Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe, South America, and the United States of America (USA). The aim of the trial is to investigate efficacy and safety of FIAsp in a basal-bolus regimen versus basal insulin therapy, both in combination with metformin in adult subjects with type 2 diabetes.
Interventions
DRUGFaster-acting insulin aspart
Administrated subcutaneously (s.c., under the skin) at each main meal.
DRUGbasal insulin
Administrated subcutaneously (s.c., under the skin) once daily.
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
* Type 2 diabetes (diagnosed clinically) for at least 6 months prior to the screening visit (Visit 1) * Current treatment with once daily insulin detemir, insulin glargine or human isophane insulin, NPH for at least 3 months prior to the screening visit (Visit 1) * Current treatment with a) metformin with unchanged dosing for at least 3 months prior to screening (visit 1). The metformin dose must be at least 1000 mg or b) metformin in combination with sulfonylurea (SU) or glinide or Dipeptidyl peptidase-IV inhibitors and/or alpha-glucosidase inhibitors (AGI) with unchanged dosing for at least 3 months prior to screening (visit 1). The metformin dose must be at least 1000 mg * HbA1c by central laboratory a) 7.5-9.5% (58 - 80 mmol/mol) (both inclusive) in the metformin group at the screening visit (Visit 1) or b) 7.5-9.0% (58 - 75 mmol/mol) (both inclusive) in the metformin + other oral antidiabetic drug (OAD) (sulphonylurea (SU), glinide, dipeptidyl peptidase-IV (DDP-IV) inhibitors, alpha-glucosidase inhibitors (AGI) combination group at the screening visit (Visit 1) * Body mass index (BMI) equal or less than 40.0 kg/m\^2
Exclusion criteria
* Any use of bolus insulin, except short-term use due to intermittent illness (no longer than 14 days of consecutive treatment) and not within 3 months prior to the screening visit (Visit 1) * Use of Glucagon-like peptide-1 (GLP-1) agonists and/or Thiazolidinediones (TZD) within the last 3 months prior to screening (visit 1) * Recurrent severe hypoglycaemia (more than one severe hypoglycaemic event during the last 12 months) or hypoglycaemic unawareness as judged by the Investigator, or hospitalisation for diabetic ketoacidosis during the previous 6 months prior to screening (Visit 1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c | Week 0, week 18 | For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the end of trial data containing last available measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | After 18 weeks of randomised treatment | For this endpoint the end of trial data containing last available measurements are presented. PPG measurements were recorded by the subjects at 2 hours after each meal (breakfast, lunch and main evening meal) as part of three 7-point profiles (SMPG) prior to the visits. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements. |
| Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | After 18 weeks of randomised treatment | For this endpoint the end of trial data containing last available measurements are presented. Prandial PG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point profiles (SMPG) as the difference between the PPG value 2 hours after each meal and the PG value before each meal. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements. |
| Change From Baseline in Body Weight | Week 0, week 18 | For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the end of trial data containing last available measurements. |
| Number of Treatment Emergent Hypoglycaemic Episodes | Weeks 0-18 | Plasma glucose (PG) was measured and recorded when a hypoglycaemic episode was suspected. All PG values ≤3.9 mmol/L (70 mg/dL) or \>3.9 mmol/L (70 mg/dL) when they occurred in conjunction with hypoglycaemic symptoms were recorded by the subject. Numbers of treatment emergent hypoglycaemic episodes were recorded during 18 weeks of treatment. |
| Number of Adverse Events | Weeks 0-18 | All adverse events (AEs) described here refer to treatment emergent adverse events (TEAE). A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment, week 18. |
Countries
Argentina, India, Mexico, Romania, Slovenia, United States
Participant flow
Recruitment details
The trial was conducted at 51 sites in 6 countries as follows: Argentina: 4 sites; India: 8 sites; Mexico: 3 sites; Romania: 5 sites; Slovenia: 4 sites; United States: 27 sites.
Pre-assignment details
A total of 555 subjects were screened, of which 232 subjects were screening failures and 323 subjects were enrolled and entered the run-in (pre-assignment) period. Of those, 87 subjects were run-in failures. Hence, 236 subjects were randomized to the 18 weeks of treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Faster Aspart + Basal During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day. | 116 |
| Basal During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day. | 120 |
| Total | 236 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 4 | 1 |
| Overall Study | Unclassified | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Faster Aspart + Basal | Basal | Total |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 9.9 | 57.4 years STANDARD_DEVIATION 8.5 | 57.4 years STANDARD_DEVIATION 9.2 |
| Body weight | 82.2 Kg STANDARD_DEVIATION 16.2 | 85.1 Kg STANDARD_DEVIATION 17.3 | 83.7 Kg STANDARD_DEVIATION 16.8 |
| Glycosylated haemoglobin (HbA1c) | 7.93 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.69 | 7.92 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.68 | 7.93 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.69 |
| Sex: Female, Male Female | 61 Participants | 61 Participants | 122 Participants |
| Sex: Female, Male Male | 55 Participants | 59 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 115 | 6 / 120 |
| serious Total, serious adverse events | 6 / 115 | 5 / 120 |
Outcome results
Primary
Change From Baseline in HbA1c
For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the end of trial data containing last available measurements.
Time frame: Week 0, week 18
Population: Full analysis set included all randomised subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart + Basal | Change From Baseline in HbA1c | Baseline | 7.93 Percentage of glycosylated haemoglobin | Standard Deviation 0.69 |
| Faster Aspart + Basal | Change From Baseline in HbA1c | Week 18 | 6.78 Percentage of glycosylated haemoglobin | Standard Deviation 0.92 |
| Basal | Change From Baseline in HbA1c | Baseline | 7.92 Percentage of glycosylated haemoglobin | Standard Deviation 0.68 |
| Basal | Change From Baseline in HbA1c | Week 18 | 7.7 Percentage of glycosylated haemoglobin | Standard Deviation 0.93 |
Comparison: Change from baseline in HbA1c after 18 weeks of treatment was analysed using a mixed-effect model for repeated measurements (MMRM) where all calculated changes in HbA1c from baseline at visits 16, 22 and 28 were included in the analysis. This model included treatment, region and strata 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.95% CI: [-1.17, -0.72]
Secondary
Change From Baseline in Body Weight
For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the end of trial data containing last available measurements.
Time frame: Week 0, week 18
Population: FAS included all randomised subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart + Basal | Change From Baseline in Body Weight | Baseline | 82.2 Kg | Standard Deviation 16.2 |
| Faster Aspart + Basal | Change From Baseline in Body Weight | Week 18 | 83.9 Kg | Standard Deviation 16.9 |
| Basal | Change From Baseline in Body Weight | Baseline | 85.1 Kg | Standard Deviation 17.3 |
| Basal | Change From Baseline in Body Weight | Week 18 | 85.4 Kg | Standard Deviation 17.5 |
Secondary
Number of Adverse Events
All adverse events (AEs) described here refer to treatment emergent adverse events (TEAE). A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment, week 18.
Time frame: Weeks 0-18
Population: The SAS included all subjects receiving at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Faster Aspart + Basal | Number of Adverse Events | 123 Number of events |
| Basal | Number of Adverse Events | 121 Number of events |
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes
Plasma glucose (PG) was measured and recorded when a hypoglycaemic episode was suspected. All PG values ≤3.9 mmol/L (70 mg/dL) or \>3.9 mmol/L (70 mg/dL) when they occurred in conjunction with hypoglycaemic symptoms were recorded by the subject. Numbers of treatment emergent hypoglycaemic episodes were recorded during 18 weeks of treatment.
Time frame: Weeks 0-18
Population: The Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Faster Aspart + Basal | Number of Treatment Emergent Hypoglycaemic Episodes | 1908 Number of episodes |
| Basal | Number of Treatment Emergent Hypoglycaemic Episodes | 347 Number of episodes |
Secondary
Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)
For this endpoint the end of trial data containing last available measurements are presented. PPG measurements were recorded by the subjects at 2 hours after each meal (breakfast, lunch and main evening meal) as part of three 7-point profiles (SMPG) prior to the visits. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.
Time frame: After 18 weeks of randomised treatment
Population: FAS included all randomised subjects. Number analysed for individual time-points = treatment wise number of subjects who contributed to analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart + Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | PPG breakfast; SMPG | 7.2 mmol/L | Standard Deviation 1.8 |
| Faster Aspart + Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | PPG lunch; SMPG | 7.1 mmol/L | Standard Deviation 1.9 |
| Faster Aspart + Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | PPG main evening meal; SMPG | 7.4 mmol/L | Standard Deviation 1.9 |
| Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | PPG breakfast; SMPG | 9 mmol/L | Standard Deviation 2.4 |
| Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | PPG lunch; SMPG | 9.7 mmol/L | Standard Deviation 2.6 |
| Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | PPG main evening meal; SMPG | 10.1 mmol/L | Standard Deviation 2.9 |
Secondary
Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)
For this endpoint the end of trial data containing last available measurements are presented. Prandial PG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point profiles (SMPG) as the difference between the PPG value 2 hours after each meal and the PG value before each meal. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.
Time frame: After 18 weeks of randomised treatment
Population: FAS included all randomised subjects. Number analysed for individual time-points = treatment wise number of subjects who contributed to analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart + Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | Breakfast increment; SMPG | 1.2 mmol/L | Standard Deviation 1.8 |
| Faster Aspart + Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | Lunch increment; SMPG | 0.9 mmol/L | Standard Deviation 2 |
| Faster Aspart + Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | Main evening meal increment; SMPG | 0.7 mmol/L | Standard Deviation 1.7 |
| Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | Breakfast increment; SMPG | 2.9 mmol/L | Standard Deviation 2.4 |
| Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | Lunch increment; SMPG | 1.8 mmol/L | Standard Deviation 2.2 |
| Basal | Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) | Main evening meal increment; SMPG | 1.4 mmol/L | Standard Deviation 1.9 |