Efficacy and Safety of Faster-acting Insulin Aspart Compared to NovoRapid® Both in Combination With Insulin Degludec in Adults With Type 1 Diabetes

Change from baseline (week 0) in HbA1c was evaluated after 26 weeks of randomisation. The results are based on the last in-trial value, which included the last available measurement in the in-trial period. In-trial period: the observation period from date of randomisation until last trial-related subject-site contact.

The 1-hour PPG increment was analysed based on the laboratory-measured values in the meal test, and was derived using the 1-hour PPG measurement minus the pre-prandial plasma glucose (PG). The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The percentage of subjects who achieved the HbA1c target of <7.0% 26 weeks after randomisation. Subjects without an HbA1c measurement at week 26 were treated as non-responders.

The percentage of subjects who achieved the HbA1c target of <7.0% without severe hypoglycaemia 26 weeks after randomisation. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Subjects without an HbA1c measurement at week 26 were treated as non-responders.

The percentage of subjects who achieved the HbA1c target of <7.0% without severe hypoglycaemia and with minimal weight gain (defined as less than a 3% increase) 26 weeks after randomisation. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Subjects without an HbA1c measurement at week 26 or without body weight measurement at week 26 were treated as non-responders.

Laboratory measured PG from the meal test was analysed for 30, 60, 120, 180, and 240 minutes PPG separately. The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

Laboratory measured PG from the meal test was analysed for 30, 60, 120, 180, and 240 minutes PPG separately. The corresponding PPG increments were derived separately using each PPG measurement minus the pre-prandial PG. The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The subject was instructed to perform a 7-9-7 SMPG point profile on the 3 consecutive days just before selected visit. 7-point profile (day 3 and day 1 before selected visit): before breakfast, 60 minutes after the start of breakfast, before lunch, 60 minutes after the start of lunch, before main evening meal, 60 minutes after the start of main evening meal, and at bedtime. 9-point profile (day 2 before selected visit) included all timepoints of 7-points profile with addition of SMPG measurement at 4 a.m. and before breakfast on the following day. The mean of the 7-9-7-point profile was defined as the area under the curve profile divided by the measurement time, and was calculated using the linear trapezoidal technique. The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The subject was instructed to perform a 7-9-7 SMPG point profile on the 3 consecutive days just before selected visit. 7-point profile (day 3 and day 1 before selected visit): before breakfast, 60 minutes after the start of breakfast, before lunch, 60 minutes after the start of lunch, before main evening meal, 60 minutes after the start of main evening meal, and at bedtime. 9-point profile (day 2 before selected visit) included all timepoints of 7-points profile with addition of SMPG measurement at 4 a.m. and before breakfast on the following day. Results were derived from the three profiles: post-breakfast, post-lunch, post-main evening meal. The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The subject was instructed to perform a 7-9-7 SMPG point profile on the 3 consecutive days just before selected visit. 7-point profile (day 3 and day 1 before selected visit): before breakfast, 60 minutes after the start of breakfast, before lunch, 60 minutes after the start of lunch, before main evening meal, 60 minutes after the start of main evening meal, and at bedtime. 9-point profile (day 2 before selected visit) included all timepoints of 7-points profile with addition of SMPG measurement at 4 a.m. and before breakfast on the following day. PPG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point and 9-point profile as the difference between PPG values and the PG value before the meal in each separate profile. The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The subject was instructed to perform a 7-9-7 SMPG point profile on the 3 consecutive days just before selected visit. 7-point profile (day 3 and day 1 before selected visit): before breakfast, 60 minutes after the start of breakfast, before lunch, 60 minutes after the start of lunch, before main evening meal, 60 minutes after the start of main evening meal, and at bedtime. 9-point profile (day 2 before selected visit) included all timepoints of 7-points profile with addition of SMPG measurement at 4 a.m. and before breakfast on the following day. Fluctuation in SMPG profile was the average absolute difference from the mean of the SMPG profile. Change from baseline is represented as ratio to baseline value. The results are based on the last in-trial value, which included the last available measurement in the in-trial period.

The subject was instructed to perform 7-9-7 SMPG point profile on 3 consecutive days just before selected visit. 7-point profile (day 3 and day 1 before selected visit): before breakfast,60 minutes after the start of breakfast,before lunch,60 minutes after the start of lunch, before main evening meal,60 minutes after the start of main evening meal,and at bedtime. 9-point profile (day 2 before selected visit) included all timepoints of 7-points profile with addition of SMPG measurement at 4 a.m. and before breakfast on following day. Change from baseline in nocturnal PG values (nocturnal increments) was assessed by considering differences between PG values available at bedtime, at 4 a.m and the before breakfast value the following day: (04:00 PG value minus at bedtime PG value), (before breakfast PG value minus at bedtime PG value) and (before breakfast PG value minus 04:00 PG value). Results are based on the last in-trial value (the last available measurement in the in-trial period).

Percentage of subjects achieving an overall mean 1-hour PPG ≤7.8 mmol/L [140 mg/dL] 26 weeks after randomisation. Subjects without an overall mean 1-hour PPG at week 26 were treated as non-responders.

Percentage of subjects achieving an overall mean 1-hour PPG ≤7.8 mmol/L [140 mg/dL] 26 weeks after randomisation without severe hypoglycaemia. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Subjects without an overall mean 1-hour PPG at week 26 were treated as non-responders.

The percentage of subjects who achieved overall mean 1 hour PPG ≤7.8 mmol/L [140 mg/dL], had HbA1c < 7.0% and had minimal weight gain (increase in body weight from baseline <3.0%) 26 weeks after randomisation, and without severe hypoglycaemic episodes. Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Subjects without an overall mean 1-hour PPG or an HbA1c value or a body weight at week 26 were treated as non-responders.

Change from baseline in HDL cholesterol, LDL cholesterol and total cholesterol 26 weeks after randomization are represented as ratio to baseline values. The results are based on the last in-trial value (the last available measurement in the in-trial period).

The insulin doses were summarised descriptively at week 0 and week 26 both by meal type and as total daily dose (total daily and separately for each mealtime dose). Week 26 results are based on the last on-treatment value, which included the last available measurement in the on-treatment period.

A treatment emergent adverse event (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 seven days after the last day of randomised treatment.

A treatment emergent event 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 seven days after the last day of randomised treatment.

ADA classification includes following criteria: Severe,Documented symptomatic,Asymptomatic,Probable symptomatic,Pseudo-hypoglycaemia.

NN Classification:

• Severe:same as per ADA classification
• Symptomatic blood glucose (BG) confirmed: PG<3.1 mmol/L with symptoms consistent with hypoglycaemia
• Asymptomatic BG confirmed:PG<3.1 mmol/L without symptoms consistent with hypoglycaemia
• Severe or BG confirmed symptomatic:severe according to ADA classification or BG confirmed by PG<3.1 mmol/L with symptoms consistent with hypoglycaemia
• BG confirmed:PG<3.1 mmol/L with or without symptoms consistent with hypoglycaemia
• Severe or BG confirmed:severe according to ADA classification or BG confirmed by PG<3.1 mmol/L with or without symptoms consistent with hypoglycaemia
• Unclassifiable Results represent total number of hypoglycaemic episodes. Treatment emergent episode: an event that has onset up to 1 day after last day of randomised treatment and excluding events occurring in run-in period.

ADA classification includes following criteria: Severe, Documented symptomatic, Asymptomatic, Probable symptomatic, Pseudo-hypoglycaemia.

NN Classification:

• Severe: same as per ADA classification
• Symptomatic BG confirmed: PG<3.1 mmol/L with symptoms consistent with hypoglycaemia
• Asymptomatic BG confirmed: PG<3.1 mmol/L without symptoms consistent with hypoglycaemia
• Severe or BG confirmed symptomatic: severe according to the ADA classification or BG confirmed by PG<3.1 mmol/Lwith symptoms consistent with hypoglycaemia
• BG confirmed: PG<3.1 mmol/L with or without symptoms consistent with hypoglycaemia
• Severe or BG confirmed: severe according to the ADA classification or BG confirmed by PG<3.1 mmol/L with or without symptoms consistent with hypoglycaemia
• Unclassifiable Results represent total number of hypoglycaemic episodes. Nocturnal hypoglycaemic episodes were episodes occurring between 00:01 and 05:59 both inclusive.

ADA classification includes following criteria: Severe, Documented symptomatic, Asymptomatic, Probable symptomatic, Pseudo-hypoglycaemia.

NN Classification:

• Severe: same as per ADA classification
• Symptomatic BG confirmed: PG<3.1 mmol/L with symptoms consistent with hypoglycaemia
• Asymptomatic BG confirmed: PG<3.1 mmol/L without symptoms consistent with hypoglycaemia
• Severe or BG confirmed symptomatic: severe according to the ADA classification or BG confirmed by PG<3.1 mmol/Lwith symptoms consistent with hypoglycaemia
• BG confirmed: PG<3.1 mmol/L with or without symptoms consistent with hypoglycaemia
• Severe or BG confirmed: severe according to the ADA classification or BG confirmed by PG<3.1 mmol/L with or without symptoms consistent with hypoglycaemia
• Unclassifiable Results represent total number of hypoglycaemic episodes related to meals.

The physical examination parameters included head, ears, eyes, nose, throat, neck; respiratory system; cardiovascular system; gastrointestinal system including mouth; musculoskeletal system; central and peripheral nervous system; and skin. The examinations were measured as 'normal', 'abnormal, not clinically significant' (Abn, NCS) or 'abnormal, clinically significant' (Abn, CS). Reported results are percentage of subjects with 'normal', 'Abn, NCS' and 'Abn, CS' physical examinations at week 0 and week 26. Week 26 results are based on the last on-treatment value (last value), which included the last available measurement in the on-treatment period.

Change from baseline in systolic blood pressure and diastolic blood pressure 26 weeks after randomisation. Results are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Results are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

The electrocardiogram was interpreted by the investigator into following categories: Normal; Abn, NCS; Abnormal, CS. Reported results are percentage of subjects with 'normal', 'Abn, NCS' and 'Abn, CS' physical examinations at week 0 and week 26. Week 26 data are based on the last on-treatment value which contains the last available measurement in the on-treatment period.

The result of the fundus photography/dilated fundoscopy was interpreted by the investigator into following categories: Normal; Abn, NCS; Abnormal, CS. Reported results are percentage of subjects with 'normal', 'Abn, NCS' and 'Abn, CS' fundoscopy/fundus photography results at week 0 and week 26. Week 26 data are based on the last on-treatment value which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.

Presence of ketone in urine was assessed by urine dipstick and categorised as: Negative, Positive, Trace, 1+, 2+, 3+. Change from baseline is represented in terms of percentage of patients with ketone values at week 0 and week 26 (last on-treatment value). Last on-treatment value contains the last available measurement in the on-treatment period.

Presence of protein in urine was assessed by urine dipstick and categorised as: Negative, Positive, Trace, 1+, 2+, 3+. Change from baseline is represented in terms of percentage of patients with protein values at week 0 and week 26 (last on-treatment value). Last on-treatment value contains the last available measurement in the on-treatment period.

Presence of erythrocytes in urine was assessed by urine dipstick and categorised as: Negative, Positive, Trace, 1+, 2+, 3+. Change from baseline is represented in terms of percentage of patients with erythrocytes values at week 0 and week 26 (last on-treatment value). Last on-treatment value contains the last available measurement in the on-treatment period.

Insulin aspart antibody titres (antibodies specific for insulin aspart and those cross-reacting with human insulin) measured at baseline and at 26 weeks. Week 26 data are based on the last on-treatment value which contains the last available measurement in the on-treatment period. Anti-insulin aspart antibody was measured as % bound radioactivity-labelled insulin aspart/Total added radioactivity-labelled insulin aspart (%B/T).

The results are based on the last on-treatment value, which included the last available measurement in the on-treatment period.

The results are based on the last on-treatment value, which included the last available measurement in the on-treatment period.