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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 Children and Adolescents with Type 1 Diabetes

    Summary
    EudraCT number
    		 2014-002568-33
    Trial protocol
    		 BG   CZ   EE   DE   LV   LT   FI   PL   IT  
    Global end of trial date
    03 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2018
    First version publication date
    19 Sep 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NN1218-4101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02670915
    WHO universal trial number (UTN)
    		 U1111-1158-1170
    Other trial identifiers
    		 Japanese trial registration: JapicCTI-163248
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the effect of treatment with meal-time faster-acting insulin aspart in terms of glycaemic control by comparing it to meal-time NovoRapid® both in combination with insulin degludec using a non-inferiority approach in children and adolescents with type 1 diabetes.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice, including archiving of essential documents 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
    Bulgaria: 48
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Estonia: 17
    Country: Number of subjects enrolled
    Finland: 13
    Country: Number of subjects enrolled
    India: 59
    Country: Number of subjects enrolled
    Israel: 31
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Japan: 66
    Country: Number of subjects enrolled
    Lithuania: 10
    Country: Number of subjects enrolled
    Latvia: 13
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Russian Federation: 104
    Country: Number of subjects enrolled
    Serbia: 20
    Country: Number of subjects enrolled
    Turkey: 36
    Country: Number of subjects enrolled
    Ukraine: 60
    Country: Number of subjects enrolled
    United States: 195
    Worldwide total number of subjects
    777
    EEA total number of subjects
    206
    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)
    347
    Adolescents (12-17 years)
    430
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The trial was conducted at 150 sites in 17 countries(number of sites with screened/randomised subjects)-Bulgaria: 4/4; Czech Republic: 6/6; Estonia: 2/2; Finland: 3/3; Germany: 6/6; India: 7/7; Israel: 6/6; Italy: 5/5; Japan: 34/34; Latvia: 1/1; Lithuania: 1/1; Poland: 4/4; Russia: 11/11; Serbia: 4/4; Turkey: 7/7; Ukraine: 9/9; United States: 40/39

    Pre-assignment
    Screening details
    		 12 week run-in period (834 subjects): Subjects were switched from previous insulin treatment to insulin degludec once daily, and mealtime NovoRapid®/NovoLog®. Insulin degludec treatment was optimised on a weekly basis to the pre-breakfast glycaemic target of 4.0−8.0 mmol/L. 57 subjects were run-in failures and 777 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
    		 Subject, Investigator
    Blinding implementation details
    The trial was partly double-blinded. The bolus treatment was double-blind for the mealtime faster aspart and NovoRapid®/NovoLog® treatment groups and open-label for the postmeal faster aspart treatment group.

    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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed. A total of 260 subjects randomized to this arm; however, One subject randomised to the faster aspart (post) group, received mealtime faster aspart throughout the treatment period. Hence, total number of exposed to faster aspart (meal)=261.
    Arm type
    		 Experimental

    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, preferably at the same time every day and injected subcutaneously. During the 12-week run-in period, insulin degludec treatment was titrated by the investigator on a weekly basis to the pre-breakfast glycaemic target of 4.0−8.0 mmol/L. During the 26-week treatment period, adjustment at the discretion of the investigator was allowed if needed

    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). In the 26-week treatment period, the Faster-acting insulin aspart was titrated to the pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L in a treat-to-target fashion.

    Arm title
    		 Faster aspart (post)
    Arm description
    		 Participants received s.c. injections of faster-acting insulin aspart at mealtime (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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed. A total of 259 subjects randomized to this arm; however, One subject randomised to this group, received mealtime faster aspart throughout the treatment period. Hence, total number of exposed to faster aspart (post)=258.
    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 20 minutes after the start of the meal (i.e. breakfast, lunch and main evening meal). In the 26-week treatment period, the Faster-acting insulin aspart was titrated to the pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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, preferably at the same time every day and injected subcutaneously. During the 12-week run-in period, insulin degludec treatment was titrated by the investigator on a weekly basis to the pre-breakfast glycaemic target of 4.0−8.0 mmol/L. During the 26-week treatment period, adjustment at the discretion of the investigator was allowed if needed

    Arm title
    		 NovoRapid (meal)
    Arm description
    		 After 12-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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed.
    Arm type
    		 Active comparator

    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, preferably at the same time every day and injected subcutaneously. During the 12-week run-in period, insulin degludec treatment was titrated by the investigator on a weekly basis to the pre-breakfast glycaemic target of 4.0−8.0 mmol/L. During the 26-week treatment period, adjustment at the discretion of the investigator was allowed if needed

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    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). In the 26-week treatment period, the insulin aspart was titrated to the pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L in a treat-to-target fashion.

    Number of subjects in period 1
    		Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Started
    260
    259
    258
    Completed
    256
    251
    253
    Not completed
    4
    8
    5
         Unclassified
    -
    3
    -
         Withdrawal by parent/guardian
    4
    4
    1
         Withdrawal by subject
    -
    1
    4

    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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed. A total of 260 subjects randomized to this arm; however, One subject randomised to the faster aspart (post) group, received mealtime faster aspart throughout the treatment period. Hence, total number of exposed to faster aspart (meal)=261.

    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 Participants received s.c. injections of faster-acting insulin aspart at mealtime (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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed. A total of 259 subjects randomized to this arm; however, One subject randomised to this group, received mealtime faster aspart throughout the treatment period. Hence, total number of exposed to faster aspart (post)=258.

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 After 12-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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed.

    Reporting group values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal) Total
    Number of subjects
    		 260 259 258 777
    Age Categorical
    Units: Subjects
        1 - <3 years
    		 2 2 0 4
        3 - <6 years
    		 14 14 14 42
        6 - <12 years
    		 100 100 101 301
        12 - <18 years
    		 144 143 143 430
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.72 ( 3.74 ) 11.62 ( 3.65 ) 11.70 ( 3.44 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 126 122 110 358
        Male
    		 134 137 148 419
    Glycosylated haemoglobin (HbA1c)
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 7.57 ( 0.80 ) 7.58 ( 0.84 ) 7.53 ( 0.83 ) -
    Fasting plasma glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 7.58 ( 3.56 ) 8.03 ( 3.35 ) 7.79 ( 3.48 ) -

    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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed. A total of 260 subjects randomized to this arm; however, One subject randomised to the faster aspart (post) group, received mealtime faster aspart throughout the treatment period. Hence, total number of exposed to faster aspart (meal)=261.

    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 Participants received s.c. injections of faster-acting insulin aspart at mealtime (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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed. A total of 259 subjects randomized to this arm; however, One subject randomised to this group, received mealtime faster aspart throughout the treatment period. Hence, total number of exposed to faster aspart (post)=258.

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 After 12-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 pre-meal target of 4.0−8.0 mmol/L, and the bed-time target of 6.7–10 mmol/L 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. Dose adjustment at the discretion of the investigator was allowed if needed.

    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 full analysis set (FAS) which includes all randomised subjects. 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
    260
    259
    258
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    0.06 ( 0.80 )
    0.33 ( 0.83 )
    0.23 ( 0.82 )
    Statistical analysis title
    		 Faster aspart (meal) vs. NovoRapid (meal)
    Statistical analysis description
    The primary analysis was implemented as a statistical model using multiple imputation where the subjects without any available HbA1c measurements at scheduled visits had their change from baseline HbA1c value(s) imputed from the available information from the treatment the subject had been randomised to.
    Comparison groups
    Faster aspart (meal) v NovoRapid (meal)
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.001 [2]
    Method
    		 multiple imputation
    Parameter type
    		 Treatment difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.03
    Notes
    [1] - Stepwise hierarchical testing procedure was applied: Step 1-Primary analysis: HbA1c non-inferiority of mealtime faster aspart versus mealtime NovoRapid®/NovoLog® both in combination with insulin degludec. 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 (post) vs. NovoRapid (meal)
    Statistical analysis description
    The analysis was implemented as a statistical model using multiple imputation where the subjects without any available HbA1c measurements at scheduled visits had their change from baseline HbA1c value(s) imputed from the available information from the treatment the subject had been randomised to.
    Comparison groups
    Faster aspart (post) v NovoRapid (meal)
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 multiple imputation
    Parameter type
    		 Treatment difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.26
    Notes
    [3] - Stepwise hierarchical testing procedure was applied: Step 2-Confirmatory secondary analysis: HbA1c non-inferiority of postmeal faster aspart versus mealtime NovoRapid®/NovoLog® both in combination with insulin degludec. 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%.
    [4] - 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 analysis was implemented as a statistical model using multiple imputation where the subjects without any available HbA1c measurements at scheduled visits had their change from baseline HbA1c value(s) imputed from the available information from the treatment the subject had been randomised to.
    Comparison groups
    Faster aspart (meal) v NovoRapid (meal)
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.007 [6]
    Method
    		 multiple imputation
    Parameter type
    		 Treatment difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.03
    Notes
    [5] - Stepwise hierarchical testing procedure was applied: Step 3-Confirmatory secondary analysis: HbA1c superiority of mealtime faster aspart versus mealtime NovoRapid®/NovoLog® both in combination with insulin degludec. Superiority of mealtime faster aspart was considered confirmed if the upper boundary of the two-sided 95% CI was below 0.
    [6] - p-values are from the 1-sided test for superiority evaluated at the 2.5% level.

    Secondary: Change from baseline in 8-point self-measured plasma glucose (SMPG) profile (8-point profile): - Mean postprandial glucose (PPG) and PPG increment over all three meals

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    End point title
    		 Change from baseline in 8-point self-measured plasma glucose (SMPG) profile (8-point profile): - Mean postprandial glucose (PPG) and PPG increment over all three meals
    End point description
    SMPG values were recorded at 8 time-points: before and after (60 min after the start of the meal) breakfast, lunch, main evening meal, before bedtime, and before breakfast on the next day. PPG was recorded by the subject as part of the two 8-point profiles prior to the visits. PPG increments based on the 8-point profiles were derived separately for PG measurements made 1 hour after the meal. PPG increment for each meal (breakfast, lunch, main evening meal) was derived from the 8-point profile as the difference between PPG values and the PG value before meal. 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=subjects who contributed to the analysis.
    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
    260
    259
    258
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change in PPG all meals (n=196, 200, 203)
    -0.94 ( 2.55 )
    0.36 ( 3.17 )
    -0.21 ( 2.79 )
        Change in PPG increment all meals (n=196,197,202)
    -0.92 ( 2.92 )
    0.56 ( 2.88 )
    0.14 ( 2.75 )
    No statistical analyses for this end point

    Secondary: Change from baseline in fasting plasma glucose (FPG)

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    End point title
    		 Change from baseline in fasting plasma glucose (FPG)
    End point description
    Change from baseline (week 0) in FPG 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 FPG.
    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
    173
    185
    161
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.41 ( 5.04 )
    -0.08 ( 4.49 )
    -0.13 ( 4.16 )
    No statistical analyses for this end point

    Secondary: Number of treatment emergent adverse events (AEs)

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    End point title
    		 Number of treatment emergent adverse events (AEs)
    End point description
    Treatment emergent is defined as an event that has onset up to 7 days after last day of randomised treatment and excluding the events occurring in the run-in period. Results are presented as event rate per 100 patient years of exposure (PYE). Safety analysis set (SAS) includes all subjects receiving at least one dose of the investigational product or its comparator. Subjects in the safety set will contribute to the evaluation “as treated”. One subject was randomised to the postmeal faster aspart group but was exposed to mealtime faster aspart throughout the treatment period. The subject was included in the mealtime faster aspart group for the safety analysis set. Therefore, number of subjects analysed= 261 for Faster aspart (meal), 258 for Faster aspart (post) and 258 for NovoRapid (meal).
    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
    260
    259
    258
    Units: Event rate per 100 PYE
        number (not applicable)
    448.6
    531.1
    464.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization (week 0) to week 26 + 7 days of follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Faster aspart (meal)
    Reporting group description
    		 -

    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 -

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 -

    Serious adverse events
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 261 (1.92%)
    13 / 258 (5.04%)
    9 / 258 (3.49%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 261 (0.38%)
    2 / 258 (0.78%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Diabetes mellitus management
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 258 (0.39%)
    0 / 258 (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
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 258 (0.39%)
    0 / 258 (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
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 261 (0.00%)
    2 / 258 (0.78%)
    0 / 258 (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
    Idiopathic partial epilepsy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 258 (0.00%)
    0 / 258 (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
    Abdominal pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with mixed disturbance of emotion and conduct
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 258 (0.39%)
    0 / 258 (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
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 258 (0.39%)
    0 / 258 (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
    Renal colic
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 258 (0.39%)
    0 / 258 (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
    Musculoskeletal and connective tissue disorders
    Epiphysiolysis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 258 (0.39%)
    0 / 258 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 258 (0.00%)
    0 / 258 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 258 (0.00%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 258 (0.00%)
    0 / 258 (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
    Influenza
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 258 (0.39%)
    0 / 258 (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
    Osteomyelitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 258 (0.00%)
    0 / 258 (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
    Tonsillitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 261 (0.00%)
    2 / 258 (0.78%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 258 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    2 / 258 (0.78%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 1
         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 (meal) Faster aspart (post) NovoRapid (meal)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 261 (52.49%)
    149 / 258 (57.75%)
    136 / 258 (52.71%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 261 (6.13%)
    26 / 258 (10.08%)
    22 / 258 (8.53%)
         occurrences all number
    21
    38
    35
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    22 / 261 (8.43%)
    16 / 258 (6.20%)
    18 / 258 (6.98%)
         occurrences all number
    26
    16
    20
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    9 / 261 (3.45%)
    21 / 258 (8.14%)
    7 / 258 (2.71%)
         occurrences all number
    9
    24
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 261 (3.83%)
    11 / 258 (4.26%)
    16 / 258 (6.20%)
         occurrences all number
    11
    14
    21
    Oropharyngeal pain
         subjects affected / exposed
    10 / 261 (3.83%)
    9 / 258 (3.49%)
    13 / 258 (5.04%)
         occurrences all number
    12
    13
    16
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    13 / 261 (4.98%)
    16 / 258 (6.20%)
    19 / 258 (7.36%)
         occurrences all number
    15
    17
    24
    Influenza
         subjects affected / exposed
    20 / 261 (7.66%)
    14 / 258 (5.43%)
    14 / 258 (5.43%)
         occurrences all number
    28
    19
    21
    Rhinitis
         subjects affected / exposed
    10 / 261 (3.83%)
    16 / 258 (6.20%)
    11 / 258 (4.26%)
         occurrences all number
    16
    24
    16
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 261 (8.43%)
    32 / 258 (12.40%)
    26 / 258 (10.08%)
         occurrences all number
    31
    41
    32
    Viral infection
         subjects affected / exposed
    7 / 261 (2.68%)
    9 / 258 (3.49%)
    14 / 258 (5.43%)
         occurrences all number
    8
    11
    20
    Viral upper respiratory tract infection
         subjects affected / exposed
    60 / 261 (22.99%)
    53 / 258 (20.54%)
    48 / 258 (18.60%)
         occurrences all number
    73
    79
    75

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2016
    Added ‘or equal to’ in the definition of confirming of non-inferiority in trial protocol
    06 Jun 2016
    A mistake identified in the blood sampling volume at visit 14 and visit 40 for the subjects participating in the Continuous lucose Monitoring (CGM) and meal test subgroup. Consequently the required minimum weight for participation in the CGM and meal test subgroup was increased to ensure the blood volume collected at visit 14 and visit 40 did not exceed 1% of the subjects total blood volume.
    25 Feb 2017
    1. An inaccuracy was identified in the layman language for reporting hypoglycaemic episodes. There was a need to clarify the run-in failure criteria, to provide more guidance on when to report a MESI, and that the FPG sample was to be collected using the FPG home sampling kit no matter if the FPG sample was taken at home or at site. 2. The statistical section was updated to clarify the analyses made for the primary and secondary estimands, the supportive secondary CGM and meal test related efficacy endpoints. A clarification was made to which treatment emergent hypoglycaemic episodes should be included in the analyses. 3. An appendix was updated to reflect the changes that occurred due to the change in CGM supplier shortly before trial initiation.

    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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