Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of the trial is to compare the effect on glycaemic control of biphasic insulin aspart 30 twice daily with two different dosage split regimens for Chinese subjects with type 2 diabetes who did not achieve the treatment target of a glycosylated haemoglobin A1c (HbA1c) below 7% in trial BIASP-3756 (NCT01123980).
Interventions
DRUGbiphasic insulin aspart 30
Administered subcutaneously (under the skin), twice daily with a dosage of 2/3 and 1/3 total daily dose before breakfast and before dinner, in combination with metformin.
DRUGmetformin
Tablets 500 mg administered orally with meals. Pre-trial dose and regimen unchanged
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Finalised 24 weeks of treatment with once daily BIAsp 30 or insulin glargine in combination with metformin and glimepiride in trial BIAsp-3756 * HbA1c above or equal to 7.0% * Body Mass Index (BMI) below or equal to 40.0 kg/m2
Exclusion criteria
* Known hypoglycaemia unawareness or recurrent major hypoglycaemic episodes in trial BIAsp-3756 * Known proliferative retinopathy or maculopathy requiring acute treatment * Any disease or condition which the Investigator (trial physician) feels would interfere with the trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Glycosylated Haemoglobin A1c (HbA1c) From Baseline | Week 0, week 16 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 9-point SMPG (Self Measured Plasma Glucose) Profile | Week 16 | A 9-point SMPG profile included measurements before and 120 minutes after start of breakfast, lunch and main evening meal, measurements prior to bedtime and at 2:00 -4:00 a.m., and one before breakfast the following day |
| Percentage of Subjects Achieving HbA1c Below 7.0% | Week 16 | The percentage of subjects achieving the treatment target for glycosylated haemoglobin A1c (HbA1c) after 16 weeks of treatment |
| Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | Week 16 | The percentage of subjects achieving the treatment target for glycosylated haemoglobin A1c (HbA1c) after 16 weeks of treatment |
| Number of Treatment Emergent Hypoglycaemic Episodes | Weeks 0-16 | Treatment emergent hypoglycaemic episodes (hypos): those that happened between treatment and one day after last drug day. Hypos summarised based on American Diabetes Association classification. Severe hypos: episodes requiring another person to actively administer resuscitative actions. Minor hypos: episodes with symptoms with plasma glucose below 3.1 mmol/L (56 mg/dL) handled by the subject, or any asymptomatic plasma glucose below 3.1 mmol/L (56 mg/dL). Diurnal period: between 06:00 and 23:59 (both included). Nocturnal period: between 00:00 and 05:59 a.m. (both included). |
Countries
China
Participant flow
Recruitment details
This trial was conducted at 20 sites in China.
Pre-assignment details
All subjects who completed the 24 week treatment and did not achieve the target of glycosylated haemoglobin A1c (HbA1c) below 7% in trial BIAsp-3756 (NCT01123980) were offered the possibility to go into BIAsp-3883. Subjects continued their previous treatment unchanged from trial BIASP-3756 and throughout the one-week screening period.
Participants by arm
| Arm | Count |
|---|---|
| BIAsp 30 (2:1) After discontinuation of previous treatment of once daily biphasic insulin aspart 30 (BIAsp 30) or insulin glargine combined with metformin and glimepiride in trial BIAsp-3756, subjects were adminstered BIAsp 30 twice daily with initial dosage split regimen of 2/3 and 1/3 total daily dose before breakfast and before dinner, respectively combined with metformin administered orally with meals | 89 |
| BIAsp 30 (1:1) After discontinuation of previous treatment of once daily biphasic insulin aspart 30 (BIAsp 30) or insulin glargine combined with metformin and glimepiride in trial BIAsp-3756, subjects were adminstered BIAsp 30 twice daily with initial dosage split regimen of 1/2 and 1/2 total daily dose before breakfast and before dinner, respectively combined with metformin administered orally with meals | 90 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Unclassified | 1 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | BIAsp 30 (2:1) | BIAsp 30 (1:1) | Total |
|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 9.9 | 57.1 years STANDARD_DEVIATION 9.4 | 56.1 years STANDARD_DEVIATION 9.7 |
| Body mass index (BMI) | 26.40 kg/m^2 STANDARD_DEVIATION 3.44 | 26.36 kg/m^2 STANDARD_DEVIATION 3.28 | 26.38 kg/m^2 STANDARD_DEVIATION 3.35 |
| Diabetic complications Missing data | 4 participants | 1 participants | 5 participants |
| Diabetic complications No | 69 participants | 67 participants | 136 participants |
| Diabetic complications Yes | 16 participants | 22 participants | 38 participants |
| Duration of diabetes | 9.08 years STANDARD_DEVIATION 6.05 | 10.23 years STANDARD_DEVIATION 5.89 | 9.65 years STANDARD_DEVIATION 5.98 |
| Glycosylated haemoglobin (HbA1c) at screening | 7.80 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.65 | 7.80 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.73 | 7.80 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.69 |
| Height | 165.2 cm STANDARD_DEVIATION 7.4 | 165.3 cm STANDARD_DEVIATION 8.4 | 165.3 cm STANDARD_DEVIATION 7.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 89 Participants | 90 Participants | 179 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 | 89 participants | 90 participants | 179 participants |
| Sex: Female, Male Female | 47 Participants | 48 Participants | 95 Participants |
| Sex: Female, Male Male | 42 Participants | 42 Participants | 84 Participants |
| Weight | 72.2 kg STANDARD_DEVIATION 11.1 | 72.3 kg STANDARD_DEVIATION 11.6 | 72.2 kg STANDARD_DEVIATION 11.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 89 | 0 / 90 |
| serious Total, serious adverse events | 1 / 89 | 2 / 90 |
Outcome results
Primary
Change in Glycosylated Haemoglobin A1c (HbA1c) From Baseline
Time frame: Week 0, week 16
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). Six patients discontinued trial without any post randomisation HbA1c measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 (2:1) | Change in Glycosylated Haemoglobin A1c (HbA1c) From Baseline | -0.13 percentage of glycosylated haemoglobin | Standard Deviation 0.08 |
| BIAsp 30 (1:1) | Change in Glycosylated Haemoglobin A1c (HbA1c) From Baseline | -0.12 percentage of glycosylated haemoglobin | Standard Deviation 0.08 |
Comparison: The null hypothesis is H0: μBIAsp 30 (2:1) - μBIAsp 30 (1:1) = 0 against the alternative hypothesis HA: μBIAsp 30 (2:1) - μBIAsp 30 (1:1) ≠ 0. This trial is an extension to BIAsp-3756 (NCT01123980), hence no particular sample size calculation was made.95% CI: [-0.24, 0.22]ANCOVA
Secondary
9-point SMPG (Self Measured Plasma Glucose) Profile
A 9-point SMPG profile included measurements before and 120 minutes after start of breakfast, lunch and main evening meal, measurements prior to bedtime and at 2:00 -4:00 a.m., and one before breakfast the following day
Time frame: Week 16
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 (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2 hours after breakfast | 8.56 mmol/L | Standard Error 2.28 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2 hours after dinner | 7.92 mmol/L | Standard Error 2.34 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2 hours after lunch | 8.91 mmol/L | Standard Error 2.59 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Bedtime | 7.29 mmol/L | Standard Error 1.99 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before lunch | 6.42 mmol/L | Standard Error 1.62 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2:00 - 4:00 a.m. | 6.05 mmol/L | Standard Error 1.53 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before dinner | 6.64 mmol/L | Standard Error 1.95 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before breakfast the following day | 6.30 mmol/L | Standard Error 1.38 |
| BIAsp 30 (2:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before breakfast | 6.02 mmol/L | Standard Error 1.09 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before breakfast the following day | 6.22 mmol/L | Standard Error 1.4 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before breakfast | 6.23 mmol/L | Standard Error 1.23 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2 hours after breakfast | 8.61 mmol/L | Standard Error 2.41 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before lunch | 6.79 mmol/L | Standard Error 2.49 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2 hours after lunch | 9.17 mmol/L | Standard Error 2.7 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Before dinner | 7.07 mmol/L | Standard Error 2.07 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2 hours after dinner | 7.94 mmol/L | Standard Error 1.98 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | Bedtime | 7.03 mmol/L | Standard Error 1.91 |
| BIAsp 30 (1:1) | 9-point SMPG (Self Measured Plasma Glucose) Profile | 2:00 - 4:00 a.m. | 6.34 mmol/L | Standard Error 1.65 |
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp 30 OD/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.256995% CI: [-0.15, 0.56]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.81295% CI: [-0.63, 0.8]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.284395% CI: [-0.29, 0.99]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.461495% CI: [-0.5, 1.11]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.159195% CI: [-0.17, 1.04]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.932795% CI: [-0.63, 0.69]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.406395% CI: [-0.84, 0.34]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.219895% CI: [-0.18, 0.79]Mixed Models Analysis
Comparison: A mixed effect model was fitted to the 9-point SMPG profile data. The model included treatment, time, interaction between treatment and time and previous therapy (BIAsp-30 once daily (OD)/insulin glargine OD) as factors and subject as random effect. From the model, mean profile by treatment and relevant treatment differences was estimated and explored.p-value: 0.842495% CI: [-0.47, 0.38]Mixed Models Analysis
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes
Treatment emergent hypoglycaemic episodes (hypos): those that happened between treatment and one day after last drug day. Hypos summarised based on American Diabetes Association classification. Severe hypos: episodes requiring another person to actively administer resuscitative actions. Minor hypos: episodes with symptoms with plasma glucose below 3.1 mmol/L (56 mg/dL) handled by the subject, or any asymptomatic plasma glucose below 3.1 mmol/L (56 mg/dL). Diurnal period: between 06:00 and 23:59 (both included). Nocturnal period: between 00:00 and 05:59 a.m. (both included).
Time frame: Weeks 0-16
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 (NUMBER) |
|---|---|---|---|
| BIAsp 30 (2:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Diurnal | 84 episodes |
| BIAsp 30 (2:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Nocturnal | 18 episodes |
| BIAsp 30 (2:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Severe | 0 episodes |
| BIAsp 30 (2:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Minor | 20 episodes |
| BIAsp 30 (2:1) | Number of Treatment Emergent Hypoglycaemic Episodes | All episodes | 108 episodes |
| BIAsp 30 (1:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Minor | 35 episodes |
| BIAsp 30 (1:1) | Number of Treatment Emergent Hypoglycaemic Episodes | All episodes | 143 episodes |
| BIAsp 30 (1:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Nocturnal | 11 episodes |
| BIAsp 30 (1:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Diurnal | 127 episodes |
| BIAsp 30 (1:1) | Number of Treatment Emergent Hypoglycaemic Episodes | Severe | 0 episodes |
Comparison: The number of hypos was analysed using a negative binomial regression model with a log-link function and the logarithm of the time period in which a hypo is considered emergent as offset. The model included treatment and previous therapy (BIAsp 30 OD/insulin glargine OD) as factors. The rate ratio was estimated and 95% confidence intervals were calculated accordingly.p-value: 0.191195% CI: [0.43, 1.18]Negative binomial regression model
Comparison: The number of hypos was analysed using a negative binomial regression model with a log-link function and the logarithm of the time period in which a hypo is considered emergent as offset. The model included treatment and previous therapy (BIAsp 30 OD/insulin glargine OD) as factors. The rate ratio was estimated and 95% confidence intervals were calculated accordingly.p-value: 0.294995% CI: [0.66, 3.92]Negative binomial regression model
Comparison: The number of hypos was analysed using a negative binomial regression model with a log-link function and the logarithm of the time period in which a hypo is considered emergent as offset. The model included treatment and previous therapy (BIAsp 30 OD/insulin glargine OD) as factors. The rate ratio was estimated and 95% confidence intervals were calculated accordingly.p-value: 0.07795% CI: [0.38, 1.05]Negative binomial regression model
Comparison: The number of hypos was analysed using a negative binomial regression model with a log-link function and the logarithm of the time period in which a hypo is considered emergent as offset. The model included treatment and previous therapy (BIAsp 30 OD/insulin glargine OD) as factors. The rate ratio was estimated and 95% confidence intervals were calculated accordingly.p-value: 0.168795% CI: [0.25, 1.27]Negative binomial regression model
Secondary
Percentage of Subjects Achieving HbA1c Below 7.0%
The percentage of subjects achieving the treatment target for glycosylated haemoglobin A1c (HbA1c) after 16 weeks of treatment
Time frame: Week 16
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 (2:1) | Percentage of Subjects Achieving HbA1c Below 7.0% | 12.4 percentage of subjects |
| BIAsp 30 (1:1) | Percentage of Subjects Achieving HbA1c Below 7.0% | 14.4 percentage of subjects |
Comparison: Responder analyses were based on logistics regression model using treatment and previous therapy (BIAsp 30 OD or insulin glargine OD) as factors and baseline HbA1c as covariate.p-value: 0.731295% CI: [0.36, 2.06]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 (HbA1c) after 16 weeks of treatment
Time frame: Week 16
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 (2:1) | Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | 2.2 percentage of subjects |
| BIAsp 30 (1:1) | Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | 7.8 percentage of subjects |
Comparison: Responder analyses were based on logistics regression model using treatment and previous therapy (BIAsp 30 OD or insulin glargine OD) as factors and baseline HbA1c as covariate.p-value: 0.125795% CI: [0.05, 1.44]Regression, Logistic