Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and North America. The aim of the trial is to compare FIAsp (faster-acting insulin aspart) to insulin aspart, both in combination with insulin glargine and metformin in adults with type 2 diabetes.
Interventions
DRUGFaster-acting insulin aspart
Mealtime FIAsp administered subcutaneously (s.c., under the skin). Dose individually adjusted.
DRUGInsulin aspart
Mealtime insulin aspart administered subcutaneously (s.c., under the skin). Dose individually adjusted.
DRUGInsulin glargine
Administered s.c. once daily at subjects' pre-trial dose. Subjects will continue their metformin treatment without changing the frequency or dose throughout the trial.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Type 2 diabetes (diagnosed clinically) for 6 months or longer at time of screening (visit 1) - Treated with basal insulin for at least 6 months prior to screening (visit 1) - Current once daily treatment with insulin NPH (Neutral Protamine Hagedorn), insulin detemir or glargine 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 DPP-IV (dipeptidyl peptidase-4) 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. 7.0 - 9.5% (53 - 80 mmol/mol) (both inclusive) in the metformin group at the screening visit (visit 1) or b. 7.0 - 9.0% (53 - 75 mmol/mol) (both inclusive) in the metformin + other OAD (oral antidiabetic drug) (SU, glinide, DDP-IV inhibitors, AGI) combination group at the screening visit (visit 1) - Body mass index (BMI) equal to or below 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 consecutive treatment) and not 3 months prior to the screening visit (visit 1) - Use of GLP-1 (glucagon-like peptide-1) agonists and/or TZDs within the last 3 months prior to screening (visit 1) - Recurrent severe hypoglycaemia (more than 1 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) - Cardiovascular disease, within the last 6 months prior to screening (visit 1), defined as: stroke, decompensated heart failure New York Heart Association (NYHA) class III or IV, myocardial infarction, unstable angina pectoris or coronary arterial bypass graft or angioplasty
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c | Week 0, Week 26 | The primary endpoint was change from baseline in HbA1c after 26 weeks of randomized treatment. For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour PPG Increment (Meal Test) | Week 0, week 26 | For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement. |
| Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | From Week 0 to Week 26. | A hypoglycaemic episode was defined as treatment-emergent if the onset of the episode was on or after the first day of exposure to randomized treatment and no later than 1 day after the last day of randomized treatment. A severe or blood glucose (BG) confirmed hypoglycaemic episode was an episode that was severe according to the American Diabetes Association (ADA) classification (an episode that required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) 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 Body Weight | Week 0, week 26 | For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement. |
Countries
Canada, Croatia, India, Israel, Puerto Rico, Russia, Serbia, Slovakia, United Kingdom, United States
Participant flow
Recruitment details
Out of 150 sites, which were selected for recruitment, 128 sites in 9 countries enrolled subjects in the run-in period, of which 123 sites later assigned subjects to randomized treatment: Canada:9 sites; Croatia:6 sites; India:6 sites; Israel:6 sites; Russia:12 sites; Serbia:9 sites; Slovakia:5 sites; United Kingdom:7 sites; United States:63 sites.
Pre-assignment details
The trial included an 8-week run-in period and a 26-week treatment period. During the run-in period, the subjects received insulin glargine along with metformin. In total, 881 subjects entered the run-in period, of these 192 subjects were run-in failures. Hence, 689 subjects entered the 26-week treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Faster Aspart At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose. | 345 |
| NovoRapid At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was \<4.0 mmol/L or \>6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose. | 344 |
| Total | 689 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 5 | 2 |
| Overall Study | Other, Subject moved out of the country | 0 | 1 |
| Overall Study | Other, Subject wanted HbA1c to be > 7% | 1 | 0 |
| Overall Study | Other, weight gain, hypoglycaemic events | 1 | 0 |
| Overall Study | Withdrawal by Subject | 15 | 15 |
| Overall Study | Withdrawal Criteria | 20 | 15 |
Baseline characteristics
| Characteristic | Faster Aspart | NovoRapid | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 104 Participants | 96 Participants | 200 Participants |
| Age, Categorical Between 18 and 65 years | 241 Participants | 248 Participants | 489 Participants |
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 9.3 | 59.4 Years STANDARD_DEVIATION 9.6 | 59.5 Years STANDARD_DEVIATION 9.4 |
| Body Weight | 89.0 Kg STANDARD_DEVIATION 16.9 | 88.3 Kg STANDARD_DEVIATION 16.7 | 88.7 Kg STANDARD_DEVIATION 16.8 |
| Glycosylated haemoglobin A1c (HbA1c) | 7.96 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.68 | 7.89 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.71 | 7.92 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 |
| Sex: Female, Male Female | 182 Participants | 171 Participants | 353 Participants |
| Sex: Female, Male Male | 163 Participants | 173 Participants | 336 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 49 / 341 | 53 / 341 |
| serious Total, serious adverse events | 15 / 341 | 24 / 341 |
Outcome results
Primary
Change From Baseline in HbA1c
The primary endpoint was change from baseline in HbA1c after 26 weeks of randomized treatment. For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
Time frame: Week 0, Week 26
Population: The analysis of this efficacy endpoint was based on the full analysis set (FAS). FAS included all randomized subjects. The statistical evaluation of the FAS was to follow the intention-to-treat (ITT) principle and subjects contributed to the evaluation 'as randomized'.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart | Change From Baseline in HbA1c | Baseline (week 0) | 7.96 Percentage of glycosylated haemoglobin | Standard Deviation 0.68 |
| Faster Aspart | Change From Baseline in HbA1c | Week 26 | 6.63 Percentage of glycosylated haemoglobin | Standard Deviation 0.88 |
| NovoRapid | Change From Baseline in HbA1c | Baseline (week 0) | 7.89 Percentage of glycosylated haemoglobin | Standard Deviation 0.71 |
| NovoRapid | Change From Baseline in HbA1c | Week 26 | 6.59 Percentage of glycosylated haemoglobin | Standard Deviation 0.84 |
Comparison: Change from baseline in HbA1c is analysed using a mixed-effect model for repeated measurements including changes from baseline in HbA1c at visit 14, 18, 22, 26, 30 and 36. The model includes treatment, region and continuous glucose monitoring (CGM) strata as fixed effects, subject as random effect, HbA1c at baseline as covariate and interaction between all fixed effects and visit, and between the covariate and visit.95% CI: [-0.15, 0.1]
Secondary
Change From Baseline in 2-hour PPG Increment (Meal Test)
For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
Time frame: Week 0, week 26
Population: This endpoint was summarized using the Full Analysis Set (FAS). FAS included all randomized subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart | Change From Baseline in 2-hour PPG Increment (Meal Test) | Baseline (week 0) | 7.57 mmol/L | Standard Deviation 3.19 |
| Faster Aspart | Change From Baseline in 2-hour PPG Increment (Meal Test) | Week 26 | 4.55 mmol/L | Standard Deviation 3.13 |
| NovoRapid | Change From Baseline in 2-hour PPG Increment (Meal Test) | Baseline (week 0) | 7.34 mmol/L | Standard Deviation 3.12 |
| NovoRapid | Change From Baseline in 2-hour PPG Increment (Meal Test) | Week 26 | 4.9 mmol/L | Standard Deviation 3.36 |
Secondary
Change From Baseline in Body Weight
For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
Time frame: Week 0, week 26
Population: This endpoint was summarized using the FAS. FAS included all randomized subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart | Change From Baseline in Body Weight | Baseline (week 0) | 89.0 Kg | Standard Deviation 16.9 |
| Faster Aspart | Change From Baseline in Body Weight | Week 26 | 91.6 Kg | Standard Deviation 18.2 |
| NovoRapid | Change From Baseline in Body Weight | Baseline (week 0) | 88.3 Kg | Standard Deviation 16.7 |
| NovoRapid | Change From Baseline in Body Weight | Week 26 | 90.8 Kg | Standard Deviation 17.7 |
Secondary
Number of Treatment Emergent Confirmed Hypoglycaemic Episodes
A hypoglycaemic episode was defined as treatment-emergent if the onset of the episode was on or after the first day of exposure to randomized treatment and no later than 1 day after the last day of randomized treatment. A severe or blood glucose (BG) confirmed hypoglycaemic episode was an episode that was severe according to the American Diabetes Association (ADA) classification (an episode that required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.
Time frame: From Week 0 to Week 26.
Population: This endpoint was summarized using the safety analysis set. Safety analysis set included all subjects receiving at least one dose of the test product or comparator. Subjects in the safety analysis set contributed to the evaluation 'as treated'.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Faster Aspart | Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | 2857 Number of episodes |
| NovoRapid | Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | 2692 Number of episodes |