Diabetes, Type 2 Diabetes Mellitus
Conditions
Brief summary
This trial is conducted in Asia. The aim of the trial is to compare efficacy and safety of thrice daily versus twice daily NovoMix® 30 (Biphasic insulin aspart 30) in subjects with type 2 diabetes inadequately controlled with basal insulin.
Interventions
DRUGbiphasic insulin aspart 30
Administered subcutaneously (s.c., under the skin) thrice daily or twice daily. Subjects will continue with metformin all throughout the trial.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, age at least 18 years at the time of signing informed consent. For Algeria only: age at least 19 years at the time of signing informed consent * Type 2 diabetes subjects clinically diagnosed for at least 12 months prior to the day of screening (Visit 1) * Treated with basal insulin for at least 90 days prior to the day of screening (Visit 1). The following basal insulin are allowed : insulin analogue once daily (OD) Neutral Protamine Hagedorn (NPH) OD or BID (twice daily) * Treatment with metformin with or without one additional OAD (oral antidiabetic drug) for at least 90 days prior to the day of screening (Visit 1) Metformin must be at a stable dose of at least 1500 mg daily or maximum tolerated dose for at least 60 days prior to screening (Visit 1) One additional OAD:Sulphonylurea/Glinides/ a-glucosidase inhibitors/Dipeptidyl-peptidase-4 inhibitors/Sodium glucose co-transporter 2 (SGLT2) inhibitors (if applicable) * HbA1c (glycosylated haemoglobin) 7.5%-10.0% (both inclusive) by central laboratory analysis at screening (Visit 1) * Able and willing to intake three main meals daily (breakfast, lunch and main evening meal) throughout the trial. Definition of main meal as judged by the investigator
Exclusion criteria
* Previous insulin intensification regimen for more than 14 days: premixed insulin thrice daily, basal-bolus regimen or continuous subcutaneous insulin infusion (CSII). Treatment during hospitalisation or during gestational diabetes is allowed for periods longer than 14 days * Anticipated initiation or change in concomitant medications for more than 14 consecutive days or on a frequent basis known to affect weight or glucose metabolism (e.g. orlistat, thyroid hormones, systemic corticosteroids) * Impaired liver function, defined as alanine aminotransferase (ALT) equal to or above 2.5 times upper normal limit at screening (Visit 1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) | Week 0, Week 24 | Change from baseline in HbA1c was evaluated after 24 weeks of treatment. Missing data was imputed using the last observation carried forward (LOCF) method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. | Week 24 | Percentage of subjects achieving HbA1c \<7.0% (yes or no) without severe hypoglycaemic episodes was evaluated after 24 weeks of treatment. Severe hypoglycaemia: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration. |
| Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) | Week 24 | Percentage of subjects achieving HbA1c \<7.0% (yes or no) without severe or BG confirmed hypoglycaemic episodes (according to the Novo Nordisk classification) was evaluated after 24 weeks of treatment. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose (PG) value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration. |
| Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Week 0-24 | ADA classification of hypoglycaemia: 1. Severe:Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration 2. Asymptomatic:Episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L 3. Documented symptomatic:Episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤3.9 mmol/L 4. Pseudo:Episode during which person with diabetes reports any of the typical symptoms of hypoglycaemia with measured PG concentration \>3.9 mmol/L but approaching that level 5. Probable symptomatic:Episode during which symptoms of hypoglycaemia are not accompanied by PG determination but that was presumably caused by a PG concentration ≤3.9 mmol/L |
| Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Week 0-24 | Treatment emergent hypoglycaemic episodes were defined as the hypoglycaemic episodes, which occurred on or after the first day of trial product administration (in week 0), and no later than 7 days after the last day on trial product. Novo Nordisk (NN) classification of hypoglycaemia: 1. Severe hypoglycaemia: According to the ADA classification. 2. Blood glucose (BG) confirmed hypoglycaemia: an episode that is BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 3. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. |
| Change From Baseline in FPG by Central Laboratory Analysis | Week 0, Week 24 | Change from baseline in fasting plasma glucose (FPG) by central laboratory analysis was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. |
| 7-point SMPG Profile | Week 24 | 7-point self-measured plasma glucose (SMPG) profiles was evaluated after 24 weeks of treatment. Subjects were instructed to perform the following SMPG measurements: 1. Before breakfast. 2. 120 minutes after the start of breakfast. 3. Before lunch. 4. 120 minutes after the start of lunch. 5. Before main evening meal. 6. 120 minutes after the start of main evening meal. 7. At bedtime. Missing data was imputed using the LOCF method. |
| 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Week 0, Week 24 | Change from baseline in 2-hour postprandial glucose (PPG) at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. |
| 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Week 0, Week 24 | Change from baseline in PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. |
| Proportion of Subjects Achieving HbA1c Below 7.0% | Week 24 | Percentage of subjects achieving HbA1c \<7.0% (yes or no) was evaluated after 24 weeks of treatment. |
| 7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | Week 0, Week 24 | Change from baseline in mean of PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. |
| 7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile | Week 0, Week 24 | Change from baseline in mean of the 7-point SMPG profiles was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. |
| 7-point SMPG Profiles: Fluctuation in the 7-point Profile | Week 24 | Fluctuation in the 7-point SMPG profile was evaluated after 24 weeks of treatment. Fluctuation in 7-point SMPG profile was the average absolute difference to the mean of the profile of the 7-point SMPG measurements accumulated over the profile. Missing data was imputed using the LOCF method. |
| Incidence of Treatment Emergent Adverse Events (TEAEs) | Week 0-24 | Incidence of TEAEs was recorded during 24 weeks of treatment. A TEAE was defined as an event that has onset date (or increase in severity) on or after the first day of exposure to trial product (in week 0) and no later than 7 days after the last day on trial product. |
| Total Daily Insulin Dose | Week 1, Week 24 | Total daily insulin dose was the sum of doses given before breakfast and before main evening meal for the BID treatment group, and the sum of doses given before breakfast, before lunch and before main evening meal for the TID treatment group. Missing data was imputed using the LOCF method. |
| Change From Baseline in Body Weight | Week 0, Week 24 | Change from baseline in body weight was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. |
| Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Week 0, Week 24 | Change from baseline in patient-reported treatment satisfaction (as assessed by the DTSQs) was evaluated after 24 weeks of treatment. The DTSQs is a self-completion questionnaire used to investigate the subject's treatment satisfaction. The DTSQ contained 8 questions, which were scored on a scale from 0 to 6. Out of 8 questions, 6 were related to the overall treatment satisfaction and 2 were related to glycaemic control (hypoglycaemia and hyperglycaemia). Results for the 6 questions relating to overall treatment satisfaction are presented together whereas the 2 questions relating to blood glucose are presented separately. For the overall treatment satisfaction, a higher score (0-36) was related to a better perception of treatment satisfaction. For hypoglycaemia and hyperglycaemia, a lower score (0-6) was related to a better blood glucose control. Missing data was imputed using the LOCF method. |
| 7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | Week 0, Week 24 | Change from baseline in mean of 2-hour PPG at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. |
Countries
Algeria, China, Hong Kong, India, Taiwan, Turkey (Türkiye), Ukraine
Participant flow
Recruitment details
A total of 50 sites were approved for recruiting subjects, of which 48 sites (in 2 regions) screened and randomized the subjects (China region, including mainland China, Hong Kong and Taiwan; non-China region, including other 4 countries) as follows: Algeria: 3; mainland China: 23; Hong Kong: 1; India: 8; Taiwan: 4; Turkey: 5; Ukraine: 4.
Participants by arm
| Arm | Count |
|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period. | 220 |
| Biphasic Insulin Aspart 30 (Twice Daily) Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period. | 217 |
| Total | 437 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Unclassified | 2 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 11 |
Baseline characteristics
| Characteristic | Biphasic Insulin Aspart 30 (Three Times Daily) | Biphasic Insulin Aspart 30 (Twice Daily) | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 9.8 | 56.6 years STANDARD_DEVIATION 9.3 | 56.8 years STANDARD_DEVIATION 9.5 |
| Body weight | 71.57 kg STANDARD_DEVIATION 13.38 | 72.24 kg STANDARD_DEVIATION 13.01 | 71.90 kg STANDARD_DEVIATION 13.19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 218 Participants | 217 Participants | 435 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fasting plasma glucose (FPG) | 8.68 mmol/L STANDARD_DEVIATION 2.68 | 8.72 mmol/L STANDARD_DEVIATION 2.39 | 8.70 mmol/L STANDARD_DEVIATION 2.54 |
| Glycosylated haemoglobin (HbA1c) | 8.74 Percentage of HbA1c STANDARD_DEVIATION 0.69 | 8.68 Percentage of HbA1c STANDARD_DEVIATION 0.69 | 8.71 Percentage of HbA1c STANDARD_DEVIATION 0.69 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 181 Participants | 170 Participants | 351 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 | 39 Participants | 47 Participants | 86 Participants |
| Sex: Female, Male Female | 112 Participants | 108 Participants | 220 Participants |
| Sex: Female, Male Male | 108 Participants | 109 Participants | 217 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 220 | 0 / 217 |
| other Total, other adverse events | 34 / 220 | 36 / 217 |
| serious Total, serious adverse events | 12 / 220 | 9 / 217 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c)
Change from baseline in HbA1c was evaluated after 24 weeks of treatment. Missing data was imputed using the last observation carried forward (LOCF) method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Change in Glycosylated Haemoglobin (HbA1c) | -1.66 Percentage (%) of HbA1c | Standard Deviation 1 |
| Biphasic Insulin Aspart 30 (Twice Daily) | Change in Glycosylated Haemoglobin (HbA1c) | -1.52 Percentage (%) of HbA1c | Standard Deviation 0.94 |
Comparison: The analysis was based on a mixed-effect model for repeated measures including changes from baseline in HbA1c at visit 6, 10, 14, 18, 22 and 26 (in week 4, 8, 12, 16, 20 and 24, respectively). The model included treatment, strata and region as fixed factors, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.p-value: 0.260195% CI: [-0.23, 0.06]Mixed model for repeated measurements
Secondary
7-point SMPG Profile
7-point self-measured plasma glucose (SMPG) profiles was evaluated after 24 weeks of treatment. Subjects were instructed to perform the following SMPG measurements: 1. Before breakfast. 2. 120 minutes after the start of breakfast. 3. Before lunch. 4. 120 minutes after the start of lunch. 5. Before main evening meal. 6. 120 minutes after the start of main evening meal. 7. At bedtime. Missing data was imputed using the LOCF method.
Time frame: Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profile | Before breakfast | 6.87 mmol/L | Standard Deviation 1.61 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profile | 120 minutes after start of breakfast | 9.33 mmol/L | Standard Deviation 3.14 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profile | Before lunch | 6.86 mmol/L | Standard Deviation 2.21 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profile | 120 minutes after start of lunch | 9.48 mmol/L | Standard Deviation 3.02 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profile | Before main evening meal | 7.26 mmol/L | Standard Deviation 2.08 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profile | 120 minutes after start of main evening meal | 8.77 mmol/L | Standard Deviation 3 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profile | At bedtime | 7.69 mmol/L | Standard Deviation 2.5 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profile | At bedtime | 8.24 mmol/L | Standard Deviation 3.15 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profile | Before breakfast | 6.86 mmol/L | Standard Deviation 1.71 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profile | Before main evening meal | 7.68 mmol/L | Standard Deviation 2.53 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profile | 120 minutes after start of breakfast | 9.04 mmol/L | Standard Deviation 3.2 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profile | Before lunch | 7.09 mmol/L | Standard Deviation 2.72 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profile | 120 minutes after start of main evening meal | 9.09 mmol/L | Standard Deviation 3.29 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profile | 120 minutes after start of lunch | 9.92 mmol/L | Standard Deviation 3.54 |
Secondary
7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal)
Change from baseline in 2-hour postprandial glucose (PPG) at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG breakfast | -4.17 mmol/L | Standard Deviation 4.84 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG lunch | -3.43 mmol/L | Standard Deviation 4.56 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG main evening meal | -4.38 mmol/L | Standard Deviation 4.44 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG breakfast | -4.03 mmol/L | Standard Deviation 4.22 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG lunch | -3.27 mmol/L | Standard Deviation 4.59 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG main evening meal | -4.09 mmol/L | Standard Deviation 4.71 |
Secondary
7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal)
Change from baseline in mean of 2-hour PPG at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | -3.98 mmol/L | Standard Deviation 3.59 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | -3.77 mmol/L | Standard Deviation 3.48 |
Secondary
7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal)
Change from baseline in mean of PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | -0.96 mmol/L | Standard Deviation 2.53 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | -1.22 mmol/L | Standard Deviation 2.68 |
Secondary
7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile
Change from baseline in mean of the 7-point SMPG profiles was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile | -3.58 mmol/L | Standard Deviation 3.08 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile | -3.27 mmol/L | Standard Deviation 2.84 |
Secondary
7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal)
Change from baseline in PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG increment breakfast | -2.06 mmol/L | Standard Deviation 4.44 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG increment lunch | -0.13 mmol/L | Standard Deviation 4.38 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG increment main evening meal | -0.64 mmol/L | Standard Deviation 4.55 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG increment lunch | -0.14 mmol/L | Standard Deviation 4.4 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG increment main evening meal | -1.60 mmol/L | Standard Deviation 4.72 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change in PPG increment breakfast | -2.02 mmol/L | Standard Deviation 3.95 |
Secondary
7-point SMPG Profiles: Fluctuation in the 7-point Profile
Fluctuation in the 7-point SMPG profile was evaluated after 24 weeks of treatment. Fluctuation in 7-point SMPG profile was the average absolute difference to the mean of the profile of the 7-point SMPG measurements accumulated over the profile. Missing data was imputed using the LOCF method.
Time frame: Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | 7-point SMPG Profiles: Fluctuation in the 7-point Profile | 1.04 mmol/L | Geometric Coefficient of Variation 54.04 |
| Biphasic Insulin Aspart 30 (Twice Daily) | 7-point SMPG Profiles: Fluctuation in the 7-point Profile | 1.05 mmol/L | Geometric Coefficient of Variation 54.39 |
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Change From Baseline in Body Weight | 1.45 Kilogram (kg) | Standard Deviation 3.11 |
| Biphasic Insulin Aspart 30 (Twice Daily) | Change From Baseline in Body Weight | 1.65 Kilogram (kg) | Standard Deviation 2.85 |
Secondary
Change From Baseline in FPG by Central Laboratory Analysis
Change from baseline in fasting plasma glucose (FPG) by central laboratory analysis was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Change From Baseline in FPG by Central Laboratory Analysis | -1.34 mmol/L | Standard Deviation 3.1 |
| Biphasic Insulin Aspart 30 (Twice Daily) | Change From Baseline in FPG by Central Laboratory Analysis | -1.07 mmol/L | Standard Deviation 2.64 |
Secondary
Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs)
Change from baseline in patient-reported treatment satisfaction (as assessed by the DTSQs) was evaluated after 24 weeks of treatment. The DTSQs is a self-completion questionnaire used to investigate the subject's treatment satisfaction. The DTSQ contained 8 questions, which were scored on a scale from 0 to 6. Out of 8 questions, 6 were related to the overall treatment satisfaction and 2 were related to glycaemic control (hypoglycaemia and hyperglycaemia). Results for the 6 questions relating to overall treatment satisfaction are presented together whereas the 2 questions relating to blood glucose are presented separately. For the overall treatment satisfaction, a higher score (0-36) was related to a better perception of treatment satisfaction. For hypoglycaemia and hyperglycaemia, a lower score (0-6) was related to a better blood glucose control. Missing data was imputed using the LOCF method.
Time frame: Week 0, Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Overall treatment satisfaction | 2 Score on a scale |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Hypoglycaemia | 0 Score on a scale |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Hyperglycaemia | -1 Score on a scale |
| Biphasic Insulin Aspart 30 (Twice Daily) | Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Overall treatment satisfaction | 4 Score on a scale |
| Biphasic Insulin Aspart 30 (Twice Daily) | Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Hypoglycaemia | 0 Score on a scale |
| Biphasic Insulin Aspart 30 (Twice Daily) | Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Hyperglycaemia | -1 Score on a scale |
Secondary
Incidence of Treatment Emergent Adverse Events (TEAEs)
Incidence of TEAEs was recorded during 24 weeks of treatment. A TEAE was defined as an event that has onset date (or increase in severity) on or after the first day of exposure to trial product (in week 0) and no later than 7 days after the last day on trial product.
Time frame: Week 0-24
Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30). Number analyzed = number of subjects with corresponding numbers of TEAEs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Incidence of Treatment Emergent Adverse Events (TEAEs) | 275 Number of adverse events |
| Biphasic Insulin Aspart 30 (Twice Daily) | Incidence of Treatment Emergent Adverse Events (TEAEs) | 251 Number of adverse events |
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition
Treatment emergent hypoglycaemic episodes were defined as the hypoglycaemic episodes, which occurred on or after the first day of trial product administration (in week 0), and no later than 7 days after the last day on trial product. Novo Nordisk (NN) classification of hypoglycaemia: 1. Severe hypoglycaemia: According to the ADA classification. 2. Blood glucose (BG) confirmed hypoglycaemia: an episode that is BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 3. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.
Time frame: Week 0-24
Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | BG confirmed | 249 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Severe or BG confirmed symptomatic | 195 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Severe or BG confirmed | 252 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | NN unclassifiable | 905 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Severe | 3 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | NN unclassifiable | 983 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Severe | 3 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | BG confirmed | 249 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Severe or BG confirmed | 252 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Severe or BG confirmed symptomatic | 223 Count of hypoglycaemic episodes |
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition
ADA classification of hypoglycaemia: 1. Severe:Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration 2. Asymptomatic:Episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L 3. Documented symptomatic:Episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤3.9 mmol/L 4. Pseudo:Episode during which person with diabetes reports any of the typical symptoms of hypoglycaemia with measured PG concentration \>3.9 mmol/L but approaching that level 5. Probable symptomatic:Episode during which symptoms of hypoglycaemia are not accompanied by PG determination but that was presumably caused by a PG concentration ≤3.9 mmol/L
Time frame: Week 0-24
Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30). Treatment emergent hypoglycaemic episodes were defined as the hypoglycaemic episodes, which occurred on or after the first day of trial product administration (in week 0), and no later than 7 days after the last day on trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Asymptomatic | 397 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Pseudo-hypoglycaemia | 54 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Documented symptomatic | 642 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Probable symptomatic | 61 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Severe | 3 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Probable symptomatic | 30 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Severe | 3 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Asymptomatic | 344 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Documented symptomatic | 765 Count of hypoglycaemic episodes |
| Biphasic Insulin Aspart 30 (Twice Daily) | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | Pseudo-hypoglycaemia | 93 Count of hypoglycaemic episodes |
Secondary
Proportion of Subjects Achieving HbA1c Below 7.0%
Percentage of subjects achieving HbA1c \<7.0% (yes or no) was evaluated after 24 weeks of treatment.
Time frame: Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% | No | 45.5 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% | Yes | 54.5 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Twice Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% | No | 52.5 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Twice Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% | Yes | 47.5 Percentage (%) of participants |
Secondary
Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes.
Percentage of subjects achieving HbA1c \<7.0% (yes or no) without severe hypoglycaemic episodes was evaluated after 24 weeks of treatment. Severe hypoglycaemia: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration.
Time frame: Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. | Yes | 50.0 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. | No | 50.0 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Twice Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. | Yes | 44.7 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Twice Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. | No | 55.3 Percentage (%) of participants |
Secondary
Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification)
Percentage of subjects achieving HbA1c \<7.0% (yes or no) without severe or BG confirmed hypoglycaemic episodes (according to the Novo Nordisk classification) was evaluated after 24 weeks of treatment. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose (PG) value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration.
Time frame: Week 24
Population: FAS included all randomised subjects who were dosed and had any post randomisation data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) | Yes | 27.3 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) | No | 72.7 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Twice Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) | No | 78.3 Percentage (%) of participants |
| Biphasic Insulin Aspart 30 (Twice Daily) | Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) | Yes | 21.7 Percentage (%) of participants |
Secondary
Total Daily Insulin Dose
Total daily insulin dose was the sum of doses given before breakfast and before main evening meal for the BID treatment group, and the sum of doses given before breakfast, before lunch and before main evening meal for the TID treatment group. Missing data was imputed using the LOCF method.
Time frame: Week 1, Week 24
Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30). Number analyzed = number of subjects contributed to the evaluation at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Biphasic Insulin Aspart 30 (Three Times Daily) | Total Daily Insulin Dose | Week 1 | 24.5 Units (U) | Standard Deviation 10 |
| Biphasic Insulin Aspart 30 (Three Times Daily) | Total Daily Insulin Dose | Week 24 | 67.4 Units (U) | Standard Deviation 35.5 |
| Biphasic Insulin Aspart 30 (Twice Daily) | Total Daily Insulin Dose | Week 1 | 24.2 Units (U) | Standard Deviation 13 |
| Biphasic Insulin Aspart 30 (Twice Daily) | Total Daily Insulin Dose | Week 24 | 63.4 Units (U) | Standard Deviation 33.1 |