Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of this clinical trial is to investigate the blood sugar lowering effect of biphasic insulin aspart 30 once daily compared to insulin glargine once daily both in combination with metformin and glimepiride in Chinese and Japanese subjects with type 2 diabetes who have never received insulin before. The trial is conducted as a phase 4 trial in China and phase 3 in Japan.
Interventions
DRUGbiphasic insulin aspart 30
Treat-to-target titration according to titration algorithm. Subcutaneous (under the skin) injection once daily.
DRUGmetformin
China: Tablets, 500 mg. Min. 1500 mg/day. Japan: Tablets, 250 mg. Min 500 mg/day.
DRUGglimepiride
China: Tablets, 2 mg. Min. 4 mg/day. Japan: Tablets, 1 mg. Min. 4 mg/day.
DRUGinsulin glargine
Treat-to-target titration according to titration algorithm. Subcutaneous (under the skin) injection once daily.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes treated with a maximum of three different types of oral anti-diabetic drugs (OADs) (including traditional Chinese medicine which contains active ingredients of known OADs) for more than 6 months * Unchanged total daily dose of at least 1500 mg (Chinese patients) or 500 mg (Japanese patients) metformin for the last two months * Unchanged total daily dose of at least half maximum recommended total daily dose of any insulin secretagogue for the last two months * Insulin naive * HbA1c between 7.0% and 10.0% * FPG (fasting plasma glucose) equal to or above 6.1 mmol/L (110mg/dL) * Body Mass Index (BMI) below 40.0 kg/m\^2
Exclusion criteria
* Treatment with any thiazolidinedione (TZD) and GLP-1 (glucagon like peptide-1) receptor antagonists during the last 3 months before Visit 1 in this trial * Any disease or condition which the Investigator feels would interfere with the trial * Any contraindication to metformin or glimepiride (according to local labelling)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) | Week 0, week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving HbA1c Below 7.0% | Week 24 | The percentage of subjects achieving the treatment target for glycosylated haemoglobin A1c after 24 weeks of treatment |
| Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | Week 24 | The percentage of subjects achieving the treatment target for glycosylated haemoglobin A1c after 24 weeks of treatment |
| 9-point Plasma Glucose Profiles | Week 24 | Glycaemic control measured by 9-point plasma glucose (SPMG) profiles. The 9 timepoints for self-measurement during the day were: before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, before bedtime, at 2-4 a.m. and before breakfast the following day. |
| Number of Hypoglycaemic Episodes - Severe and Minor | Weeks 0-24 | Hypoglycaemic episodes (hypos) summarised based on American Diabetes Association classification (severe, documented symptomatic, asymptomatic, probable symptomatic, and relative hypoglycaemia) and according to additional definition (minor hypoglycaemia). Severe hypos: requiring another person to actively administer resuscitative actions. Minor hypos: symptoms with plasma glucose below 3.1 mmol/L (56 mg/dl), or any asympomatic plasma glucose below 3.1 mmol/L. |
| Number of Hypoglycaemic Episodes | Weeks 0-24 | All episodes classified into nocturnal (time of onset between 00:00 (included) and 05:59 (included)). |
| Number of Hypoglycaemic Episodes - All | Weeks 0-24 | — |
Countries
China, Japan
Participant flow
Recruitment details
The trial was conducted at 35 sites in two countries: China (21 sites) and Japan (14 sites).
Pre-assignment details
At the screening, eligible subjects entered the run-in period before being randomised. During the 3 week run-in period, subjects switched from insulin secretagogue to glimepiride. During the last 2 weeks, the total dose of glimepiride was kept at 4mg/day. Subjects continued their pre-trial metformin dose.
Participants by arm
| Arm | Count |
|---|---|
| BIAsp 30 0.1-0.2 U/kg (starting dose) administered once daily (OD) immediately before dinner in combination with at least 1500 mg (Chinese patients) or 500 mg (Japanese patients) total daily dose of metformin and at least 4 mg glimepiride | 261 |
| Insulin Glargine 0.1-0.2U/kg (starting dose) administered once daily (OD) at bedtime in combination with at least 1500 mg (Chinese patients) or 500 mg (Japanese patients) total daily dose of metformin and at least 4 mg glimepiride | 260 |
| Total | 521 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 6 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 6 | 6 |
| Overall Study | Unclassified | 6 | 7 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Total | Insulin Glargine | BIAsp 30 |
|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 9.6 | 56.1 years STANDARD_DEVIATION 9.9 | 56.6 years STANDARD_DEVIATION 9.4 |
| Body Mass Index (BMI) | 25.65 kg/m^2 STANDARD_DEVIATION 3.41 | 25.76 kg/m^2 STANDARD_DEVIATION 3.44 | 25.53 kg/m^2 STANDARD_DEVIATION 3.39 |
| Diabetic complications at baseline No | 374 participants | 185 participants | 189 participants |
| Diabetic complications at baseline Yes | 147 participants | 75 participants | 72 participants |
| Duration of diabetes | 9.35 years STANDARD_DEVIATION 6.88 | 9.47 years STANDARD_DEVIATION 6.61 | 9.23 years STANDARD_DEVIATION 7.15 |
| Gender Female | 233 Participants | 119 Participants | 114 Participants |
| Gender Male | 288 Participants | 141 Participants | 147 Participants |
| HbA1c (glycosylated haemoglobin) at randomisation | 8.15 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.87 | 8.14 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.86 | 8.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.88 |
| Height | 165.3 cm STANDARD_DEVIATION 8.4 | 165.2 cm STANDARD_DEVIATION 8.2 | 165.3 cm STANDARD_DEVIATION 8.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 521 Participants | 260 Participants | 261 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 422 participants | 212 participants | 210 participants |
| Region of Enrollment Japan | 99 participants | 48 participants | 51 participants |
| Weight | 70.3 kg STANDARD_DEVIATION 12.1 | 70.6 kg STANDARD_DEVIATION 12.5 | 70.0 kg STANDARD_DEVIATION 11.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 261 | 28 / 260 |
| serious Total, serious adverse events | 2 / 261 | 5 / 260 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c)
Time frame: Week 0, week 24
Population: Full analysis set using LOCF (last observation carried forward) consists of all randomised subjects who were exposed to at least one dose of trial product(s)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in Glycosylated Haemoglobin (HbA1c) | -0.68 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Insulin Glargine | Change in Glycosylated Haemoglobin (HbA1c) | -0.56 percentage of glycosylated haemoglobin | Standard Error 0.06 |
Comparison: H0: The mean treatment difference (BIAsp 30 minus insulin glargine) \> 0.4%. HA: The mean treatment difference (BIAsp 30 minus insulin glargine) =\< 0.4%. Sample size was calculated to achieve a power of at least 90%, assuming an equal change in HbA1c and a common standard deviation of 1.25%p-value: <0.00195% CI: [-0.25, 0.02]ANCOVA
Secondary
9-point Plasma Glucose Profiles
Glycaemic control measured by 9-point plasma glucose (SPMG) profiles. The 9 timepoints for self-measurement during the day were: before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, before bedtime, at 2-4 a.m. and before breakfast the following day.
Time frame: Week 24
Population: Full analysis set using LOCF (last observation carried forward) consists of all randomised subjects who were exposed to at least one dose of the trial product(s).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | 9-point Plasma Glucose Profiles | At 2-4 a.m. | 6.58 mmol/L | Standard Error 0.13 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | 2 hours after lunch | 10.50 mmol/L | Standard Error 0.2 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | 2 hours after breakfast | 10.18 mmol/L | Standard Error 0.19 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | Before dinner | 7.67 mmol/L | Standard Error 0.16 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | Before breakfast | 6.46 mmol/L | Standard Error 0.09 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | 2 hours after dinner | 9.36 mmol/L | Standard Error 0.19 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | Before lunch | 7.35 mmol/L | Standard Error 0.17 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | Before bedtime | 8.14 mmol/L | Standard Error 0.18 |
| BIAsp 30 | 9-point Plasma Glucose Profiles | Before breakfast the following day | 6.51 mmol/L | Standard Error 0.1 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | Before lunch | 7.22 mmol/L | Standard Error 0.17 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | At 2-4 a.m. | 7.06 mmol/L | Standard Error 0.13 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | Before breakfast the following day | 6.35 mmol/L | Standard Error 0.1 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | Before breakfast | 6.49 mmol/L | Standard Error 0.09 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | 2 hours after breakfast | 10.11 mmol/L | Standard Error 0.19 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | Before bedtime | 9.39 mmol/L | Standard Error 0.18 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | 2 hours after lunch | 10.22 mmol/L | Standard Error 0.2 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | Before dinner | 7.03 mmol/L | Standard Error 0.16 |
| Insulin Glargine | 9-point Plasma Glucose Profiles | 2 hours after dinner | 10.88 mmol/L | Standard Error 0.19 |
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-0.24, 0.19]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-0.45, 0.58]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-0.31, 0.58]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-0.26, 0.82]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [0.22, 1.06]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-2.03, -1]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-1.73, -0.78]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-0.81, -0.13]Mixed Models Analysis
Comparison: Repeated measures mixed model with an unstructured residual covarience matrix, including treatment, time, the treatment-by-time interaction, country and previous OADs as factors.p-value: <0.00195% CI: [-0.06, 0.4]Mixed Models Analysis
Secondary
Number of Hypoglycaemic Episodes
All episodes classified into nocturnal (time of onset between 00:00 (included) and 05:59 (included)).
Time frame: Weeks 0-24
Population: The safety analysis set contains all subjects exposed to at least one dose of investigational product(s).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIAsp 30 | Number of Hypoglycaemic Episodes | 97 episodes |
| Insulin Glargine | Number of Hypoglycaemic Episodes | 63 episodes |
Secondary
Number of Hypoglycaemic Episodes - All
Time frame: Weeks 0-24
Population: The safety analysis set contains all subjects exposed to at least one dose of investigational product(s).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIAsp 30 | Number of Hypoglycaemic Episodes - All | 745 episodes |
| Insulin Glargine | Number of Hypoglycaemic Episodes - All | 605 episodes |
Secondary
Number of Hypoglycaemic Episodes - Severe and Minor
Hypoglycaemic episodes (hypos) summarised based on American Diabetes Association classification (severe, documented symptomatic, asymptomatic, probable symptomatic, and relative hypoglycaemia) and according to additional definition (minor hypoglycaemia). Severe hypos: requiring another person to actively administer resuscitative actions. Minor hypos: symptoms with plasma glucose below 3.1 mmol/L (56 mg/dl), or any asympomatic plasma glucose below 3.1 mmol/L.
Time frame: Weeks 0-24
Population: The safety analysis set contains all subjects exposed to at least one dose of investigational product(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 30 | Number of Hypoglycaemic Episodes - Severe and Minor | Severe | 0 episodes |
| BIAsp 30 | Number of Hypoglycaemic Episodes - Severe and Minor | Minor | 154 episodes |
| Insulin Glargine | Number of Hypoglycaemic Episodes - Severe and Minor | Severe | 1 episodes |
| Insulin Glargine | Number of Hypoglycaemic Episodes - Severe and Minor | Minor | 125 episodes |
Secondary
Percentage of Subjects Achieving HbA1c Below 7.0%
The percentage of subjects achieving the treatment target for glycosylated haemoglobin A1c after 24 weeks of treatment
Time frame: Week 24
Population: Full analysis set using LOCF (last observation carried forward) consists of all randomised subjects who were exposed to at least one dose of the trial product(s).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIAsp 30 | Percentage of Subjects Achieving HbA1c Below 7.0% | 29.1 percentage (%) of subjects |
| Insulin Glargine | Percentage of Subjects Achieving HbA1c Below 7.0% | 30.0 percentage (%) of subjects |
Comparison: The responder analysis was based on logistic regression model using treatment, country and previous OAD therapy (with or without a third OAD) as factors and baseline HbA1c as covariate.p-value: 0.858395% CI: [0.64, 1.46]Regression, Logistic
Secondary
Percentage of Subjects Achieving HbA1c Below or Equal to 6.5%
The percentage of subjects achieving the treatment target for glycosylated haemoglobin A1c after 24 weeks of treatment
Time frame: Week 24
Population: Full analysis set using LOCF (last observation carried forward) consists of all randomised subjects who were exposed to at least one dose of the trial product(s).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIAsp 30 | Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | 14.9 percentage (%) of subjects |
| Insulin Glargine | Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | 14.2 percentage (%) of subjects |
Comparison: The responder analysis was based on logistic regression model using treatment, country and previous OAD therapy (with or without a third OAD) as factors and baseline HbA1c as covariate.p-value: 0.801395% CI: [0.64, 1.79]Regression, Logistic