Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of the trial is to investigate the efficacy and safety of biphasic insulin aspart 50 (BIAsp 50) twice daily versus biphasic human insulin 50 (BHI 50) twice daily, both in combination with metformin, in Chinese subjects with type 2 diabetes mellitus.
Interventions
Administered subcutaneously (s.c., under the skin) twice daily (BID). Dose individually adjusted. All subjects will receive metformin in combination with trial insulin.
Administered subcutaneously (s.c., under the skin) twice daily (BID). Dose individually adjusted. All subjects will receive metformin in combination with trial insulin.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus (diagnosed clinically) for at least 12 months * Currently treated with premixed human insulin 50 BID for at least 3 months prior to screening visit (Visit 1) * Currently treated with unchanged total daily dose of at least 1500 mg metformin or maximum tolerated dose at least 1000 mg/day metformin for at least 2 months prior to screening visit * Glycosylated haemoglobin (HbA1c) 7.0% and 9.0% (both inclusive) (central laboratory)
Exclusion criteria
* Treatment with any insulin secretagogue, alfa-glucosidase inhibitors, thiazolidinedione (TZD), dipeptidyl peptidase-4 (DPP-4) inhibitors and Glucagon-like peptide-1 (GLP-1) receptor agonists within the last 3 months prior to screening * Previous use of any insulin other than premixed human insulin 50 BID within 3 months prior to Visit 1 * Previous use of insulin intensification treatment (premixed insulin thrice daily, basal bolus regimen, and continuous subcutaneous insulin infusion (CSII)) for more than 14 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-hour PPG (Postprandial Plasma Glucose) Increment Following a Standard Meal Test | After 4 weeks of treatment in each treatment sequence | The 2-hour PPG increment is the difference between the plasma glucose (PG) value at 120 minutes after standard meal test and the fasting PG value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| -IAUC (Incremental Area Under the Curve) for PPG (0-2 Hours) Following a Standard Meal Test | After 4 weeks of treatment in each treatment sequence | AUC for plasma glucose was calculated by the trapezoidal method using 30-min sampling time points, and IAUC for PPG (0-2h) data was analyzed using a normal linear mixed model. |
| 2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile | After 4 weeks of treatment in each treatment sequence | PPG increments over each of the 3 main meals were derived from the 8-point SMPG profile as the difference between PG values available 120 minutes after meal and before meal. |
| -1-hour PPG Increment Following a Standard Meal Test | After 4 weeks of treatment in each treatment sequence | The 1-h PPG increment is the difference between the plasma glucose (PG) value at 60 minutes after standard meal test and the fasting PG value. |
| Incidence of Hypoglycemic Episodes | During 4 weeks of treatment in each treatment sequence | Treatment Emergent Hypoglycemic Episode refers to those the onset of the episode is on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment. Results are presented by American Diabetes Association classification of hypoglycemia. |
| Incidence of AEs (Adverse Event) | During 4 weeks of treatment in each treatment sequence | Treatment emergent AE (TEAE) is defined as an event that has onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment. |
| The Mean 2-hour PPG Increments of the 3 Main Meals in 8-point SMPG Profile | After 4 weeks of treatment in each treatment sequence | Mean post prandial PG increment over all meals was derived as the mean of all available meal increments. |
Countries
China
Participant flow
Recruitment details
This trial was conducted in 14 sites in one country (China).
Pre-assignment details
There were no significant events following enrolment of subjects, and prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects In this multi-center, randomized, open-labelled, 2-sequence, 2-period crossover trial, the eligible subjects were randomized to 2 groups to receive biphasic insulin aspart 50 (BIAsp 50) and biphasic human insulin 50 (BHI 50) in different sequences. Group A received BIAsp 50 twice daily (BID) during the first 4 weeks (period 1), then switched to BHI 50 BID for further 4 weeks (period 2). Group B received BHI 50 BID during the first 4 weeks (period 1), then switched to BIAsp 50 BID for further 4 weeks (period 2). BIAsp 50 (NovoMix® 50) was administered subcutaneously (s.c.) using NovoPen 4 immediately before breakfast and dinner. And BHI 50 was administered s.c. using NovoPen 4 at least 30 minutes before breakfast and dinner. All subjects received metformin throughout this trial. Insulin dose was adjusted twice weekly based on self-measured plasma glucose (SMPG). | 161 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 1 |
| Period 1 | Protocol Violation | 2 | 4 |
| Period 1 | Unclassified | 0 | 1 |
| Period 2 | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 88 Participants |
| Sex: Female, Male Male | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 155 | 2 / 158 |
| serious Total, serious adverse events | 1 / 155 | 1 / 158 |
Outcome results
Primary
2-hour PPG (Postprandial Plasma Glucose) Increment Following a Standard Meal Test
The 2-hour PPG increment is the difference between the plasma glucose (PG) value at 120 minutes after standard meal test and the fasting PG value.
Time frame: After 4 weeks of treatment in each treatment sequence
Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Three (3) subjects in BIAsp 50 group and 9 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 50 | 2-hour PPG (Postprandial Plasma Glucose) Increment Following a Standard Meal Test | 5.30 mmol/L | Standard Deviation 3.17 |
| BHI 50 | 2-hour PPG (Postprandial Plasma Glucose) Increment Following a Standard Meal Test | 6.41 mmol/L | Standard Deviation 2.83 |
Comparison: Let D be the treatment difference (BIAsp 50 BID + metformin minus BHI 50 BID + metformin) of 2-h PPG increment after a 4-week treatment. The null hypothesis was D = 0 mmol/L. The alternative hypothesis was D ≠ 0 mmol/L. Sample size was determined using a two-sided one sample t-test at a = 0.05 under the assumption of 0.8 mmol/L mean treatment different and 80% power.p-value: <0.00195% CI: [-1.66, -0.58]Mixed Models Analysis
Secondary
-1-hour PPG Increment Following a Standard Meal Test
The 1-h PPG increment is the difference between the plasma glucose (PG) value at 60 minutes after standard meal test and the fasting PG value.
Time frame: After 4 weeks of treatment in each treatment sequence
Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Three (3) subjects in BIAsp 50 group and 8 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 50 | -1-hour PPG Increment Following a Standard Meal Test | 4.42 mmol/L | Standard Deviation 2.49 |
| BHI 50 | -1-hour PPG Increment Following a Standard Meal Test | 4.74 mmol/L | Standard Deviation 2.24 |
Secondary
2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile
PPG increments over each of the 3 main meals were derived from the 8-point SMPG profile as the difference between PG values available 120 minutes after meal and before meal.
Time frame: After 4 weeks of treatment in each treatment sequence
Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Subjects were excluded from analysis due to lack of post-randomization measurements. See table.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 50 | 2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile | Increment at breakfast, N=151, 149 | 2.52 mmol/L | Standard Error 0.2 |
| BIAsp 50 | 2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile | Increment at Lunch, N=150, 148 | 3.58 mmol/L | Standard Error 0.26 |
| BIAsp 50 | 2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile | Increment at dinner, N=151, 149 | 1.08 mmol/L | Standard Error 0.26 |
| BHI 50 | 2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile | Increment at breakfast, N=151, 149 | 2.86 mmol/L | Standard Error 0.2 |
| BHI 50 | 2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile | Increment at Lunch, N=150, 148 | 2.93 mmol/L | Standard Error 0.26 |
| BHI 50 | 2-hour PPG Increments Over Each of the 3 Main Meals in 8-point SMPG (Self-measured Plasma Glucose) Profile | Increment at dinner, N=151, 149 | 0.99 mmol/L | Standard Error 0.26 |
Secondary
-IAUC (Incremental Area Under the Curve) for PPG (0-2 Hours) Following a Standard Meal Test
AUC for plasma glucose was calculated by the trapezoidal method using 30-min sampling time points, and IAUC for PPG (0-2h) data was analyzed using a normal linear mixed model.
Time frame: After 4 weeks of treatment in each treatment sequence
Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Three (3) subjects in BIAsp 50 group and 9 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 50 | -IAUC (Incremental Area Under the Curve) for PPG (0-2 Hours) Following a Standard Meal Test | 465.39 min*mmol/L | Standard Deviation 228 |
| BHI 50 | -IAUC (Incremental Area Under the Curve) for PPG (0-2 Hours) Following a Standard Meal Test | 503.64 min*mmol/L | Standard Deviation 215 |
Secondary
Incidence of AEs (Adverse Event)
Treatment emergent AE (TEAE) is defined as an event that has onset date on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment.
Time frame: During 4 weeks of treatment in each treatment sequence
Population: Safety analysis set included all subjects receiving at least one dose of investigational products.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIAsp 50 | Incidence of AEs (Adverse Event) | 322.7 Events/100 years of patient exposure |
| BHI 50 | Incidence of AEs (Adverse Event) | 245.1 Events/100 years of patient exposure |
Secondary
Incidence of Hypoglycemic Episodes
Treatment Emergent Hypoglycemic Episode refers to those the onset of the episode is on or after the first day of exposure to randomized treatment and no later than the last day of randomized treatment. Results are presented by American Diabetes Association classification of hypoglycemia.
Time frame: During 4 weeks of treatment in each treatment sequence
Population: Safety analysis set included all subjects receiving at least one dose of investigational products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 50 | Incidence of Hypoglycemic Episodes | Asymptomatic | 1.29 events per patient per year |
| BIAsp 50 | Incidence of Hypoglycemic Episodes | All events | 12.10 events per patient per year |
| BIAsp 50 | Incidence of Hypoglycemic Episodes | Probable Symptomatic | 2.58 events per patient per year |
| BIAsp 50 | Incidence of Hypoglycemic Episodes | Relative | 2.10 events per patient per year |
| BIAsp 50 | Incidence of Hypoglycemic Episodes | Documented Symptomatic | 5.97 events per patient per year |
| BIAsp 50 | Incidence of Hypoglycemic Episodes | Unclassifiable | 0.16 events per patient per year |
| BIAsp 50 | Incidence of Hypoglycemic Episodes | Severe | 0 events per patient per year |
| BHI 50 | Incidence of Hypoglycemic Episodes | Unclassifiable | 0 events per patient per year |
| BHI 50 | Incidence of Hypoglycemic Episodes | All events | 14.38 events per patient per year |
| BHI 50 | Incidence of Hypoglycemic Episodes | Severe | 0.08 events per patient per year |
| BHI 50 | Incidence of Hypoglycemic Episodes | Documented Symptomatic | 8.33 events per patient per year |
| BHI 50 | Incidence of Hypoglycemic Episodes | Asymptomatic | 2.53 events per patient per year |
| BHI 50 | Incidence of Hypoglycemic Episodes | Relative | 1.72 events per patient per year |
| BHI 50 | Incidence of Hypoglycemic Episodes | Probable Symptomatic | 1.72 events per patient per year |
Secondary
The Mean 2-hour PPG Increments of the 3 Main Meals in 8-point SMPG Profile
Mean post prandial PG increment over all meals was derived as the mean of all available meal increments.
Time frame: After 4 weeks of treatment in each treatment sequence
Population: Of the 161 randomized subjects, 155 subjects received BIAsp 50 and 158 subjects received BHI 50 (152 subjects received both, 3 subjects only received BIAsp 50 and 6 subjects only received BHI 50). Four (4) subjects in BIAsp 50 group and 9 subjects in BHI 50 group did not contribute to the analysis due to lack of post-randomization measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 50 | The Mean 2-hour PPG Increments of the 3 Main Meals in 8-point SMPG Profile | 2.39 mmol/L | Standard Error 0.15 |
| BHI 50 | The Mean 2-hour PPG Increments of the 3 Main Meals in 8-point SMPG Profile | 2.25 mmol/L | Standard Error 0.15 |