (conc.) using the hyperglycaemic clamp (HC) technique, per intravenous glucose perfusion by a catheter. Change from baseline for insulin conc peaks (highest conc level) was calculated as the Month 36 value minus the baseline value. Insulin secretion was assessed by calculating AUC during the first 10 minutes of HC (incremental and total AUC0-10 min) and the AUC after the first 10 minutes of the HC (10-180min).
Time frame: Baseline and Month 36
Population: Intent-to-Treat (ITT) Population: participants receiving at least one dose of study drug with an available efficacy evaluation (HC at M18 or M36). The measurement was conducted on participants who had baseline and M18 and M36 HC test data available. Each HC was validated at both Baseline and Month 36, resulting in different ns for each category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total AUC(0-10 min), n=24, 26 | -3.9 picomoles/L per minute (pmol/L*min) |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental AUC(0-10 min), n=22, 23 | 7.0 picomoles/L per minute (pmol/L*min) |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total concentration peak(0-10 min), n=25, 26 | -8.6 picomoles/L per minute (pmol/L*min) |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental concentration peak(0-10 min), n=24, 26 | -1.8 picomoles/L per minute (pmol/L*min) |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total AUC(10-180 min), n=20, 24 | 40.6 picomoles/L per minute (pmol/L*min) |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental AUC(10-180 min), n=19, 24 | 67.0 picomoles/L per minute (pmol/L*min) |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total concentration peak(10-180 min), n=27, 29 | 7.9 picomoles/L per minute (pmol/L*min) |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental concentation peak(10-180 min), n=25,29 | 10.8 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental concentation peak(10-180 min), n=25,29 | 11.5 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total AUC(0-10 min), n=24, 26 | -75.3 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total AUC(10-180 min), n=20, 24 | -21.2 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental AUC(0-10 min), n=22, 23 | 74.6 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total concentration peak(10-180 min), n=27, 29 | -9.3 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Total concentration peak(0-10 min), n=25, 26 | 3.6 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental AUC(10-180 min), n=19, 24 | 13.6 picomoles/L per minute (pmol/L*min) |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Incremental concentration peak(0-10 min), n=24, 26 | 10.8 picomoles/L per minute (pmol/L*min) |
p-value: 0.376Van Elteren
p-value: 0.99Van Elteren
Secondary
Mean Change From Baseline in CPP Concentration Peak and Incremental Concentration Peak T0-T30 After a 36-month Treatment
Time frame: Baseline and Month 36
Secondary
Mean Change From Baseline in CPP Total and Incremental AUC T0-T30 After a 36-month Treatment
Time frame: Baseline and Month 36
Secondary
Mean Change From Baseline in FBG at Month 36
Change from baseline was calculated as the Month 36 value minus the baseline value. FBG levels were measured by blood draw.
Time frame: Baseline and Month 36
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of study drug and had an available efficacy evaluation (hyperglycaemic clamp at M18 or M36). This measurement was conducted on participants in the ITT Population who had baseline and M18 and M36 clamp test data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone + Metformin 4 mg/2 g/Day | Mean Change From Baseline in FBG at Month 36 | -1.6 millimoles per Liter (mmol/L) | Standard Deviation 1.9 |
| Gliclazide + Metformin 80 mg/2 g/Day | Mean Change From Baseline in FBG at Month 36 | -0.2 millimoles per Liter (mmol/L) | Standard Deviation 2.4 |
Secondary
Mean Change From Baseline in HbA1c at Month 36
Change from baseline was calculated as the Month 36 value minus the baseline value. HbA1c levels were measured by blood draw.
Time frame: Baseline and Month 36
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of study drug and had an available efficacy evaluation (hyperglycaemic clamp at M18 or M36). This measurement was conducted on participants in the ITT Population who had baseline and M18 and M36 clamp test data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone + Metformin 4 mg/2 g/Day | Mean Change From Baseline in HbA1c at Month 36 | -0.22 percent change | Standard Deviation 1.3 |
| Gliclazide + Metformin 80 mg/2 g/Day | Mean Change From Baseline in HbA1c at Month 36 | 0.3 percent change | Standard Deviation 1.2 |
Secondary
Mean Change From Baseline in Insulin Sensitivity Index at Months 18 and 36
Change from baseline was calculated as the Month 18 and 36 values minus the baseline value. Insulin sensitivity is measured as the quantity of glucose metabolized per unit of plasma insulin concentration.
Time frame: Baseline and Months 18 and 36
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosiglitazone + Metformin 4 mg/2 g/Day | Mean Change From Baseline in Insulin Sensitivity Index at Months 18 and 36 | Month 18 | -0.00511 micromoles (umol)/kilogram/min/pmol/L | Standard Deviation 0.03451 |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Mean Change From Baseline in Insulin Sensitivity Index at Months 18 and 36 | Month 36 | 0.00040 micromoles (umol)/kilogram/min/pmol/L | Standard Deviation 0.04722 |
| Gliclazide + Metformin 80 mg/2 g/Day | Mean Change From Baseline in Insulin Sensitivity Index at Months 18 and 36 | Month 18 | -0.02045 micromoles (umol)/kilogram/min/pmol/L | Standard Deviation 0.05302 |
| Gliclazide + Metformin 80 mg/2 g/Day | Mean Change From Baseline in Insulin Sensitivity Index at Months 18 and 36 | Month 36 | -0.01702 micromoles (umol)/kilogram/min/pmol/L | Standard Deviation 0.05109 |
Secondary
Median Change From Baseline in Beta Cell Function Index (HOMA-beta) After a 36-month Treatment
Time frame: Baseline and Month 36
Secondary
Median Change From Baseline in Insulin Resistance Index (HOMA-IR) After a 36-month Treatment
Time frame: Baseline and Month 36
Secondary
Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment
Change from baseline was calculated as the Month 18 value minus the baseline value. Insulin secretion capacity is measured in blood (blood level of insulin) and is a response of the pancreatic beta-cells to hyperglycemia induced by a glucose IV bolus, then infusion. Hyperglycemic clamp (HC) is a reference technique to evaluate the initial and the secondary phases of insulin secretion.
Time frame: Baseline and Month 18
Population: Intent-to-Treat (ITT) Population: participants receiving at least one dose of study drug with an available efficacy evaluation (HC at M18 or M36). The measurement was conducted on participants who had baseline and M18 and M36 HC test data available. Each HC was validated at both Baseline and Month 36, resulting in different ns for each category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Total AUC(10-180min), n=26, 30 | 55.9 pmol/L*min |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Arginine (Arg) test, Total AUC(0-30min), n=25, 25 | 38.4 pmol/L*min |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Incremental AUC(0-10min), n=27, 26 | 22.3 pmol/L*min |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Arg test, Incremental AUC(0-30min), n=25, 25 | 15.1 pmol/L*min |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Incremental AUC(10-180min), n=26, 29 | 72.9 pmol/L*min |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Arg test, Incremental Conc. peak(0-30 min),n=26,29 | 23.3 pmol/L*min |
| Rosiglitazone + Metformin 4 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Total AUC(0-10min), n=30, 31 | 18.3 pmol/L*min |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Arg test, Incremental Conc. peak(0-30 min),n=26,29 | -111.1 pmol/L*min |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Total AUC(0-10min), n=30, 31 | -32.3 pmol/L*min |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Incremental AUC(0-10min), n=27, 26 | 60.7 pmol/L*min |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Total AUC(10-180min), n=26, 30 | -7.6 pmol/L*min |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | HC, Incremental AUC(10-180min), n=26, 29 | 14.6 pmol/L*min |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Arginine (Arg) test, Total AUC(0-30min), n=25, 25 | 10.9 pmol/L*min |
| Gliclazide + Metformin 80 mg/2 g/Day | Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Arg test, Incremental AUC(0-30min), n=25, 25 | -8.0 pmol/L*min |
Secondary
Median Change From Baseline in the Ratio M/I After a 36-month Treatment
Time frame: Baseline and Month 36