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    Clinical Trial Results:
    A 26-week double blinded, multiregional trial comparing the effect and safety of once weekly insulin icodec and once daily insulin degludec 100 units/mL, both in combination with non-insulin anti-diabetic drugs, in insulin naive subjects with type 2 diabetes

    Summary
    EudraCT number
    		 2020-000472-37
    Trial protocol
    		 CZ   AT   DK   FR  
    Global end of trial date
    23 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2023
    First version publication date
    14 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1436-4479
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04795531
    WHO universal trial number (UTN)
    		 U1111-1247-5218
    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
    25 Aug 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 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, in combination with non-insulin anti-diabetic drugs, in insulin naïve subjects withtype 2 diabtetes mellitus (T2D).
    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 reduced at randomisation by approximately 50% at the discretion of the investigator.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 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
    Argentina: 55
    Country: Number of subjects enrolled
    Austria: 28
    Country: Number of subjects enrolled
    Brazil: 51
    Country: Number of subjects enrolled
    Canada: 54
    Country: Number of subjects enrolled
    China: 100
    Country: Number of subjects enrolled
    Czechia: 51
    Country: Number of subjects enrolled
    Denmark: 32
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Mexico: 46
    Country: Number of subjects enrolled
    Taiwan: 45
    Country: Number of subjects enrolled
    United States: 95
    Worldwide total number of subjects
    588
    EEA total number of subjects
    142
    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)
    411
    From 65 to 84 years
    177
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 89 sites in 11 countries as follows (number of sites that screened participants/ number of sites that randomised participants): Argentina (4/4), Austria (3/3), Brazil (4/4), Canada (14/13), China mainland (13/13), Czech Republic (6/6), Denmark (4/4), France (9/8), Mexico (2/2), Taiwan (5/5), United States (28/27).

    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 reduced at randomisation by approximately 50% at the discretion of the investigator.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    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 using PDS290 prefilled pen-injector at a starting dose of 70 units (U) and once weekly placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter (mmol/L) based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 20 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 20 U.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin icodec 700 U/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received once weekly placebo matched to insulin icodec subcutaneously at an initial dose of 70 U using 3 mL PDS290 pre-filled pen-injector for 26 weeks.

    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
    Subjects were to receive once weekly subcutaneous (s.c.) injection of insulin icodec using PDS290 prefilled pen-injector at a starting dose of 70 units (U) and once weekly placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter (mmol/L) based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 20 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 20 U.

    Arm title
    		 Insulin degludec
    Arm description
    		 Subjects were to receive once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a starting dose of 10 U and once daily placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter mmol/L based on 3 pre-breakfast values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 3 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 3 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
    Subjects received once daily placebo matched to insulin degludec subcutaneously at an initial dose of 10 U using 3 mL PDS290 pre-filled pen-injector for 26 weeks.

    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
    Subjects were to receive once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a starting dose of 10 U and once daily placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter mmol/L based on 3 pre-breakfast values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 3 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 3 U.

    Number of subjects in period 1
    		Insulin icodec Insulin degludec
    Started
    294
    294
    Full analysis set (FAS)
    294
    294
    Safety analysis set (SAS)
    293
    294
    Completed
    288
    286
    Not completed
    6
    8
         Consent withdrawn by subject
    4
    4
         Physician decision
    -
    2
         Death
    2
    1
         Lost to follow-up
    -
    1

    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 using PDS290 prefilled pen-injector at a starting dose of 70 units (U) and once weekly placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter (mmol/L) based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 20 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 20 U.

    Reporting group title
    Insulin degludec
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a starting dose of 10 U and once daily placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter mmol/L based on 3 pre-breakfast values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 3 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 3 U.

    Reporting group values
    		 Insulin icodec Insulin degludec Total
    Number of subjects
    		 294 294 588
    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)
    		 210 201 411
        From 65-84 years
    		 84 93 177
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.70 ( 10.19 ) 58.56 ( 9.74 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 109 110 219
        Male
    		 185 184 369

    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 using PDS290 prefilled pen-injector at a starting dose of 70 units (U) and once weekly placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter (mmol/L) based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 20 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 20 U.

    Reporting group title
    Insulin degludec
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a starting dose of 10 U and once daily placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter mmol/L based on 3 pre-breakfast values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 3 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 3 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) 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 (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
    294
    294
    Units: Percentage (%) of HbA1c
        least squares mean (standard error)
    -1.57 ( 0.05 )
    -1.36 ( 0.05 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The response and change from baseline in response after 26 weeks are analysed using an analysis of covariance (ANCOVA) model with treatment, region and SU/glinides use as fixed factors, and baseline response as covariate.
    Comparison groups
    Insulin icodec v Insulin degludec
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         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: Number of clinically significant hypoglycaemic episodes (level 2) (less than [<] 3.0 mmol/L (54 milligrams per deciliter [mg/dL]), confirmed by blood glucose [BG] meter)

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    End point title
    		 Number of clinically significant hypoglycaemic episodes (level 2) (less than [<] 3.0 mmol/L (54 milligrams per deciliter [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
    293
    294
    Units: Episodes
        number (not applicable)
    53
    23
    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
    293
    294
    Units: Episodes
        number (not applicable)
    0
    2
    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 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
    284
    290
    Units: millimoles per litre (mmol/L)
        least squares mean (standard error)
    -3.01 ( 0.11 )
    -2.99 ( 0.11 )
    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) from baseline week 0 (V2) to week 26 (V28)

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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) from baseline week 0 (V2) to week 26 (V28)
    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 26 (V28)
    End point values
    		 Insulin icodec Insulin degludec
    Number of subjects analysed
    293
    294
    Units: Episodes
        number (not applicable)
    50
    17
    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) from baseline week 0 (V2) to week 26 (V28)

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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) from baseline week 0 (V2) to week 26 (V28)
    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 26 (V28)
    End point values
    		 Insulin icodec Insulin degludec
    Number of subjects analysed
    293
    294
    Units: Episodes
        number (not applicable)
    50
    17
    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
    293
    294
    Units: Episodes
        number (not applicable)
    53
    25
    No statistical analyses for this end point

    Secondary: Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 26 (V28)

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    End point title
    		 Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 26 (V28)
    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. 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 26 (V28)
    End point values
    		 Insulin icodec Insulin degludec
    Number of subjects analysed
    293
    294
    Units: Episodes
        number (not applicable)
    0
    0
    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
    294
    294
    Units: Kilograms (kg)
        least squares mean (standard error)
    2.77 ( 0.22 )
    2.32 ( 0.24 )
    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
    Estimated mean weekly insulin dose during the last 2 weeks of treatment (from week 24 to week 26) 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 (P26) to week 26 (V28)
    End point values
    		 Insulin icodec Insulin degludec
    Number of subjects analysed
    294
    294
    Units: Units (U) of insulin
        least squares mean (confidence interval 95%)
    204.28 (189.44 to 220.29)
    186.52 (173.06 to 201.02)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From week 0 to week 31
    Adverse event reporting additional description
    All presented AEs are treatment-emergent adverse events (TEAEs). Adverse events were defined as treatment-emergent if the onset of event occurs in the on-treatment period (from week 0 to week 26). Results are based on safety analysis set which included all subjects randomly assigned to trial treatment and who took at least 1 dose of trial product.
    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 using PDS290 prefilled pen-injector at a starting dose of 10 U and once daily placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter mmol/L based on 3 pre-breakfast values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 3 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 3 U.

    Reporting group title
    Insulin Icodec
    Reporting group description
    		 Subjects were to receive once weekly subcutaneous (s.c.) injection of insulin icodec using PDS290 prefilled pen-injector at a starting dose of 70 units (U) and once weekly placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter (mmol/L) based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: dose reduced by 20 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; > 7.2 mmol/L- dose increased by 20 U.

    Serious adverse events
    		 Insulin degludec Insulin Icodec
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 294 (5.10%)
    15 / 293 (5.12%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (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
    Dyspnoea
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         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
    Accidental overdose
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 294 (0.34%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy hypertensive
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (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 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (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 / 294 (0.00%)
    1 / 293 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 293 (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
    29 / 294 (9.86%)
    52 / 293 (17.75%)
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    6 / 294 (2.04%)
    15 / 293 (5.12%)
         occurrences all number
    7
    16
    Infections and infestations
    COVID-19
         subjects affected / exposed
    14 / 294 (4.76%)
    24 / 293 (8.19%)
         occurrences all number
    14
    24
    Influenza
         subjects affected / exposed
    9 / 294 (3.06%)
    15 / 293 (5.12%)
         occurrences all number
    9
    18

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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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