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

Phase 3

Completed

Conditions: Diabetes
Diabetes Mellitus, Type 1

Interventions: Drug: insulin aspart
Drug: Faster-acting insulin aspart
Drug: insulin degludec

Registration Number: NCT02500706

Lead Sponsor: Novo Nordisk A/S

Brief Summary: This trial is conducted in Asia, Europe and North America. The purpose is to confirm efficacy in terms of glycaemic control of treatment with mealtime faster-acting insulin aspart in combination with insulin degludec in adults with Type 1 Diabetes Mellitus.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1108

Inclusion Criteria

Male or female, age greater than or equal to 18 years ( for Japan and Taiwan: age greater than or equal to 20 years) at the time of signing informed consent - Type 1 Diabetes Mellitus (based on clinical judgement and/or supported by laboratory analysis as per local guidelines) 12 months or more prior to screening - 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 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 less than or equal to 35.0 kg/m^2

Exclusion Criteria

Within the past 180 days any of the following: myocardial infarction, stroke or hospitalization for unstable angina and/or transient ischemic attack - Subjects presently classified as being in New York Heart Association (NYHA) Class IV Currently planned coronary, carotid or peripheral artery revascularisation - Diabetic ketoacidosis requiring hospitalisation within the last 180 days prior to screening (Visit 1) - Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of three months before screening (Visit 1)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mealtime NovoRapid® and insulin degludec	insulin aspart	-
Postmeal faster-acting insulin aspart and insulin degludec	insulin degludec	-
Mealtime faster-acting insulin aspart and insulin degludec	Faster-acting insulin aspart	-
Postmeal faster-acting insulin aspart and insulin degludec	Faster-acting insulin aspart	-
Mealtime faster-acting insulin aspart and insulin degludec	insulin degludec	-
Mealtime NovoRapid® and insulin degludec	insulin degludec	-

Primary Outcome Measures

Name	Time	Method
Change From Baseline in HbA1c 26 Weeks After Randomisation	Week 0, week 26	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Subjects Reaching HbA1c Targets (HbA1c < 7.0% Without Severe Hypoglycaemia and Minimal Weight Gain [<3.0%]) 26 Weeks After Randomisation	26 weeks after randomisation	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.
Change From Baseline in Fasting Plasma Glucose (FPG) 26 Weeks After Randomisation	Week 0, week 26	The results are based on the last in-trial value, which included the last available measurement in the in-trial period.
Change From Baseline in 1-hour Post Prandial Glucose (PPG) Increment 26 Weeks After Randomisation (Meal Test)	Week 0, week 26	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.
Change From Baseline in 1,5-anhydroglucitol 26 Weeks After Randomisation	Week 0, week 26	The results are based on the last in-trial value, which included the last available measurement in the in-trial period.
Percentage of Subjects Reaching HbA1c Targets (HbA1c < 7.0%) 26 Weeks After Randomisation	26 weeks after randomisation	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.
Percentage of Subjects Reaching HbA1c Targets (HbA1c < 7.0% Without Severe Hypoglycaemia) 26 Weeks After Randomisation	26 weeks after randomisation	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.
Change From Baseline in 7-9-7-point Self-measured Plasma Glucose (SMPG) 26 Weeks After Randomisation: Mean of the 7-9-7-point Profile	Week 0, week 26	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.
Change From Baseline in 30- Min, 1- Hour, 2- Hour, 3- Hour and 4- Hour PPG 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in 30- Min, 1- Hour, 2- Hour, 3- Hour and 4- Hour PPG Increment 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in 7-9-7-point SMPG 26 Weeks After Randomisation: PPG (Mean, Breakfast, Lunch, Main Evening Meal)	Week 0, week 26	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.
Change From Baseline in 7-9-7-point SMPG 26 Weeks After Randomisation: PPG Increment (Mean, Breakfast, Lunch, Main Evening Meal)	Week 0, week 26	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.
Change From Baseline in 7-9-7-point SMPG 26 Weeks After Randomisation: Fluctuation in 7-9-7-point Profile	Week 0, week 26	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.
Change From Baseline in 7-9-7-point SMPG 26 Weeks After Randomisation: Change in the Nocturnal Self-measured Plasma Glucose Measurements	Week 0, week 26	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 Reaching PPG Target (Overall Mean of Daily PPG Measurements in SMPG) 26 Weeks After Randomisation: Overall PPG (1 Hour) ≤7.8 mmol/L	26 weeks after randomisation	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 Reaching PPG Target (Overall Mean of Daily PPG Measurements in SMPG) 26 Weeks After Randomisation: Overall PPG (1 Hour) ≤7.8 mmol/L Without Severe Hypoglycaemia	26 weeks after randomisation	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.
Percentage of Subjects Reaching PPG Target (Overall Mean of Daily PPG Measurements in SMPG) 26 Weeks After Randomisation: Overall PPG (1 Hour) ≤7.8 mmol/L and HbA1c <7.0% and Minimal Weight Gain (<3.0%) Without Severe Hypoglycaemia	26 weeks after randomisation	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 Lipids-lipoproteins Profile 26 Weeks After Randomisation (Total Cholesterol, High Density Lipoproteins [HDL] Cholesterol, Low Density Lipoproteins [LDL] Cholesterol)	Week 0, week 26	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).
Insulin Dose (Basal Insulin Dose, Total and Individual Meal Insulin Dose)	Week 0, week 26	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.
Number of Treatment Emergent Adverse Events During 26 Weeks After Randomisation	Week 0 to week 26 (+7 days)	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.
Number of Treatment-emergent Injection Site Reactions During the 26 Weeks After Randomisation	Week 0 to week 26 (+7 days)	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.
Number of Hypoglycaemic Episodes Classified Both According to the American Diabetes Association (ADA) Definition and Novo Nordisk (NN) Definition During 26 Weeks After Randomisation: Overall	Week 0 to week 26 (+1 day)	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.
Change From Baseline in Aspartate Aminotransferase 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Number of Hypoglycaemic Episodes Classified Both According to the ADA Definition and Novo Nordisk Definition During 26 Weeks After Randomisation: Daytime and Nocturnal Hypoglycaemic Episodes (00:01-05:59 - Inclusive)	Week 0 to week 26 (+1 day)	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.
Change From Baseline in Total Bilirubin 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Number of Hypoglycaemic Episodes Classified Both According to the ADA Definition and Novo Nordisk Definition During 26 Weeks After Randomisation: From Start of Meal Until 1,2, 4 Hours and From 2 Hours (Exclusive) to 4 Hours (Inclusive) After Start of Meal	Week 0 to week 26 (+1 day)	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.
Change From Baseline 26 Weeks After Randomisation in Clinical Evaluations (Physical Examination)	Week 0, week 26	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 Blood Pressure 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in Pulse 26 Weeks After Randomisation	Week 0, week 26	Results are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Clinical Evaluation (Electrocardiogram) 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in Clinical Evaluation (Fundoscopy/Fundus Photography) 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in Erythrocytes 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Haematocrit 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Haemoglobin 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Leukocytes 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Thrombocytes 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Alanine Aminotransferase 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Albumin 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Alkaline Phosphatase 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Potassium 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Creatinine 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Total Protein 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Urinary Albumin-to-creatinine Ratio 26 Weeks After Randomisation	Week 0, week 26	Week 26 data are based on the last on-treatment value, which contains the last available measurement in the on-treatment period.
Change From Baseline in Urinalysis (Ketones) 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in Urinalysis (Protein) 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in Urinalysis (Erythrocytes) 26 Weeks After Randomisation	Week 0, week 26	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.
Change From Baseline in Anti-insulin Aspart (Specific and Cross-reacting With Human Insulin) Antibody Development 26 Weeks After Randomisation	Week 0, week 26	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).
Change From Baseline in Body Weight 26 Weeks After Randomisation	Week 0, week 26	The results are based on the last on-treatment value, which included the last available measurement in the on-treatment period.
Change From Baseline in Body Mass Index 26 Weeks After Randomisation	Week 0, week 26	The results are based on the last on-treatment value, which included the last available measurement in the on-treatment period.