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    Clinical Trial Results:
    Efficacy and Safety of Faster-acting Insulin Aspart compared to NovoRapid® both in combination with Insulin Degludec in Adults with Type 1 Diabetes

    Summary
    EudraCT number
    		 2015-001047-36
    Trial protocol
    		 BG   DE   AT   IT  
    Global end of trial date
    16 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2018
    First version publication date
    30 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1218-4131
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02500706
    WHO universal trial number (UTN)
    		 U1111-1167-9495
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the effect 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
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and ICH GCP (1996) and FDA 21 CFR 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    04 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 24
    Country: Number of subjects enrolled
    Bulgaria: 72
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    India: 103
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Italy: 41
    Country: Number of subjects enrolled
    Japan: 245
    Country: Number of subjects enrolled
    Russian Federation: 92
    Country: Number of subjects enrolled
    Serbia: 38
    Country: Number of subjects enrolled
    Taiwan: 31
    Country: Number of subjects enrolled
    United States: 269
    Worldwide total number of subjects
    1025
    EEA total number of subjects
    182
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    964
    From 65 to 84 years
    61
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 146 sites in 12 countries(number of sites indicates those that both screened and randomised subjects, unless otherwise noted)-Austria(4);Bulgaria(8); Canada(6); Germany(7); India(16); Israel(6); Italy(4); Japan(24); Russian Federation(10); Serbia(3); Taiwan(3); United States(55 sites screened/52 sites randomised subjects)

    Pre-assignment
    Screening details
    		 Eligible subjects were enrolled in an 8-week run-in period (1108 subjects) where subjects were switched from previous insulin treatment to insulin degludec once daily,and NovoRapid®/NovoLog® as mealtime bolus insulin. The basal insulin treatment was optimised using treat-to-target approach. 83 subjects were run-in failures and 1025 were randomised.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    The trial was partly double-blinded. The bolus treatment was double-blind for the mealtime faster aspart and NovoRapid®/NovoLog® treatment arms and open-label for the postmeal faster aspart treatment arm.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Faster aspart (meal)
    Arm description
    		 Bolus insulin: Participants received subcutaneous (s.c., into the abdominal wall) injections of faster-acting insulin aspart at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Faster-acting insulin aspart
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Faster-acting insulin aspart was administered 0−2 minutes before each of the three main meals (i.e. breakfast, lunch and main evening meal). No adjustments of faster-acting insulin aspart dose was performed by the investigator during run-in. During the 26-week treatment period, the investigator focussed on optimising the bolus insulin. The bolus insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L [71–108 mg/dL] in a treat-to-target fashion.

    Investigational medicinal product name
    Insulin degludec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin degludec was administered once daily at any time of the day, preferably at the same time every day and injected subcutaneously into the thigh, or upper arm (deltoid area). During the 8-week run-in period, the investigator focussed on optimising the treatment by using a treat-to-target approach; the basal insulin was titrated by the investigator on a weekly basis to the pre-breakfast glycaemic target of 4.0-5.0 mmol/L (71-90 mg/dL). Further adjustments of the basal insulin dose during the treatment period were done at the discretion of the Investigator, if needed.

    Arm title
    		 Faster aspart (post)
    Arm description
    		 Bolus insulin: Participants received s.c. injections of faster-acting insulin aspart at mealtime (injecting the bolus insulin at the end of the meal but no later than 20 minutes after the start of the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Faster-acting insulin aspart
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Faster-acting insulin aspart was administered at the end of the meal but no later than 20 minutes after the start of the meal (i.e. breakfast, lunch and main evening meal). No adjustments of faster-acting insulin aspart dose was performed by the investigator during run-in. During the 26-week treatment period, the investigator focussed on optimising the bolus insulin. The bolus insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L [71–108 mg/dL] in a treat-to-target fashion.

    Investigational medicinal product name
    Insulin degludec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin degludec was administered once daily at any time of the day, preferably at the same time every day and injected subcutaneously into the thigh, or upper arm (deltoid area). During the 8-week run-in period, the investigator focussed on optimising the treatment by using a treat-to-target approach; the basal insulin was titrated by the investigator on a weekly basis to the pre-breakfast glycaemic target of 4.0-5.0 mmol/L (71-90 mg/dL). Further adjustments of the basal insulin dose during the treatment period were done at the discretion of the Investigator, if needed.

    Arm title
    		 NovoRapid (meal)
    Arm description
    		 After 8-week run-in period, subjects continued using mealtime insulin aspart (NovoRapid®/NovoLog®) s.c. injections at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    NovoRapid®/NovoLog®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin aspart was administered 0−2 minutes before each of the three main meals (i.e. breakfast, lunch and main evening meal). No adjustments of faster-acting insulin aspart dose was performed by the investigator during run-in. During the 26-week treatment period, the investigator focussed on optimising the bolus insulin. The bolus insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L [71–108 mg/dL] in a treat-to-target fashion.

    Investigational medicinal product name
    Insulin degludec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin degludec was administered once daily at any time of the day, preferably at the same time every day and injected subcutaneously into the thigh, or upper arm (deltoid area). During the 8-week run-in period, the investigator focussed on optimising the treatment by using a treat-to-target approach; the basal insulin was titrated by the investigator on a weekly basis to the pre-breakfast glycaemic target of 4.0-5.0 mmol/L (71-90 mg/dL). Further adjustments of the basal insulin dose during the treatment period were done at the discretion of the Investigator, if needed.

    Number of subjects in period 1
    		Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Started
    342
    341
    342
    Exposed
    342
    341
    342
    Completed
    338
    334
    335
    Not completed
    4
    7
    7
         Consent withdrawn by subject
    4
    6
    4
         Adverse event, non-fatal
    -
    -
    1
         Unclassified
    -
    -
    1
         Lost to follow-up
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Faster aspart (meal)
    Reporting group description
    		 Bolus insulin: Participants received subcutaneous (s.c., into the abdominal wall) injections of faster-acting insulin aspart at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 Bolus insulin: Participants received s.c. injections of faster-acting insulin aspart at mealtime (injecting the bolus insulin at the end of the meal but no later than 20 minutes after the start of the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 After 8-week run-in period, subjects continued using mealtime insulin aspart (NovoRapid®/NovoLog®) s.c. injections at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Reporting group values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal) Total
    Number of subjects
    		 342 341 342 1025
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 322 319 323 964
        From 65-84 years
    		 20 22 19 61
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.48 ± 14.42 41.02 ± 14.59 40.77 ± 14.22 -
    Gender Categorical
    Units: Subjects
        Female
    		 158 155 163 476
        Male
    		 184 186 179 549

    End points

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    End points reporting groups
    Reporting group title
    Faster aspart (meal)
    Reporting group description
    		 Bolus insulin: Participants received subcutaneous (s.c., into the abdominal wall) injections of faster-acting insulin aspart at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 Bolus insulin: Participants received s.c. injections of faster-acting insulin aspart at mealtime (injecting the bolus insulin at the end of the meal but no later than 20 minutes after the start of the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 After 8-week run-in period, subjects continued using mealtime insulin aspart (NovoRapid®/NovoLog®) s.c. injections at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Primary: Change from baseline in HbA1c

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    End point title
    		 Change from baseline in HbA1c
    End point description
    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. Analysis was based on FAS. Number of subjects analysed=subject with data available for HbA1c.
    End point type
    Primary
    End point timeframe
    26 weeks after randomisation
    End point values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Number of subjects analysed
    342
    341
    342
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.12 ± 0.64
    0.005 ± 0.64
    -0.09 ± 0.65
    Statistical analysis title
    		 Faster aspart (meal) vs. NovoRapid (meal)
    Statistical analysis description
    The endpoint was analysed using an analysis of variance model after multiple imputation assuming treatment according to randomisation. The model includes treatment, region and bolus adjusting method at randomisation as factors, and baseline HbA1c as a covariate.
    Comparison groups
    NovoRapid (meal) v Faster aspart (meal)
    Number of subjects included in analysis
    684
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.001 [2]
    Method
    		 ANOVA model after multiple imputation
    Parameter type
    		 Treatment difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.07
    Notes
    [1] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 1: Primary analysis: HbA1c non-inferiority of mealtime faster aspart versus mealtime NovoRapid®/NovoLog®. Non-inferiority of mealtime faster aspart was considered confirmed if the upper boundary of the two-sided 95% CI was below or equal to 0.4%
    [2] - p-values are from the 1-sided test for non-inferiority evaluated at the 2.5% level
    Statistical analysis title
    		 Faster aspart (meal) vs. NovoRapid (meal)
    Statistical analysis description
    The endpoint was analysed using an analysis of variance model after multiple imputation assuming treatment according to randomisation. The model includes treatment, region and bolus adjusting method at randomisation as factors, and baseline HbA1c as a covariate.
    Comparison groups
    Faster aspart (meal) v NovoRapid (meal)
    Number of subjects included in analysis
    684
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.633 [4]
    Method
    		 ANOVA model after multiple imputation
    Parameter type
    		 Treatment difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.07
    Notes
    [3] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 4: HbA1c superiority of mealtime faster aspart versus mealtime NovoRapid®/NovoLog®. Superiority was to be confirmed if the upper boundary of the two-sided 95% CI of the mean treatment difference (mealtime faster aspart minus mealtime NovoRapid®/NovoLog®) was below 0%-points
    [4] - p-value from the 2-sided test for treatment difference evaluated at the 5% level
    Statistical analysis title
    		 Faster aspart (post) vs. NovoRapid (meal)
    Statistical analysis description
    The endpoint was analysed using an analysis of variance model after multiple imputation assuming treatment according to randomisation. The model includes treatment, region and bolus adjusting method at randomisation as factors, and baseline HbA1c as a covariate.
    Comparison groups
    Faster aspart (post) v NovoRapid (meal)
    Number of subjects included in analysis
    683
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 ANOVA model after multiple imputation
    Parameter type
    		 Treatment difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.004
         upper limit
    		 0.19
    Notes
    [5] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 2: HbA1c non-inferiority of postmeal faster aspart versus mealtime NovoRapid®/NovoLog®. Non-inferiority of postmeal faster aspart was considered confirmed if the upper boundary of the two-sided 95% CI was below or equal to 0.4%
    [6] - p-values are from the 1-sided test for non-inferiority evaluated at the 2.5% level

    Secondary: Change from baseline in 1-hour post prandial glucose increment (meal test)

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    End point title
    		 Change from baseline in 1-hour post prandial glucose increment (meal test)
    End point description
    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. Analysis was based on FAS. Number of subjects analysed=subject with data available for 1-hour PPG and pre-prandial PG.
    End point type
    Secondary
    End point timeframe
    26 weeks after randomisation
    End point values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Number of subjects analysed
    332
    332
    326
    Units: mmol/L
        arithmetic mean (standard deviation)
    -1.13 ± 4.04
    1.04 ± 3.53
    -0.15 ± 3.78
    Statistical analysis title
    		 Faster aspart (meal) vs. NovoRapid (meal)
    Statistical analysis description
    Change from baseline in postprandial glucose increment (meal test) is analysed using an analysis of variance model. The model includes treatment, region and bolus adjusting method at randomisation as factors, and baseline postprandial glucose increment as a covariate.
    Comparison groups
    Faster aspart (meal) v NovoRapid (meal)
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001 [8]
    Method
    		 ANOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.36
         upper limit
    		 -0.45
    Notes
    [7] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 3: 1-hour postprandial glucose (PPG) increments superiority of mealtime faster aspart versus mealtime NovoRapid®/NovoLog. Superiority was confirmed if the upper boundary of the two-sided 95% CI of the mean treatment difference (mealtime faster aspart minus mealtime NovoRapid®/NovoLog®) was below 0.
    [8] - p-value from the 2-sided test for treatment difference evaluated at the 5% level.

    Secondary: Change from baseline in 1,5-anhydroglucitol

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    End point title
    		 Change from baseline in 1,5-anhydroglucitol
    End point description
    The results are based on the last in-trial value, which included the last available measurement in the in-trial period.
    End point type
    Secondary
    End point timeframe
    26 weeks after randomisation
    End point values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Number of subjects analysed
    341
    336
    338
    Units: ug/mL
        arithmetic mean (standard deviation)
    0.22 ± 2.23
    -0.15 ± 2.10
    0.22 ± 2.25
    Statistical analysis title
    		 Faster aspart (meal) vs. NovoRapid (meal)
    Statistical analysis description
    Change from baseline in 1,5-anhydroglucitol was analysed using an analysis of variance model after multiple imputation assuming treatment according to randomisation. The model includes treatment, region and bolus adjusting method at randomisation as factors, and baseline 1,5-anhydroglucitol as a covariate.
    Comparison groups
    Faster aspart (meal) v NovoRapid (meal)
    Number of subjects included in analysis
    679
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.924 [10]
    Method
    		 ANOVA model after multiple imputation
    Parameter type
    		 Treatment difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.34
    Notes
    [9] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 5: 1,5-anhydroglucitol superiority of mealtime faster aspart versus mealtime NovoRapid®/NovoLog®. Superiority was to be confirmed if the lower boundary of the two-sided 95% CI of the mean treatment difference (mealtime faster aspart minus mealtime NovoRapid®/NovoLog®) was above 0.
    [10] - p-values are from the 2-sided test for treatment difference evaluated at the 5% level.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 0 to week 26 (+7 days)
    Adverse event reporting additional description
    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 seven days after the last day of randomised treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 Bolus insulin: Participants received s.c. injections of faster-acting insulin aspart at mealtime (injecting the bolus insulin at the end of the meal but no later than 20 minutes after the start of the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 After 8-week run-in period, subjects continued using mealtime insulin aspart (NovoRapid®/NovoLog®) s.c. injections at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Reporting group title
    Faster aspart (meal)
    Reporting group description
    		 subcutaneous (s.c., into the abdominal wall) injections of faster-acting insulin aspart at mealtime (0−2 minutes before the meal) during 26-week treatment period. Throughout the trial, the insulin was administered at each of the three main meals (i.e. breakfast, lunch and main evening meal). The insulin was titrated to the glycaemic target of pre-prandial and bedtime plasma glucose between 4.0–6.0 mmol/L (71–108 mg/dL) in a treat-to-target fashion. Basal insulin: Participants continued insulin degludec once daily s.c. injections at the dose optimized during run-in period during 26-week treatment period.

    Serious adverse events
    		 Faster aspart (post) NovoRapid (meal) Faster aspart (meal)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 341 (4.99%)
    17 / 342 (4.97%)
    20 / 342 (5.85%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Extradural haematoma
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrong drug administered
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 342 (0.58%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Haemorrhoid operation
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    3 / 341 (0.88%)
    2 / 342 (0.58%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Collagen disorder
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trigger finger
         subjects affected / exposed
    0 / 341 (0.00%)
    0 / 342 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 342 (0.29%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 342 (0.29%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 341 (0.88%)
    6 / 342 (1.75%)
    8 / 342 (2.34%)
         occurrences causally related to treatment / all
    6 / 6
    5 / 6
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia unawareness
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 342 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Faster aspart (post) NovoRapid (meal) Faster aspart (meal)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    152 / 341 (44.57%)
    161 / 342 (47.08%)
    154 / 342 (45.03%)
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    67 / 341 (19.65%)
    68 / 342 (19.88%)
    58 / 342 (16.96%)
         occurrences all number
    83
    82
    81
    Infections and infestations
    Influenza
         subjects affected / exposed
    14 / 341 (4.11%)
    10 / 342 (2.92%)
    21 / 342 (6.14%)
         occurrences all number
    14
    10
    22
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 341 (7.62%)
    27 / 342 (7.89%)
    30 / 342 (8.77%)
         occurrences all number
    34
    34
    38
    Viral upper respiratory tract infection
         subjects affected / exposed
    70 / 341 (20.53%)
    80 / 342 (23.39%)
    73 / 342 (21.35%)
         occurrences all number
    100
    118
    101

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2016
    1. Introduction of estimands into the protocol with emphasis on using the in-trial observation period for the primary estimand: Significant changes to statistical analysis section to accommodate this (primary analysis, sensitivity analysis, wording of endpoints). Differentiation between trial drug discontinuation and trial discontinuation. 2. Introduction of premature discontinuation visit into trial design. 3. Addition of sections describing criteria for run-in failure and for premature discontinuation of trial product. 4. Addition of sections describing how subjects that discontinue trial product prematurely should be followed and how a subject can withdraw from the trial. 5. Addition of section describing choice of non-inferiority margin. 6. Order of hierarchical testing changed.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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