Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Europe and the United States of America (USA). The aim of the trial is to investigate efficacy and safety of FIAsp (faster-acting insulin aspart) compared to insulin aspart, both in combination with insulin detemir in adults with type 1 diabetes. This trial consists of two periods: a 26 week treatment period followed by a 26 week additional treatment period.
Interventions
DRUGFaster-acting insulin aspart
Injected subcutaneously (s.c., under the skin), dose individually adjusted. Meal time dosing is defined as injecting 0-2 minutes before the meal.
DRUGinsulin detemir
Injected subcutaneously (s.c., under the skin), dose individually adjusted. Administrated once or twice daily.
DRUGinsulin aspart
Injected subcutaneously (s.c., under the skin), dose individually adjusted.
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 1 diabetes (diagnosed clinically) for 12 months or longer at the time of screening (Visit 1) - Currently treated with a basal-bolus insulin regimen for at least 12 months prior to screening (Visit 1) - Currently treated with a basal insulin analogue (any regimen of insulin detemir or insulin glargine) for at least 4 months prior to screening (Visit 1) - HbA1c 7.0-9.5% (53-80 mmol/mol) (both inclusive) as assessed by central laboratory - Body Mass Index (BMI) below or equal to 35.0 kg/m\^2
Exclusion criteria
- Use of any anti-diabetic drug other than insulin 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) - 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, coronary arterial bypass graft or angioplasty
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0, week 26 | Change from baseline in HbA1c after 26 weeks of randomised treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Post Meal Arm) | Week 0, week 26 | Change from baseline in HbA1c (post meal arm) after 26 weeks of randomised treatment. |
| Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | From baseline until week 26 | Observed rate of treatment emergent severe or BG confirmed hypoglycaemic events per 100 patient years of exposure (PYE) from baseline until 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 randomised treatment and no later than 1 day after the last day of randomised treatment. Severe or BG confirmed is an episode that is severe according to the American Diabetes Association (ADA) classification (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a PG 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 | Change from baseline in body weight after 26 weeks of randomised treatment. |
| Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test) | Week 0, week 26 | Change from baseline in 2-hour PPG increments after 26 weeks of randomised treatment (meal test). |
| Change in HbA1c | Week 0, week 52 | Change from baseline in HbA1c (%) after 52 weeks of randomised treatment. |
| Change in PPG (Postprandial Glucose) | Week 0, week 52 | Change from baseline in PPG and PPG increment (meal test) after 52 weeks of randomised treatment. |
| Frequency of Adverse Events | After 52 weeks of randomised treatment | All treatment emergent adverse events (TEAEs) from baseline until 52 weeks of randomised treatment. A TEAE was defined as an event that had an 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. |
Countries
Belgium, Canada, Czechia, Finland, Germany, Hungary, Poland, United Kingdom, United States
Participant flow
Recruitment details
Out of 281 sites, selected for recruitment, 165 sites in 9 countries enrolled subjects in the run-in period, of which 163 sites later assigned subjects to randomised treatment: Belgium:5 sites, Canada:12 sites, Czech Republic:5 sites; Finland:6 sites; Germany:25 sites; Hungary:5 sites; Poland:6 sites; United Kingdom:9 sites; United States:92 sites.
Pre-assignment details
Eligible subjects received once/twice daily insulin detemir and NovoRapid®/NovoLog® during 8 week run-in period. In total, 1290 subjects entered the run-in period, of those147 subjects were run-in failures. Hence 1143 subjects entered the 26-week treatment period followed by a 26 week additional treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Faster Aspart (Meal) The subjects in this arm were administered mealtime faster aspart (100 U/mL) in combination with once or twice daily insulin detemir (100 U/mL) in a basal-bolus regimen for an initial 26 weeks treatment period + a 26-week additional treatment period. Mealtime faster aspart was administered subcutaneously (s.c., under the skin) 0-2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator's recommendation. | 381 |
| Faster Aspart (Post) The subjects in this arm were administered postmeal faster aspart (100 U/mL) in combination with once or twice daily insulin detemir (100 U/mL) in a basal-bolus regimen for an initial 26 weeks treatment period. Postmeal faster aspart was administered subcutaneously (s.c., under the skin) 20 minutes after the start of the meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator's recommendation. | 382 |
| NovoRapid (Meal) The subjects in this arm were administered mealtime NovoRapid®/NovoLog®, 100 U/mL in combination with once or twice daily insulin detemir (100 U/mL) in a basal-bolus regimen for an initial 26 weeks treatment period + a 26-week additional treatment period. Mealtime NovoRapid®/NovoLog® was administered subcutaneously (s.c., under the skin) 0-2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator's recommendation. | 380 |
| Total | 1,143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 | 3 |
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 3 | 3 |
| Overall Study | Other, site closed | 1 | 1 | 0 |
| Overall Study | Other, sponsor withdrew subject | 0 | 1 | 0 |
| Overall Study | Pregnancy | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 22 | 7 | 17 |
| Overall Study | Withdrawal criteria | 12 | 10 | 16 |
Baseline characteristics
| Characteristic | Faster Aspart (Meal) | Faster Aspart (Post) | NovoRapid (Meal) | Total |
|---|---|---|---|---|
| Age, Continuous | 46.1 Years STANDARD_DEVIATION 13.8 | 43.5 Years STANDARD_DEVIATION 13.7 | 43.7 Years STANDARD_DEVIATION 14 | 44.4 Years STANDARD_DEVIATION 13.9 |
| Age, Customized Adults (18-64 years) | 346 Participants | 359 Participants | 352 Participants | 1057 Participants |
| Age, Customized From 65-85 years | 35 Participants | 23 Participants | 28 Participants | 86 Participants |
| Body Weight | 78.56 Kg STANDARD_DEVIATION 14.89 | 80.49 Kg STANDARD_DEVIATION 15.93 | 80.15 Kg STANDARD_DEVIATION 15.21 | 79.73 Kg STANDARD_DEVIATION 15.36 |
| Glycosylated haemoglobin (HbA1c) | 7.62 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.71 | 7.63 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.72 | 7.58 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.68 | 7.61 Percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 |
| Sex: Female, Male Female | 166 Participants | 163 Participants | 142 Participants | 471 Participants |
| Sex: Female, Male Male | 215 Participants | 219 Participants | 238 Participants | 672 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 252 / 386 | 189 / 377 | 236 / 380 |
| serious Total, serious adverse events | 35 / 386 | 28 / 377 | 33 / 380 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Change from baseline in HbA1c after 26 weeks of randomised treatment.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. For this endpoint, baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart (Meal) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0 (Baseline) | 7.62 Percentage of glycosylated haemoglobin | Standard Deviation 0.71 |
| Faster Aspart (Meal) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 26 | 7.31 Percentage of glycosylated haemoglobin | Standard Deviation 0.77 |
| Faster Aspart (Post) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0 (Baseline) | 7.63 Percentage of glycosylated haemoglobin | Standard Deviation 0.72 |
| Faster Aspart (Post) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 26 | 7.51 Percentage of glycosylated haemoglobin | Standard Deviation 0.77 |
| NovoRapid (Meal) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0 (Baseline) | 7.58 Percentage of glycosylated haemoglobin | Standard Deviation 0.68 |
| NovoRapid (Meal) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 26 | 7.42 Percentage of glycosylated haemoglobin | Standard Deviation 0.78 |
Comparison: Change from baseline in HbA1c analysed using a mixed effect model for repeated measurements including visit 14, 18, 22, 26, 30, 34 and 36. The model included treatment, region and strata (combination of bolus adjusting method, basal treatment regimen and continuous glucose monitoring (CGM) and frequently sampled meal test subgroup) as fixed effects, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.95% CI: [-0.23, -0.07]
Comparison: Change from baseline in HbA1c analysed using a mixedeffect model for repeated measurements including visit 14, 18, 22, 26, 30, 34 and 36. The model included treatment, region and strata (combination of bolus adjusting method, basal treatment regimen and continuous glucose monitoring (CGM) and frequently sampled meal test subgroup) as fixed effects, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.95% CI: [-0.04, 0.12]
Secondary
Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test)
Change from baseline in 2-hour PPG increments after 26 weeks of randomised treatment (meal test).
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. For this endpoint, baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement. At baseline (week 0) 379, 377, 375 and 381, 382, 380 subjects at week 26 were analysed for faster aspart (meal), faster aspart (post) and Novorapid (meal) arms respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart (Meal) | Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test) | Week 0: Baseline | 6.06 mmol/L | Standard Deviation 5.16 |
| Faster Aspart (Meal) | Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test) | Week 26 | 5.88 mmol/L | Standard Deviation 4.67 |
| Faster Aspart (Post) | Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test) | Week 0: Baseline | 6.06 mmol/L | Standard Deviation 4.9 |
| Faster Aspart (Post) | Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test) | Week 26 | 6.73 mmol/L | Standard Deviation 4.67 |
| NovoRapid (Meal) | Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test) | Week 0: Baseline | 6.24 mmol/L | Standard Deviation 4.81 |
| NovoRapid (Meal) | Change From Baseline in 2-hour PPG (Postprandial Glucose) Increment (Meal Test) | Week 26 | 6.55 mmol/L | Standard Deviation 4.78 |
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight after 26 weeks of randomised treatment.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. For this endpoint baseline, and week 26 have been presented, where week 26 data is end of trial containing last available measurement. At baseline (week 0) 381, 382, 378 and 381, 382, 380 subjects at week 26 were analysed for faster aspart (meal), faster aspart (post) and Novorapid (meal) arms respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart (Meal) | Change From Baseline in Body Weight | Week 0: Baseline | 78.56 Kg | Standard Deviation 14.89 |
| Faster Aspart (Meal) | Change From Baseline in Body Weight | Week 26 | 79.21 Kg | Standard Deviation 15.25 |
| Faster Aspart (Post) | Change From Baseline in Body Weight | Week 0: Baseline | 80.49 Kg | Standard Deviation 15.93 |
| Faster Aspart (Post) | Change From Baseline in Body Weight | Week 26 | 81.17 Kg | Standard Deviation 16.45 |
| NovoRapid (Meal) | Change From Baseline in Body Weight | Week 26 | 80.69 Kg | Standard Deviation 15.44 |
| NovoRapid (Meal) | Change From Baseline in Body Weight | Week 0: Baseline | 80.15 Kg | Standard Deviation 15.21 |
Secondary
Change From Baseline in HbA1c (Post Meal Arm)
Change from baseline in HbA1c (post meal arm) after 26 weeks of randomised treatment.
Time frame: Week 0, week 26
Population: This endpoint was summarised using the FAS, which included all randomised subjects. For this endpoint, baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart (Meal) | Change From Baseline in HbA1c (Post Meal Arm) | Week 0 (baseline) | 7.63 Percentage of glycosylated haemoglobin | Standard Deviation 0.72 |
| Faster Aspart (Meal) | Change From Baseline in HbA1c (Post Meal Arm) | Week 26 | 7.51 Percentage of glycosylated haemoglobin | Standard Deviation 0.77 |
| Faster Aspart (Post) | Change From Baseline in HbA1c (Post Meal Arm) | Week 0 (baseline) | 7.58 Percentage of glycosylated haemoglobin | Standard Deviation 0.68 |
| Faster Aspart (Post) | Change From Baseline in HbA1c (Post Meal Arm) | Week 26 | 7.42 Percentage of glycosylated haemoglobin | Standard Deviation 0.78 |
Secondary
Change in HbA1c
Change from baseline in HbA1c (%) after 52 weeks of randomised treatment.
Time frame: Week 0, week 52
Population: The FAS included all randomised subjects. The statistical evaluation of the FAS was to follow the ITT principle and subjects contributed to the evaluation 'as randomised'. For this endpoint, baseline and week 52 have been presented, where week 52 data is the end of trial containing last available measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart (Meal) | Change in HbA1c | Week 0 (baseline) | 7.62 Percentage of glycosylated haemoglobin | Standard Deviation 0.71 |
| Faster Aspart (Meal) | Change in HbA1c | Week 52 | 7.51 Percentage of glycosylated haemoglobin | Standard Deviation 0.83 |
| Faster Aspart (Post) | Change in HbA1c | Week 0 (baseline) | 7.58 Percentage of glycosylated haemoglobin | Standard Deviation 0.68 |
| Faster Aspart (Post) | Change in HbA1c | Week 52 | 7.58 Percentage of glycosylated haemoglobin | Standard Deviation 0.86 |
Secondary
Change in PPG (Postprandial Glucose)
Change from baseline in PPG and PPG increment (meal test) after 52 weeks of randomised treatment.
Time frame: Week 0, week 52
Population: The FAS included all randomised subjects. The number of subjects with data available for PPG at 120 mins at baseline were 379, 379 and 380, 380 at week 52 and for PPG increment (120 mins) at baseline were 379, 375 and 381, 380 at week 26 for faster aspart (meal) and Novorapid (meal) respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Faster Aspart (Meal) | Change in PPG (Postprandial Glucose) | PPG at 120 minutes (Baseline) | 14.51 mmol/L | Standard Deviation 6.09 |
| Faster Aspart (Meal) | Change in PPG (Postprandial Glucose) | PPG at 120 minutes (Week 52) | 14.26 mmol/L | Standard Deviation 5.76 |
| Faster Aspart (Meal) | Change in PPG (Postprandial Glucose) | PPG increment at 120 mins (Baseline) | 6.06 mmol/L | Standard Deviation 5.16 |
| Faster Aspart (Meal) | Change in PPG (Postprandial Glucose) | PPG increment at 120 mins(Week 52) | 5.71 mmol/L | Standard Deviation 4.92 |
| Faster Aspart (Post) | Change in PPG (Postprandial Glucose) | PPG increment at 120 mins(Week 52) | 6.14 mmol/L | Standard Deviation 4.86 |
| Faster Aspart (Post) | Change in PPG (Postprandial Glucose) | PPG at 120 minutes (Baseline) | 14.14 mmol/L | Standard Deviation 5.69 |
| Faster Aspart (Post) | Change in PPG (Postprandial Glucose) | PPG increment at 120 mins (Baseline) | 6.24 mmol/L | Standard Deviation 4.81 |
| Faster Aspart (Post) | Change in PPG (Postprandial Glucose) | PPG at 120 minutes (Week 52) | 14.51 mmol/L | Standard Deviation 6.02 |
Secondary
Frequency of Adverse Events
All treatment emergent adverse events (TEAEs) from baseline until 52 weeks of randomised treatment. A TEAE was defined as an event that had an 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.
Time frame: After 52 weeks of randomised treatment
Population: The safety analysis set included all subjects receiving at least one dose of trial product/its comparator and contributed to the evaluation as treated. Five (5) subjects randomised to the faster aspart (post) group have consistently taken their bolus insulin before meals throughout the trial and are handled as treated with faster aspart (meal).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Faster Aspart (Meal) | Frequency of Adverse Events | 445.8 event /100 patient yrs of exposure |
| Faster Aspart (Post) | Frequency of Adverse Events | 441 event /100 patient yrs of exposure |
| NovoRapid (Meal) | Frequency of Adverse Events | 411 event /100 patient yrs of exposure |
Secondary
Number of Treatment Emergent Confirmed Hypoglycaemic Episodes
Observed rate of treatment emergent severe or BG confirmed hypoglycaemic events per 100 patient years of exposure (PYE) from baseline until 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 randomised treatment and no later than 1 day after the last day of randomised treatment. Severe or BG confirmed is an episode that is severe according to the American Diabetes Association (ADA) classification (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a PG value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.
Time frame: From baseline until week 26
Population: The safety analysis set included all subjects receiving at least one dose of trial product/its comparator and contributed to the evaluation as treated. Five (5) subjects randomised to the faster aspart (post) group have consistently taken their bolus insulin before meals throughout the trial and are handled as treated with faster aspart (meal).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Faster Aspart (Meal) | Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | 5899 event rate/100 patient yrs of exposure |
| Faster Aspart (Post) | Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | 5443 event rate/100 patient yrs of exposure |
| NovoRapid (Meal) | Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | 5865 event rate/100 patient yrs of exposure |