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    Clinical Trial Results:
    A 26-week trial comparing the effect and safety of once weekly insulin icodec and once daily insulin degludec, both with or without non-insulin anti-diabetic drugs, in subjects with type 2 diabetes treated with basal insulin

    Summary
    EudraCT number
    		 2020-000454-10
    Trial protocol
    		 DE   PT   BG  
    Global end of trial date
    01 Mar 2022

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1436-4478
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04770532
    WHO universal trial number (UTN)
    		 U1111-1247-4945
    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 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to demonstrate the effect on glycaemic control of once weekly insulin icodec, with or without non-insulin anti-diabetic drugs, in subjects with type 2 diabetes (T2D) treated with basal insulin.
    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 (ICH) Good Clinical Practice, including archiving of essential documents (Current Step 4 version, Nov 2016), and 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 After randomisation subjects continued their pre-trial non-insulin anti-diabetic background medication throughout the entire trial except from sulfonylureas and glinides, which had to be discontinued at randomisation.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 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
    Bulgaria: 33
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Japan: 100
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 70
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Portugal: 29
    Country: Number of subjects enrolled
    South Africa: 50
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    United States: 139
    Worldwide total number of subjects
    526
    EEA total number of subjects
    137
    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)
    294
    From 65 to 84 years
    232
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 71 sites in 9 countries as follows: United States of America (USA) (26), Ukraine (4), Portugal (6), Poland (3), Republic of Korea (7), Japan (9), Germany (6), Bulgaria (4), South Africa (6).

    Pre-assignment
    Screening details
    		 After randomisation subjects continued their pre-trial non-insulin anti-diabetic background medication throughout the entire trial except from sulfonylureas and glinides, which had to be discontinued at randomisation.

    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
    Arm description
    		 Subjects were to receive once weekly subcutaneous (s.c.) injection of Insulin icodec for 26 weeks, using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% of their 7 times total daily basal insulin dose. The following weekly dose was 7 times the total daily dose of the 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 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin icodec 700 U/mL PDS290
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin icodec was administered once-weekly subcutaneously at a dose strength of 700 units/ milliliter (mL).

    Arm title
    		 Insulin degludec
    Arm description
    		 Subjects were to receive once daily s.c. injection of Insulin degludec for 26 weeks, 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 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 20 U.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tresiba 100 units/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin degludec was administered once daily subcutaneously at a dose strength of 100 units/mL.

    Number of subjects in period 1
    		Insulin Icodec Insulin degludec
    Started
    263
    263
    Full analysis set (FAS)
    263
    263
    Safety analysis set (SAS)
    262
    263
    Completed
    260
    258
    Not completed
    3
    5
         Physician decision
    1
    -
         Consent withdrawn by subject
    -
    3
         Death
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin Icodec
    Reporting group description
    		 Subjects were to receive once weekly subcutaneous (s.c.) injection of Insulin icodec for 26 weeks, using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% of their 7 times total daily basal insulin dose. The following weekly dose was 7 times the total daily dose of the 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 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.

    Reporting group title
    Insulin degludec
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of Insulin degludec for 26 weeks, 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 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 20 U.

    Reporting group values
    		 Insulin Icodec Insulin degludec Total
    Number of subjects
    		 263 263 526
    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)
    		 145 149 294
        From 65-84 years
    		 118 114 232
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.35 ± 9.79 62.60 ± 8.42 -
    Gender Categorical
    Units: Subjects
        Female
    		 101 123 224
        Male
    		 162 140 302

    End points

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    End points reporting groups
    Reporting group title
    Insulin Icodec
    Reporting group description
    		 Subjects were to receive once weekly subcutaneous (s.c.) injection of Insulin icodec for 26 weeks, using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% of their 7 times total daily basal insulin dose. The following weekly dose was 7 times the total daily dose of the 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 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.

    Reporting group title
    Insulin degludec
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of Insulin degludec for 26 weeks, 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 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 20 U.

    Primary: Change in glycated haemoglobin (HbA1c)

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    End point title
    		 Change in glycated haemoglobin (HbA1c)
    End point description
    Change in HbA1c from baseline week 0 (V2) to week 26 (V28) was presented. The endpoint data was evaluated based on the in-trial observation 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) and death for subjects who died before any of the above. Full analysis set (FAS) included all randomised subjects.
    End point type
    Primary
    End point timeframe
    From baseline week 0 (V2) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    263
    263
    Units: Percentage (%) of HbA1c
        least squares mean (standard error)
    -0.93 ± 0.05
    -0.71 ± 0.06
    Statistical analysis title
    		 Statistical Analysis Set 1
    Statistical analysis description
    The response and change from baseline in response after 26 weeks were analysed using an analysis of covariance (ANCOVA) model with treatment, region and personal continuous glucose monitoring (CGM) device use as fixed factors, and baseline response as covariate.
    Comparison groups
    Insulin Icodec v Insulin degludec
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 -0.08
    Notes
    [1] - Non-inferiority of insulin icodec was considered confirmed if the upper limit of the two-sided 95% confidence interval (CI) for mean treatment difference (insulin icodec minus insulin degludec) was strictly below 0.3%.

    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 week 0 (V2) to week 26 (V28) is presented. The endpoint data was evaluated based on the in-trial observation 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) and death for subjects who died before any of the above. FAS included all randomised subjects. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    260
    257
    Units: millimoles per liter (mmol/L)
        least squares mean (standard error)
    -1.58 ± 0.12
    -1.62 ± 0.12
    No statistical analyses for this end point

    Secondary: Time in target-range 3.9–10.0 mmol/L (70-180 milligrams per deciliter [mg/dL]) using continuous glucose monitoring (CGM) system, Dexcom G6

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    End point title
    		 Time in target-range 3.9–10.0 mmol/L (70-180 milligrams per deciliter [mg/dL]) using continuous glucose monitoring (CGM) system, Dexcom G6
    End point description
    Percentage of time in target-range 3.9–10.0 mmol/L (70-180 milligrams per deciliter [mg/dL]) using continuous glucose monitoring (CGM) system, Dexcom G6 is presented. Time in target range is defined as 100 times the number of recorded measurements in glycaemic target range 3.9-10.0 mmol/L (70-180 mg/dL), both inclusive, divided by the total number of recorded measurements. The endpoint data was evaluated based on the in-trial observation 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) and death for subjects who died before any of the above. FAS included all randomised subjects. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From week 22 (V24) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    238
    239
    Units: Percentage (%) of time
        arithmetic mean (standard deviation)
    63.13 ± 17.40
    59.50 ± 18.92
    No statistical analyses for this end point

    Secondary: Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment satisfaction

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    End point title
    		 Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment satisfaction
    End point description
    Change in DTSQs in total treatment satisfaction is presented. The DTSQ domain score was calculated by adding six item scores of items 1 and 4-8. Higher scores indicate higher levels of treatment satisfaction for items 1, 4 -8. For items 2 and 3, a higher score indicates a subject perceived experience of hyperglycaemia and hypoglycaemia. Lower scores indicate that blood glucose levels were unacceptably high (item 2) or low (item 3). The score has a minimum of 0 and a maximum of 36. The endpoint data was evaluated based on in-trial observation period. The period started at randomisation and ended at the date of: Last direct subject-site contact, withdrawal for subjects who withdrew their informed consent, Last subject-investigator contact as defined by investigator for subjects who were lost to follow-up and death for subjects who died before any of the above. FAS included all randomised subjects. Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    252
    244
    Units: Score on a scale
        least squares mean (standard error)
    4.22 ± 0.30
    2.96 ± 0.31
    No statistical analyses for this end point

    Secondary: Number of severe hypoglycaemic episodes (level 3)

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    End point title
    		 Number of severe hypoglycaemic episodes (level 3)
    End point description
    Number of severe hypoglycaemic episodes (level 3) is presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. The endpoint data was evaluated based on the on-treatment observation period. The 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 of trial visit (V30), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin (corresponding to 5 weeks after the end of the dosing interval for both treatment arms) and the end-date for the in-trial observation period. The on-treatment period represented the time period in which a subject was considered exposed to trial product. 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 (V2) to week 31 (V30)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    262
    263
    Units: Episodes
        number (not applicable)
    0
    1
    No statistical analyses for this end point

    Secondary: Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L [54 mg/dL], confirmed by blood glucose [BG] meter)

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    End point title
    		 Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L [54 mg/dL], confirmed by blood glucose [BG] meter)
    End point description
    Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 millimoles per liter [mmol/L] (54 mg/dL), confirmed by BG meter) is 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. The endpoint data was evaluated based on on-treatment observation period. On-treatment period started at the date of first dose of trial product and ended at the first date of any of the following: End of trial visit (V30), Last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin (corresponding to 5 weeks after the end of dosing interval for both treatment arms) and the end-date for in-trial observation period. The on-treatment period represented the time period in which a subject was considered exposed to trial product. 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 (V2) to week 31 (V30)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    262
    263
    Units: Episodes
        number (not applicable)
    113
    41
    No statistical analyses for this end point

    Secondary: Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3)

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    End point title
    		 Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3)
    End point description
    Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) is presented. 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. The endpoint data was evaluated based on on-treatment observation period. On-treatment period started at the date of first dose of trial product and ended at the first date of any of the following: The end of trial visit (V30), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin and the end-date for in-trial observation 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 (V2) to week 31 (V30)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    262
    263
    Units: Episodes
        number (not applicable)
    113
    42
    No statistical analyses for this end point

    Secondary: Time spent > 10 mmol/L (180 mg/dL) using CGM system, Dexcom G6

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    End point title
    		 Time spent > 10 mmol/L (180 mg/dL) using CGM system, Dexcom G6
    End point description
    Percentage of time spent > 10 mmol/L (180 mg/dL) using CGM system, Dexcom G6 is presented. The endpoint data was evaluated based on the in-trial observation 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) and death for subjects who died before any of the above. Full analysis set included all randomised subjects. Number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From week 22 (V24) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    238
    239
    Units: Percentage of time
        arithmetic mean (standard deviation)
    35.52 ± 17.95
    39.71 ± 19.34
    No statistical analyses for this end point

    Secondary: Time spent < 3.0 mmol/L (54 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6

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    End point title
    		 Time spent < 3.0 mmol/L (54 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6
    End point description
    Percentage of time spent less than (<) 3.0 mmol/L (54 mg/dL) using CGM system, Dexcom G6 is presented. The endpoint data was evaluated based on the in-trial observation 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) and death for subjects who died before any of the above. Full analysis set included all randomised subjects. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From week 22 (V24) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    238
    239
    Units: Percentage of time
        arithmetic mean (standard deviation)
    0.34 ± 0.88
    0.22 ± 0.45
    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 week 0 (V2) to week 26 (V28) is presented. The endpoint data was evaluated based on the in-trial observation 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) and 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 (V2) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    263
    263
    Units: Kilograms (kg)
        least squares mean (standard error)
    1.40 ± 0.32
    -0.30 ± 0.36
    No statistical analyses for this end point

    Secondary: Mean weekly insulin dose

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    End point title
    		 Mean weekly insulin dose
    End point description
    Mean weekly insulin dose is presented. The endpoint data was evaluated based on the on-treatment observation period. The 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 of trial visit (V30), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin (corresponding to 5 weeks after the end of the dosing interval for both treatment arms) and the end-date for the in-trial observation period. The on-treatment period represented the time period in which a subject was considered exposed to trial product. FAS included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From week 24 (V26) to week 26 (V28)
    End point values
    		 Insulin Icodec Insulin degludec
    Number of subjects analysed
    263
    263
    Units: Units of Insulin
        least squares mean (confidence interval 95%)
    267.96 (252.19 to 284.70)
    244.22 (229.99 to 259.33)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline (Week 0) to Week 31
    Adverse event reporting additional description
    Safety analysis set included all randomised subjects who were randomly assigned to trial treatment and who took at least 1 dose of trial product. A treatment-emergent AE (TEAE) was defined as an AE that initiated or worsened on or after the date of first dose of study drug up to the end of trial (week 31). All presented AEs are treatment emergent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Insulin Degludec
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of Insulin degludec for 26 weeks, 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 mmol/L: dose reduced by 20 U; 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: dose increased by 20 U.

    Reporting group title
    Insulin Icodec
    Reporting group description
    		 Subjects were to receive once weekly subcutaneous (s.c.) injection of Insulin icodec for 26 weeks, using PDS290 prefilled pen-injector at a starting dose of 7 times the pre-trial total daily basal insulin dose + 50% of their 7 times total daily basal insulin dose. The following weekly dose was 7 times the total daily dose of the 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 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.

    Serious adverse events
    		 Insulin Degludec Insulin Icodec
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 263 (6.08%)
    22 / 262 (8.40%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer stage II
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    Toe amputation
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         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
    Hand fracture
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric dysplasia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic pseudocyst
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral stenosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (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 / 263 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraspinal abscess
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (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
    0 / 263 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 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 Icodec
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 263 (14.83%)
    50 / 262 (19.08%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 263 (3.42%)
    14 / 262 (5.34%)
         occurrences all number
    10
    20
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    16 / 263 (6.08%)
    10 / 262 (3.82%)
         occurrences all number
    17
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 263 (3.42%)
    14 / 262 (5.34%)
         occurrences all number
    9
    17
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 263 (3.80%)
    22 / 262 (8.40%)
         occurrences all number
    14
    28

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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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