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    Clinical Trial Results:
    Efficacy and Safety of Once Weekly Insulin Icodec Compared to Once Daily Insulin Degludec 100 Units/mL, Both in Combination With Insulin Aspart, in Adults With Type 1 Diabetes. A 26-week, Randomised, Multicentre, Open-label, Active-controlled, Parallel Group, Two Armed, Treat-to-target Trial Investigating the Effect on Glycaemic Control and Safety of Treatment With Once Weekly Insulin Icodec Compared to Once Daily Insulin Degludec, Both in Combination With Insulin Aspart in Adults With Type 1 Diabetes, With a 26-week Extension Investigating Long Term Safety

    Summary
    EudraCT number
    		 2020-002374-27
    Trial protocol
    		 DE   NL   AT   IT  
    Global end of trial date
    02 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Dec 2023
    First version publication date
    17 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1436-4625
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04848480
    WHO universal trial number (UTN)
    		 U1111-1251-7315
    Other trial identifiers
    		 Japanese trial registration number: jRCT2031210031
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Office (2834), 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
    21 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the effect on glycaemic control of once weekly insulin icodec in combination with insulin aspart, in subjects with T1D. This includes comparing the difference in change from baseline in HbA1c between once weekly insulin icodec and once daily insulin degludec both in combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (64th World Medical Association [WMA] general Assembly; Oct 2013) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents (Current Step 4 version, Nov 2016), and 21 US Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    30 Apr 2021
    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: 15
    Country: Number of subjects enrolled
    Canada: 29
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    United Kingdom: 45
    Country: Number of subjects enrolled
    India: 36
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Japan: 80
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Russian Federation: 67
    Country: Number of subjects enrolled
    Turkey: 31
    Country: Number of subjects enrolled
    United States: 162
    Worldwide total number of subjects
    582
    EEA total number of subjects
    132
    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)
    538
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 97 sites in 12 countries as follows (number of sites that screened subjects/ number of sites that randomised subject): Austria-(6/6), Canada-(5/5), Germany-(8/8), India-(6/6), Italy-(5/5), Japan-(7/7), Netherlands-(3/3), Russia-(10/10), Spain-(4/4), Turkey-(7/7), United Kingdom-(8/8), United States-(29/28).

    Pre-assignment
    Screening details
    		 This was a 52-week trial. The first 26 weeks of the trial constituted the main phase which was followed by a 26-week extension phase with focus on evaluating long term safety and provide long-term exposure data.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Insulin icodec + insulin aspart
    Arm description
    		 Subjects received insulin icodec with insulin aspart for 52 weeks subcutaneously. Subjects received once weekly subcutaneous (s.c.) injection of insulin icodec using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% or 100% of their 7 times total daily basal insulin dose depending on insulin regime and HbA1c level. Following weekly dose was 7 times the total daily dose of respective subjects ('unit to unit switch' approach: current daily dose x 7). Subjects were to perform once daily pre-breakfast self-monitoring plasma glucose (SMPG). The dose was adjusted based on 3 pre-breakfast SMPG values measured on 2 previous days and the day of contact. If at least one pre-breakfast SMPG value was: <4.4 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; >7.2 mmol/L: dose increased by 20 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured weekly.
    Arm type
    		 Experimental

    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 s.c. for 52 weeks. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured weekly.

    Investigational medicinal product name
    Insulin icodec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Once weekly s.c. injection of insulin icodec was administered using PDS290 prefilled pen-injector for 52 weeks.

    Arm title
    		 Insulin degludec + insulin aspart
    Arm description
    		 Subjects received insulin degludec along with insulin aspart for 52 weeks subcutaneously. Subjects received once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a dose in accordance with local label. Subjects were to perform once daily SMPG. The dose was adjusted based on 3 pre-breakfast SMPG values measured on the 2 previous days and the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 millimoles per liter (mmol/L): dose reduced by 3 units (U); 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 3 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime SMPG measured weekly.
    Arm type
    		 Experimental

    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 s.c. for 52 weeks. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured weekly.

    Investigational medicinal product name
    Insulin degludec
    Investigational medicinal product code
    Other name
    Tresiba 100 units/mL solution for injection in pre-filled pen
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Once daily s.c. injection of insulin degludec was administered using PDS290 prefilled pen-injector for 52 weeks.

    Number of subjects in period 1
    		Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Started
    290
    292
    Completed
    274
    281
    Not completed
    16
    11
         Physician decision
    1
    -
         Consent withdrawn by subject
    13
    9
         Death
    1
    -
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin icodec + insulin aspart
    Reporting group description
    		 Subjects received insulin icodec with insulin aspart for 52 weeks subcutaneously. Subjects received once weekly subcutaneous (s.c.) injection of insulin icodec using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% or 100% of their 7 times total daily basal insulin dose depending on insulin regime and HbA1c level. Following weekly dose was 7 times the total daily dose of respective subjects ('unit to unit switch' approach: current daily dose x 7). Subjects were to perform once daily pre-breakfast self-monitoring plasma glucose (SMPG). The dose was adjusted based on 3 pre-breakfast SMPG values measured on 2 previous days and the day of contact. If at least one pre-breakfast SMPG value was: <4.4 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; >7.2 mmol/L: dose increased by 20 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured weekly.

    Reporting group title
    Insulin degludec + insulin aspart
    Reporting group description
    		 Subjects received insulin degludec along with insulin aspart for 52 weeks subcutaneously. Subjects received once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a dose in accordance with local label. Subjects were to perform once daily SMPG. The dose was adjusted based on 3 pre-breakfast SMPG values measured on the 2 previous days and the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 millimoles per liter (mmol/L): dose reduced by 3 units (U); 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 3 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime SMPG measured weekly.

    Reporting group values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart Total
    Number of subjects
    		 290 292 582
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 267 271 538
        From 65-84 years
    		 23 21 44
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.08 ( 14.07 ) 44.28 ( 14.07 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 125 120 245
        Male
    		 165 172 337

    End points

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    End points reporting groups
    Reporting group title
    Insulin icodec + insulin aspart
    Reporting group description
    		 Subjects received insulin icodec with insulin aspart for 52 weeks subcutaneously. Subjects received once weekly subcutaneous (s.c.) injection of insulin icodec using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% or 100% of their 7 times total daily basal insulin dose depending on insulin regime and HbA1c level. Following weekly dose was 7 times the total daily dose of respective subjects ('unit to unit switch' approach: current daily dose x 7). Subjects were to perform once daily pre-breakfast self-monitoring plasma glucose (SMPG). The dose was adjusted based on 3 pre-breakfast SMPG values measured on 2 previous days and the day of contact. If at least one pre-breakfast SMPG value was: <4.4 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; >7.2 mmol/L: dose increased by 20 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured weekly.

    Reporting group title
    Insulin degludec + insulin aspart
    Reporting group description
    		 Subjects received insulin degludec along with insulin aspart for 52 weeks subcutaneously. Subjects received once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a dose in accordance with local label. Subjects were to perform once daily SMPG. The dose was adjusted based on 3 pre-breakfast SMPG values measured on the 2 previous days and the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 millimoles per liter (mmol/L): dose reduced by 3 units (U); 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 3 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime SMPG measured weekly.

    Primary: Change in Glycosylated Haemoglobin (HbA1c) at Week 26

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    End point title
    		 Change in Glycosylated Haemoglobin (HbA1c) at Week 26
    End point description
    Change in HbA1c from baseline to week 26 is presented. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct subject-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for subjects who died before any of the above. Full analysis set included all randomised subjects.
    End point type
    Primary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Percentage of HbA1c
        least squares mean (standard error)
    -0.47 ( 0.07 )
    -0.51 ( 0.06 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Change from baseline in HbA1c after 26 weeks was analysed using ANCOVA model with treatment, region, HbA1c group at screening and pre-trial basal insulin treatment as fixed factors, and baseline response as covariate. Non-inferiority was considered confirmed if the estimated treatment difference was below 0.3%.
    Comparison groups
    Insulin icodec + insulin aspart v Insulin degludec + insulin aspart
    Number of subjects included in analysis
    582
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0065
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.23

    Secondary: Change in Glycosylated Haemoglobin (HbA1c) at Week 52

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    End point title
    		 Change in Glycosylated Haemoglobin (HbA1c) at Week 52
    End point description
    Change in HbA1c from baseline to week 52 is presented. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct subject-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for subjects who died before any of the above. Full analysis set included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 52
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Percentage of HbA1c
        least squares mean (standard error)
    -0.37 ( 0.05 )
    -0.54 ( 0.05 )
    No statistical analyses for this end point

    Secondary: Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in Total Treatment Satisfaction

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    End point title
    		 Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in Total Treatment Satisfaction
    End point description
    Change in DTSQs in total treatment satisfaction from baseline to week 26 is presented. The sum score for DTSQ in total treatment satisfaction was calculated by adding the six item scores of items 1, 4, 5, 6, 7 and 8. The sum score for DTSQ can range from 0 to 36, with 0 being the lowest and 36 being the highest score in total treatment satisfaction. Higher scores on the DTSQ total score indicate higher treatment satisfaction. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct subject-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for subjects who died before any of the above. Full analysis set included all randomised subjects. Number of Subjects Analyzed = Subjects with sufficient available data.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    288
    291
    Units: Score on a scale
        least squares mean (standard error)
    1.97 ( 0.27 )
    3.06 ( 0.27 )
    No statistical analyses for this end point

    Secondary: Percentage of Time in Range 3.9–10.0 mmol/L (70-180 Milligrams Per Deciliter [mg/dL]) Using Continuous Glucose Monitoring (CGM) System

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    End point title
    		 Percentage of Time in Range 3.9–10.0 mmol/L (70-180 Milligrams Per Deciliter [mg/dL]) Using Continuous Glucose Monitoring (CGM) System
    End point description
    Percentage of time in range 3.9–10.0 mmol/L (70-180 mg/dL) using CGM system from week 22 to week 26 is presented. Time in range is defined as 100 times the number of recorded measurements in glycaemic range 3.9-10.0 mmol/L (70-180 mg/dL), both inclusive, divided by the total number of recorded measurements. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct subject-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for subjects who died before any of the above. Full analysis set included all randomised subjects. Number of Subjects Analyzed = Subjects with sufficient available data.
    End point type
    Secondary
    End point timeframe
    From week 22 to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    261
    272
    Units: Percentage of time
        arithmetic mean (standard deviation)
    59.10 ( 15.66 )
    60.85 ( 15.03 )
    No statistical analyses for this end point

    Secondary: Change in Fasting Plasma Glucose (FPG)

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    End point title
    		 Change in Fasting Plasma Glucose (FPG)
    End point description
    Change in FPG from baseline to week 26 is presented. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct subjects-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for subjects who died before any of the above. Full analysis set included all randomised subjects. Number of Subjects Analyzed = Subjects with sufficient available data.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    276
    287
    Units: millimoles per liter (mmol/l)
        least squares mean (standard error)
    -0.84 ( 0.20 )
    -1.87 ( 0.20 )
    No statistical analyses for this end point

    Secondary: Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26

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    End point title
    		 Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26
    End point description
    Number of severe hypoglycaemic episodes (level 3) from baseline to week 26 are presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for ‘main-on-treatment’ period. The main-on-treatment period started at the date of first dose of trial product as recorded on the electronic case report form (eCRF), and ended at the first date of any of the following: the end date of the on-treatment period; week 26. On-treatment: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit, the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    47
    17
    No statistical analyses for this end point

    Secondary: Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57

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    End point title
    		 Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57
    End point description
    Number of severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for ‘on-treatment’ period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 57
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    56
    25
    No statistical analyses for this end point

    Secondary: Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by Blood Glucose [BG] Meter): From Baseline (Week 0) to Week 26

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    End point title
    		 Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by Blood Glucose [BG] Meter): From Baseline (Week 0) to Week 26
    End point description
    Number of clinically significant hypoglycaemic episodes (level 2) from baseline to week 26 are presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Data is reported for ‘main-on-treatment’ period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    2789
    1478
    No statistical analyses for this end point

    Secondary: Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26

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    End point title
    		 Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26
    End point description
    Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of <3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for ‘main-on-treatment’ period, started at date of 1st dose of trial product as recorded on eCRF, and ended at first date of any of following: end date of on-treatment period; week 26. On-treatment period: Onset date on or after first dose of trial product and no later than first date of either follow-up visit (FU2), last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or end-date for in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    2836
    1495
    No statistical analyses for this end point

    Secondary: Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by BG Meter): From Baseline (Week 0) to Week 57

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    End point title
    		 Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by BG Meter): From Baseline (Week 0) to Week 57
    End point description
    Number of clinically significant hypoglycaemic episodes (level 2) from baseline to week 57 are presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Data is reported for ‘on-treatment’ period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 57
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    5047
    2811
    No statistical analyses for this end point

    Secondary: Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26

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    End point title
    		 Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26
    End point description
    Nocturnal: The period between 00:01 and 05:59 (both included). Clinically significant hypoglycaemia (level 2): Plasma glucose value of < 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3): Hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for ‘main-on-treatment’ period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. On-treatment period: Onset date on or after first dose of trial product and no later than first date of either follow-up visit, last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    481
    227
    No statistical analyses for this end point

    Secondary: Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57

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    End point title
    		 Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57
    End point description
    Number of clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for ‘on-treatment’ period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 57
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    5103
    2836
    No statistical analyses for this end point

    Secondary: Percentage of Time spent Less Than (<) 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System

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    End point title
    		 Percentage of Time spent Less Than (<) 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System
    End point description
    Percentage of time spent < 3.0 mmol/L using CGM system from week 22 to week 26 is presented. Time spent below threshold (< 3.0 mmol/L [54 mg/dL]) was defined as 100 times the number of recorded measurements below the threshold, divided by the total number of recorded measurements. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct participant-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above. Full analysis set included all randomised subjects. Number of Subjects Analyzed = Subjects with sufficient available data.
    End point type
    Secondary
    End point timeframe
    From week 22 to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    261
    272
    Units: Percentage of time
        arithmetic mean (standard deviation)
    1.02 ( 1.64 )
    0.68 ( 1.27 )
    No statistical analyses for this end point

    Secondary: Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57

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    End point title
    		 Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57
    End point description
    Number of nocturnal clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Nocturnal: The period between 00:01 and 05:59 (both included). Clinically significant hypoglycaemia (level 2): Plasma glucose value of < 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3): Hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for ‘on-treatment’ period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Safety analysis set included all subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 57
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: Episodes
        number (not applicable)
    870
    462
    No statistical analyses for this end point

    Secondary: Percentage of Time spent Greater Than (>) 10 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System

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    End point title
    		 Percentage of Time spent Greater Than (>) 10 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System
    End point description
    Percentage of time spent > 10 mmol/L using CGM system from week 22 to week 26 is presented. Time spent above threshold (> 10 mmol/L [180 mg/dL]) was defined as 100 times the number of recorded measurements above the threshold, divided by the total number of recorded measurements. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct subject-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for participants who died before any of the above. Full analysis set included all randomised subjects. Number of Subjects Analyzed = Subjects with sufficient available data.
    End point type
    Secondary
    End point timeframe
    From week 22 to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    261
    272
    Units: Percentage of time
        arithmetic mean (standard deviation)
    37.03 ( 16.21 )
    36.25 ( 15.61 )
    No statistical analyses for this end point

    Secondary: Mean Total Weekly Insulin Dose: From Week 24 to Week 26

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    End point title
    		 Mean Total Weekly Insulin Dose: From Week 24 to Week 26
    End point description
    Mean total weekly insulin dose from week 24 to week 26 is presented. Data is reported for ‘main-on-treatment’ period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Full analysis set included all randomised subjects. Number of Subjects Analyzed = Subjects with sufficient available data.
    End point type
    Secondary
    End point timeframe
    From week 24 to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    274
    271
    Units: Units of insulin
        least squares mean (confidence interval 95%)
    310.52 (295.70 to 326.08)
    322.68 (307.46 to 338.66)
    No statistical analyses for this end point

    Secondary: Mean Total Weekly Insulin Dose: From Week 50 to Week 52

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    End point title
    		 Mean Total Weekly Insulin Dose: From Week 50 to Week 52
    End point description
    Mean total weekly insulin dose from week 50 to week 52 is presented. Data is reported for ‘on-treatment’ period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Full analysis set included all randomised subjects. Number of Subjects Analyzed = Subjects with sufficient available data.
    End point type
    Secondary
    End point timeframe
    From week 50 to week 52
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    273
    269
    Units: Units of insulin
        least squares mean (confidence interval 95%)
    310.14 (294.85 to 326.22)
    328.90 (312.86 to 345.75)
    No statistical analyses for this end point

    Secondary: Change in Body Weight

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    End point title
    		 Change in Body Weight
    End point description
    Change in body weight from baseline to week 26 is presented. Data is reported for ‘in-trial’ period. In-trial observation period started at randomisation and ended at the date of: the last direct subject-site contact; withdrawal for subjects who withdrew their informed consent; the last subject-investigator contact as defined by the investigator for subjects who were lost to follow-up (i.e. possibly an unscheduled phone visit); death for subjects who died before any of the above. Full analysis set included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin icodec + insulin aspart Insulin degludec + insulin aspart
    Number of subjects analysed
    290
    292
    Units: kilograms
        least squares mean (standard error)
    1.29 ( 0.23 )
    1.01 ( 0.23 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 1 to week 57
    Adverse event reporting additional description
    Treatment emergent adverse events that had onset date during on-treatment period: started 1st dose date of trial product as recorded on eCRF & ended at 1st date of any of: end of trial V56, last date on trial product+5 weeks for once daily insulin &+6 weeks for once weekly insulin, end-date for in-trial observation period. Safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Insulin degludec + insulin aspart
    Reporting group description
    		 Subjects received insulin degludec along with insulin aspart for 52 weeks subcutaneously. Subjects received once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a dose in accordance with local label. Subjects were to perform once daily SMPG. The dose was adjusted based on 3 pre-breakfast SMPG values measured on the 2 previous days and the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 millimoles per liter (mmol/L): dose reduced by 3 units (U); 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 3 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime SMPG measured weekly.

    Reporting group title
    Insulin icodec + insulin aspart
    Reporting group description
    		 Subjects received insulin icodec with insulin aspart for 52 weeks subcutaneously. Subjects received once weekly subcutaneous (s.c.) injection of insulin icodec using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% or 100% of their 7 times total daily basal insulin dose depending on insulin regime and HbA1c level. Following weekly dose was 7 times the total daily dose of respective subjects ('unit to unit switch' approach: current daily dose x 7). Subjects were to perform once daily pre-breakfast self-monitoring plasma glucose (SMPG). The dose was adjusted based on 3 pre-breakfast SMPG values measured on 2 previous days and the day of contact. If at least one pre-breakfast SMPG value was: <4.4 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; >7.2 mmol/L: dose increased by 20 U. Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured weekly.

    Serious adverse events
    		 Insulin degludec + insulin aspart Insulin icodec + insulin aspart
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 292 (6.85%)
    24 / 290 (8.28%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Brachiocephalic artery stenosis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac ablation
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion threatened
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device site dermatitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         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
    Acute respiratory failure
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose fluctuation
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product administration error
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         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 / 292 (0.34%)
    0 / 290 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis ulcerative
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis escherichia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (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 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 290 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 292 (0.34%)
    8 / 290 (2.76%)
         occurrences causally related to treatment / all
    1 / 1
    12 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Insulin degludec + insulin aspart Insulin icodec + insulin aspart
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    162 / 292 (55.48%)
    145 / 290 (50.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 292 (5.48%)
    17 / 290 (5.86%)
         occurrences all number
    22
    27
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    20 / 292 (6.85%)
    16 / 290 (5.52%)
         occurrences all number
    25
    22
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    26 / 292 (8.90%)
    24 / 290 (8.28%)
         occurrences all number
    29
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 292 (5.14%)
    12 / 290 (4.14%)
         occurrences all number
    16
    13
    Back pain
         subjects affected / exposed
    17 / 292 (5.82%)
    5 / 290 (1.72%)
         occurrences all number
    31
    5
    Infections and infestations
    COVID-19
         subjects affected / exposed
    83 / 292 (28.42%)
    74 / 290 (25.52%)
         occurrences all number
    88
    80
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 292 (3.77%)
    15 / 290 (5.17%)
         occurrences all number
    13
    18
    Nasopharyngitis
         subjects affected / exposed
    61 / 292 (20.89%)
    48 / 290 (16.55%)
         occurrences all number
    84
    75

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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