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    Clinical Trial Results:
    Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination with Insulin Glargine and Metformin in Adults with Type 2 Diabetes

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2010-024051-93
    Trial protocol
    		 GB   SK  
    Global end of trial date
    22 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jul 2016
    First version publication date
    27 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1218-3853
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01819129
    WHO universal trial number (UTN)
    		 U1111-1118-2509
    Other trial identifiers
    		 Clinical Trials Registry - India ID: CTRI/2014/01/004285
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaérd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR,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
    30 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm efficacy of treatment with mealtime faster-acting insulin aspart (FIAsp) in terms of glycaemic control measured by glycosylated haemoglobin (HbA1c) after 26 weeks of randomised treatment, by comparing to meal time insulin aspart, both in combination with once daily insulin glargine and metformin, using a non-inferiority approach.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice and FDA 21 CFR 312.120.
    Background therapy
    		 Metformin: All subjects continued their pre-trial metformin treatment without changing the frequency or dose throughout the trial. Insulin glargine: Before randomisation, subjects were switched unit-to-unit from their previous basal insulin to once-daily insulin glargine. During run-in period, the investigator titrated the basal insulin (insulin glargine) on a weekly basis in a treat-to-target fashion. When needed, dose adjustments of basal insulin were allowed after the run-in period also.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    09 Sep 2013
    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
    Canada: 23
    Country: Number of subjects enrolled
    Croatia: 16
    Country: Number of subjects enrolled
    India: 74
    Country: Number of subjects enrolled
    Israel: 34
    Country: Number of subjects enrolled
    Russian Federation: 107
    Country: Number of subjects enrolled
    Serbia: 95
    Country: Number of subjects enrolled
    United States: 262
    Country: Number of subjects enrolled
    Slovakia: 54
    Country: Number of subjects enrolled
    United Kingdom: 24
    Worldwide total number of subjects
    689
    EEA total number of subjects
    94
    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)
    489
    From 65 to 84 years
    200
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 There were 128 sites in 9 countries, which enrolled subjects in the run-in period, of which 123 sites later assigned subjects to randomised treatment: Canada: 9 sites; Croatia: 6 sites; India: 6 sites; Israel: 6 sites; Russia: 12 sites; Serbia: 9 sites; Slovakia: 5 sites; United Kingdom: 7 sites; United States: 63 sites

    Pre-assignment
    Screening details
    		 The trial included a screening visit which took place within 2 weeks prior to the run-in visit, to assess the subject’s eligibility. If the subject was found eligible, the subject was to continue in the 8-week run-in period where insulin glargine was initiated and no other oral anti-diabetic treatment than metformin was allowed.

    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 treatment was double-blinded for the faster aspart and NovoRapid®/NovoLog® arms and insulin glargine and metformin were open-labelled. NovoRapid®/NovoLog® and faster aspart were titrated following the same recommendations, since the trial was double-blinded. In case safety committee recommended unblinding of any data, an independent adhoc group was established to maintain the blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Faster aspart
    Arm description
    		 The subjects in this arm started on 4 units of mealtime faster aspart (subcutaneous (sc)) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. Faster aspart was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of faster aspart were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Faster-acting insulin aspart
    Investigational medicinal product code
    Other name
    Insulin aspart
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Faster aspart, 100 units/mL, 3 mL prefilled pen-injector (PDS290), for sc injection. Bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion. Faster aspart dose adjustments were considered daily based on pre-prandial and bedtime SMPG on the previous day. Pre-breakfast bolus insulin was adjusted according to the pre-lunch SMPG the previous day; Pre-lunch bolus insulin was adjusted according to the pre-dinner SMPG the previous day; Pre-dinner bolus insulin was adjusted according to the bedtime SMPG the previous day. The adjustments were +1 or -1 if the pre-prandial or bedtime SMPG was >6.0 mmol/L (>108 mg/dL) or <4.0 mmol/L (<71 mg/dL), respectively. No adjustment was done when the pre-prandial or bedtime SMPG was 4.0 - 6.0 mmol/L (71-108 mg/dL).

    Arm title
    		 NovoRapid
    Arm description
    		 The subjects in this arm started on 4 units of mealtime NovoRapid®/NovoLog® (sc) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of NovoRapid®/NovoLog® were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    NovoRapid®, NovoLog®
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NovoRapid®, 100 units/mL, 3 mL prefilled pen-injector (PDS290), for sc injection. Bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion. NovoRapid®/NovoLog® dose adjustments were considered daily based on pre-prandial and bedtime SMPG on the previous day. Pre-breakfast bolus insulin was adjusted according to the pre-lunch SMPG the previous day; Pre-lunch bolus insulin was adjusted according to the pre-dinner SMPG the previous day; Pre-dinner bolus insulin was adjusted according to the bedtime SMPG the previous day. The adjustments were +1 or -1 if the pre-prandial or bedtime SMPG was >6.0 mmol/L (>108 mg/dL) or <4.0 mmol/L (<71 mg/dL), respectively. No adjustment was done when the pre-prandial or bedtime SMPG was 4.0 - 6.0 mmol/L (71-108 mg/dL).

    Number of subjects in period 1
    		Faster aspart NovoRapid
    Started
    345
    344
    Exposed
    341
    341
    Completed
    301
    305
    Not completed
    44
    39
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    15
    15
         Adverse event, non-fatal
    1
    4
         Withdrawal criteria
    20
    15
         Other, due to weight gain and hypoglycaemic events
    1
    -
         Other, subject wanted HbA1c to be >7%
    1
    -
         Other, subject moved out of country
    -
    1
         Lost to follow-up
    5
    2
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Faster aspart
    Reporting group description
    		 The subjects in this arm started on 4 units of mealtime faster aspart (subcutaneous (sc)) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. Faster aspart was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of faster aspart were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.

    Reporting group title
    NovoRapid
    Reporting group description
    		 The subjects in this arm started on 4 units of mealtime NovoRapid®/NovoLog® (sc) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of NovoRapid®/NovoLog® were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.

    Reporting group values
    		 Faster aspart NovoRapid Total
    Number of subjects
    		 345 344 689
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 241 248 489
        From 65-84 years
    		 104 96 200
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.6 ( 9.3 ) 59.4 ( 9.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 182 171 353
        Male
    		 163 173 336
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 89 ( 16.9 ) 88.3 ( 16.7 ) -
    HbA1c
    Units: percentage of haemoglobin
        arithmetic mean (standard deviation)
    		 7.96 ( 0.68 ) 7.89 ( 0.71 ) -

    End points

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    End points reporting groups
    Reporting group title
    Faster aspart
    Reporting group description
    		 The subjects in this arm started on 4 units of mealtime faster aspart (subcutaneous (sc)) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. Faster aspart was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of faster aspart were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.

    Reporting group title
    NovoRapid
    Reporting group description
    		 The subjects in this arm started on 4 units of mealtime NovoRapid®/NovoLog® (sc) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of NovoRapid®/NovoLog® were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.

    Primary: Change from baseline in HbA1c

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    End point title
    		 Change from baseline in HbA1c
    End point description
    The analysis of this efficacy endpoint was based on the full analysis set (FAS). FAS included all randomised subjects. The statistical evaluation of the FAS was to follow the intention-to-treat (ITT) principle and subjects contributed to the evaluation ‘as randomised’. For this endpoint baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
    End point type
    Primary
    End point timeframe
    After 26 weeks of randomised treatment
    End point values
    		 Faster aspart NovoRapid
    Number of subjects analysed
    345
    344
    Units: percentage
    arithmetic mean (standard deviation)
        Baseline
    7.96 ( 0.68 )
    7.89 ( 0.71 )
        Week 26
    6.63 ( 0.88 )
    6.59 ( 0.84 )
    Statistical analysis title
    		 Primary statistical analysis
    Statistical analysis description
    Change from baseline in HbA1c was analysed using a mixed-effect model for repeated measurements including changes from baseline in HbA1c at visit 14, 18, 22, 26, 30 and 36. The model included treatment, region and continuous glucose monitoring (CGM) strata as fixed effects, subject as random effect, HbA1c at baseline as covariate and interaction between all fixed effects and visit, and between the covariate and visit.
    Comparison groups
    Faster aspart v NovoRapid
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.1
    Notes
    [1] - The assessment was by comparing the difference of faster aspart vs. NovoRapid®/NovoLog® in change from baseline in HbA1c after 26 weeks of randomised treatment to a non-inferiority limit of 0.4%.

    Secondary: Change from baseline in 2-hour PPG increment (meal test)

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    End point title
    		 Change from baseline in 2-hour PPG increment (meal test)
    End point description
    This endpoint was summarised using the FAS. FAS included all randomised subjects. For this endpoint baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement. Here, 'n' specifies the number of subjects with data available for 2-hour PPG increment at baseline (Faster aspart=338 and NovoRapid=331) and at week 26 (Faster aspart=342 and NovoRapid=342).
    End point type
    Secondary
    End point timeframe
    After 26 weeks of randomised treatment
    End point values
    		 Faster aspart NovoRapid
    Number of subjects analysed
    345
    344
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline (n=338,331)
    7.57 ( 3.19 )
    7.34 ( 3.12 )
        Week 26 (n=342,342)
    4.55 ( 3.13 )
    4.9 ( 3.36 )
    No statistical analyses for this end point

    Secondary: Number of treatment emergent confirmed hypoglycaemic episodes

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    End point title
    		 Number of treatment emergent confirmed hypoglycaemic episodes
    End point description
    A hypoglycaemic episode was defined as treatment-emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment. A severe or blood glucose (BG) confirmed hypoglycaemic episode was an episode that was severe according to the American Diabetes Association (ADA) classification (an episode that required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. This endpoint was summarised using the safety analysis set. Subjects in the safety analysis set contributed to the evaluation ‘as treated’.
    End point type
    Secondary
    End point timeframe
    From baseline to 26 weeks of randomised treatment
    End point values
    		 Faster aspart NovoRapid
    Number of subjects analysed
    341
    341
    Units: Number of episodes
        Severe or BG confirmed
    2857
    2692
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight

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    End point title
    		 Change from baseline in body weight
    End point description
    This endpoint was summarised using the FAS. FAS included all randomised subjects. For this endpoint baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement. Here, 'n' specifies the number of subjects with data available for body weight at baseline (Faster aspart=344 and NovoRapid=344) and at week 26 (Faster aspart=345 and NovoRapid=344).
    End point type
    Secondary
    End point timeframe
    After 26 weeks of randomised treatment
    End point values
    		 Faster aspart NovoRapid
    Number of subjects analysed
    345
    344
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=344,344)
    89 ( 16.9 )
    88.3 ( 16.7 )
        Week 26 (n=345,344)
    91.6 ( 18.2 )
    90.8 ( 17.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomised treatment until no later than 7 days after the last day of randomised treatment.
    Adverse event reporting additional description
    Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator (NovoRapid)."Note: The number of deaths causally related to treatment is the data considered to present under ‘total number of deaths resulting from AEs'"
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Faster aspart
    Reporting group description
    		 The subjects in this arm started on 4 units of mealtime faster aspart (sc) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. Faster aspart was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of faster aspart were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.

    Reporting group title
    NovoRapid
    Reporting group description
    		 The subjects in this arm started on 4 units of mealtime NovoRapid®/NovoLog® (sc) in combination with once-daily insulin glargine (sc) and metformin (oral) in a basal−bolus regimen. NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal, hereafter the bolus insulin was titrated to the pre-prandial glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) in a treat-to-target fashion in accordance with the titration guideline. Dose adjustments of NovoRapid®/NovoLog® were considered daily based on pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The investigator assisted the subjects for dose adjustment once weekly and subjects performed self-adjustment for the remaining days of the week. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.

    Serious adverse events
    		 Faster aspart NovoRapid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 341 (4.40%)
    24 / 341 (7.04%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cardiac myxoma
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Refractory anaemia with an excess of blasts
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer stage II
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery bypass
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Investigations
    Arteriogram coronary
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 341 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrong drug administered
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery occlusion
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 341 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 341 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Aural polyp
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stasis dermatitis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 341 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    2 / 341 (0.59%)
    3 / 341 (0.88%)
         occurrences causally related to treatment / all
    4 / 4
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Faster aspart NovoRapid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 341 (14.37%)
    53 / 341 (15.54%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 341 (4.69%)
    22 / 341 (6.45%)
         occurrences all number
    19
    27
    Nasopharyngitis
         subjects affected / exposed
    17 / 341 (4.99%)
    24 / 341 (7.04%)
         occurrences all number
    20
    27
    Urinary tract infection
         subjects affected / exposed
    20 / 341 (5.87%)
    13 / 341 (3.81%)
         occurrences all number
    27
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2013
    To support the cardiovascular risk assessment and analysis, a 30-day follow-up visit was introduced to collect information on potential major adverse cardiovascular events occurring in the follow-up period and furthermore, smoking history was collected for all subjects at randomisation. Post-trial diabetes treatment was collected after end-of-treatment and was used for causality assessment of AEs and possible cardiovascular events in the follow-up period. The CGM data collection period was increased from 3−7 days to 10−14 days with the simultaneous decrease from 120 to 60 subjects in the CGM subgroup. This was done in order to have more reliable CGM data from individual subjects at fewer clinical sites, thus improving data quality. The ADA classification of hypoglycaemia was updated to reflect the latest ADA classification. Based on a request during the approval of another phase 3a trial in the faster aspart development program, the text was updated so sponsor was not to be contacted prior to breaking the blinded code and also a section about handling of missing data was included. To comply with Clinical Data Interchange Standards Consortium terminology, the final outcome definition of AEs was updated. The master subject information/informed consent form and the CGM diaries were updated according to the protocol implemented changes as applicable.

    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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