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    Clinical Trial Results:
    A trial comparing the effect and safety of insulin degludec versus insulin detemir, both in combination with insulin aspart, in the treatment of pregnant women with type 1 diabetes.

    Summary
    EudraCT number
    		 2017-000048-17
    Trial protocol
    		 DK   GB   AT   IE   GR   ES   HR   IT  
    Global end of trial date
    17 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Dec 2021
    First version publication date
    25 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1250-4300
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03377699
    WHO universal trial number (UTN)
    		 U1111-1191-3018
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Transparency Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Transparency Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect on glycaemic control of insulin degludec once daily plus insulin aspart 2-4 times daily with meals and insulin detemir once daily or twice daily plus insulin aspart 2-4 times daily with meals in a population of pregnant women with type 1 diabetes mellitus.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Last amended by the 64th World Medical Association General Assembly, Fortaleza, Brazil. October 2013) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents (Nov 2016) and 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    22 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Brazil: 31
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Ireland: 6
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Russian Federation: 67
    Country: Number of subjects enrolled
    Serbia: 14
    Worldwide total number of subjects
    225
    EEA total number of subjects
    51
    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)
    225
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 56 sites in 14 countries as follows (number of sites that screened subjects/ number of sites that randomised subjects):Argentina (5/4); Australia (7/7); Austria (3/3); Brazil (6/6); Canada (6/5); Croatia (1/1); Denmark (2/2); Greece (3/3); Ireland (3/2); Israel (2/2); Italy (5/5); Russia (8/8); Serbia (2/2) and UK (8/6).

    Pre-assignment
    Screening details
    		 Based on subject pregnancy status, either non-pregnant with the intention to become pregnant or pregnant from gestational Week (GW) 8-13 + 6 days were randomised in a 1:1 ratio to receive either Insulin Degludec (IDeg) or Insulin Detemir (IDet) in combination with Insulin Aspart (IAsp) as subcutaneous injection.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IDeg
    Arm description
    		 Subjects were to receive IDeg once daily in combination with IAsp 2-4 times daily with meals as subcutaneous injection using FlexTouch and FlexPen pen injectors respectively. After randomization, the IDeg doses were adjusted once weekly to reach the glycaemic target of 4.0 – 5.0 millimoles per liter (mmol/L). It was based on mean of 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 days prior to visit and on the day of the visit. If one of the SMPG values was below target of 4.0 mmol/L, the insulin dose was reduced: (less than) <3.1: -4 units (U) and 3.1 – 3.9: -2U. If the mean was: 4.0-5.0: no adjustment; 5.1 – 10.0: +2U, 10.1 – 15.0: +4U and (greater than) >15.0: +6U. On the other hand, for pregnant women, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized at investigator's discretion based on the subject's SMPG values with target value (less than or equal to) ≤7.8 mmol/L.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Degludec
    Investigational medicinal product code
    Other name
    Tresiba®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive IDeg once daily with meals as subcutaneous injection using FlexTouch pen injector. After randomization, the IDeg doses were adjusted once weekly to reach the glycaemic target of 4.0 – 5.0 mmol/L. It was based on mean of 3 pre-breakfast SMPG values measured on 2 days prior to visit and on the day of the visit. If one of the SMPG values was below target of 4.0 mmol/L, the insulin dose was reduced: (less than) <3.1 mmol/L: -4 units (U) and 3.1 – 3.9 mmol/L: -2U. If the mean was: 4.0-5.0 mmol/L: no adjustment; 5.1 – 10.0 mmol/L: +2U, 10.1 – 15.0 mmol/L: +4U and (greater than) >15.0 mmol/L- +6U.

    Investigational medicinal product name
    IAsp
    Investigational medicinal product code
    Other name
    NovoRapid®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive IAsp, 2-4 times daily with meals as subcutaneous injection using FlexPen pen injector. After randomization, the IAsp dose adjustments were at investigator's discretion based on the subject's SMPG values. For pregnant women, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized with target SMPG value ≤ 7.8 mmol/L.

    Arm title
    		 IDet
    Arm description
    		 Subjects were to receive IDet once or twice daily in combination with IAsp 2-4 times daily with meals as subcutaneous injection using FlexPen pen injector. The dose adjustments were made with a glycaemic target of 4.0 – 5.0 mmol/L. Dose adjustments: for IDet once daily - based on mean of 3 pre-breakfast SMPG values; for IDet twice daily - morning doses - based on mean pre-main evening meal SMPG values whereas the evening doses - based on mean pre-breakfast SMPG values. If one of the pre-main evening meal SMPG values were below target of 4.0 mmol/L, the insulin dose was reduced: <3.1 mmol/L: -4U and 3.1 – 3.9 mmol/L: -2U. If the mean was: 4.0-5.0 mmol/L- no adjustment; 5.1 – 10.0 mmol/L: +2U, 10.1 – 15.0 mmol/L: +4U and >15.0 mmol/L: +6U. For pregnant, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized at investigator's discretion based on the subject's SMPG values with target value ≤7.8 mmol/L.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    IDet
    Investigational medicinal product code
    Other name
    Levemir®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received IDet once or twice daily in combination with IAsp 2-4 times daily with meals as subcutaneous injection. Dose adjustments were made with glycaemic target of 4.0–5.0 mmol/L. Dose adjustments: for IDet once daily - based on mean of 3 pre-breakfast SMPG values; for IDet twice daily - morning doses - based on mean pre-main evening meal SMPG values whereas the evening doses - based on mean pre-breakfast SMPG values. If one of the pre-main evening meal SMPG values were below target of 4.0 mmol/L, the insulin dose was reduced: <3.1: -4U and 3.1 – 3.9: -2U. If the mean was: 4.0-5.0 mmol/L- no adjustment; 5.1 – 10.: +2U, 10.1 – 15.0: +4U and >15.0: +6U.

    Investigational medicinal product name
    IAsp
    Investigational medicinal product code
    Other name
    NovoRapid®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive IAsp, 2-4 times daily with meals as subcutaneous injection using FlexPen pen injector. After randomization, the IAsp dose adjustments were at investigator's discretion based on the subject's SMPG values. For pregnant women, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized with target SMPG value ≤ 7.8 mmol/L.

    Number of subjects in period 1
    		IDeg IDet
    Started
    111
    114
    Completed
    89
    89
    Not completed
    22
    25
         Consent withdrawn by subject
    2
    9
         Unclassified
    19
    15
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IDeg
    Reporting group description
    		 Subjects were to receive IDeg once daily in combination with IAsp 2-4 times daily with meals as subcutaneous injection using FlexTouch and FlexPen pen injectors respectively. After randomization, the IDeg doses were adjusted once weekly to reach the glycaemic target of 4.0 – 5.0 millimoles per liter (mmol/L). It was based on mean of 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 days prior to visit and on the day of the visit. If one of the SMPG values was below target of 4.0 mmol/L, the insulin dose was reduced: (less than) <3.1: -4 units (U) and 3.1 – 3.9: -2U. If the mean was: 4.0-5.0: no adjustment; 5.1 – 10.0: +2U, 10.1 – 15.0: +4U and (greater than) >15.0: +6U. On the other hand, for pregnant women, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized at investigator's discretion based on the subject's SMPG values with target value (less than or equal to) ≤7.8 mmol/L.

    Reporting group title
    IDet
    Reporting group description
    		 Subjects were to receive IDet once or twice daily in combination with IAsp 2-4 times daily with meals as subcutaneous injection using FlexPen pen injector. The dose adjustments were made with a glycaemic target of 4.0 – 5.0 mmol/L. Dose adjustments: for IDet once daily - based on mean of 3 pre-breakfast SMPG values; for IDet twice daily - morning doses - based on mean pre-main evening meal SMPG values whereas the evening doses - based on mean pre-breakfast SMPG values. If one of the pre-main evening meal SMPG values were below target of 4.0 mmol/L, the insulin dose was reduced: <3.1 mmol/L: -4U and 3.1 – 3.9 mmol/L: -2U. If the mean was: 4.0-5.0 mmol/L- no adjustment; 5.1 – 10.0 mmol/L: +2U, 10.1 – 15.0 mmol/L: +4U and >15.0 mmol/L: +6U. For pregnant, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized at investigator's discretion based on the subject's SMPG values with target value ≤7.8 mmol/L.

    Reporting group values
    		 IDeg IDet Total
    Number of subjects
    		 111 114 225
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 111 114 225
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.2 ( 5.20 ) 31.1 ( 5.28 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 111 114 225

    End points

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    End points reporting groups
    Reporting group title
    IDeg
    Reporting group description
    		 Subjects were to receive IDeg once daily in combination with IAsp 2-4 times daily with meals as subcutaneous injection using FlexTouch and FlexPen pen injectors respectively. After randomization, the IDeg doses were adjusted once weekly to reach the glycaemic target of 4.0 – 5.0 millimoles per liter (mmol/L). It was based on mean of 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 days prior to visit and on the day of the visit. If one of the SMPG values was below target of 4.0 mmol/L, the insulin dose was reduced: (less than) <3.1: -4 units (U) and 3.1 – 3.9: -2U. If the mean was: 4.0-5.0: no adjustment; 5.1 – 10.0: +2U, 10.1 – 15.0: +4U and (greater than) >15.0: +6U. On the other hand, for pregnant women, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized at investigator's discretion based on the subject's SMPG values with target value (less than or equal to) ≤7.8 mmol/L.

    Reporting group title
    IDet
    Reporting group description
    		 Subjects were to receive IDet once or twice daily in combination with IAsp 2-4 times daily with meals as subcutaneous injection using FlexPen pen injector. The dose adjustments were made with a glycaemic target of 4.0 – 5.0 mmol/L. Dose adjustments: for IDet once daily - based on mean of 3 pre-breakfast SMPG values; for IDet twice daily - morning doses - based on mean pre-main evening meal SMPG values whereas the evening doses - based on mean pre-breakfast SMPG values. If one of the pre-main evening meal SMPG values were below target of 4.0 mmol/L, the insulin dose was reduced: <3.1 mmol/L: -4U and 3.1 – 3.9 mmol/L: -2U. If the mean was: 4.0-5.0 mmol/L- no adjustment; 5.1 – 10.0 mmol/L: +2U, 10.1 – 15.0 mmol/L: +4U and >15.0 mmol/L: +6U. For pregnant, the SMPG was measured 60 minutes after main meal and the IAsp doses were optimized at investigator's discretion based on the subject's SMPG values with target value ≤7.8 mmol/L.

    Primary: Last planned glycosylated haemoglobin (HbA1c) prior to delivery

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    End point title
    		 Last planned glycosylated haemoglobin (HbA1c) prior to delivery
    End point description
    Mean of HbA1c at last planned visit prior to delivery after GW16 is presented. The endpoint was evaluated based on the data from both in-trial and on-treatment observation periods. In-trial observation period starts at randomization and ends at the date of trial completion. The date of trial completion is the date of the final scheduled follow-up visit V92 (delivery + 58 days). For subjects not attending the follow-up visit V92, the date of trial completion is the date of the last subject-investigator contact. On-treatment observation period starts at the date of first dose of trial product and ended at the date of the last day on trial product. Full analysis set for pregnant women (FASpregnant) included all randomised women who were pregnant during the trial. In the report data, Number of Subjects Analysed = number of subjects who contributed to the analysis and 'n' is number subjects assessed during in-trial and on-treatment observation periods.
    End point type
    Primary
    End point timeframe
    After gestational week 16
    End point values
    		 IDeg IDet
    Number of subjects analysed
    84
    84
    Units: Percentage point of HbA1c
    arithmetic mean (standard deviation)
        In-trial n = 84 (IDeg), 84 (IDet)
    6.30 ( 0.70 )
    6.26 ( 0.73 )
        On-treatment n = 83 (IDeg), 80 (IDet)
    6.32 ( 0.69 )
    6.26 ( 0.71 )
    Statistical analysis title
    		 IDeg vs IDet
    Statistical analysis description
    Primary Estimand. Imputation of missing data was done within two groups of participants defined by randomised treatment arm based on a multiple imputation approach (x1000). For each of the 1000 imputed datasets last planned HbA1c prior to delivery after GW 16 was analysed using an ANCOVA with treatment, region and the stratification factor as categorical fixed effects and a pregnancy status at randomisation-by-baseline HbA1c interaction.
    Comparison groups
    IDeg v IDet
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean treatment difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.08
    Notes
    [1] - The upper limit of the 95% CI for the estimated mean treatment difference in HbA1c was below the prespecified non-inferiority margin of 0.4%.
    Statistical analysis title
    		 IDeg vs IDet
    Statistical analysis description
    Secondary Estimand. Imputation of missing data was done within two groups of subjects defined by randomised treatment arm based on a multiple imputation approach (x1000). The imputation model included region and the stratification factor as categorical fixed effects, and a pregnancy status at randomisation-by-baseline HbA1c interaction. For each of the 1000 imputed datasets last planned HbA1c prior to delivery after GW 16 was analysed using an ANCOVA.
    Comparison groups
    IDeg v IDet
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.3881
    Method
    		 ANCOVA
    Parameter type
    		 Mean treatment difference
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.11
    Notes
    [2] - The upper limit of the 95% CI for the estimated mean treatment difference in HbA1c was below the prespecified non-inferiority margin of 0.4%.

    Secondary: HbA1c ≤ 6.0% (42 millimoles per mole (mmol/mol)) from last planned HbA1c prior to delivery (yes/no)

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    End point title
    		 HbA1c ≤ 6.0% (42 millimoles per mole (mmol/mol)) from last planned HbA1c prior to delivery (yes/no)
    End point description
    Number of subjects who achieved pre-defined HbA1c targets ≤ 6.0% during the in-trial pregnancy period is presented. In the reported data, ‘Yes’ infers number of subjects who have achieved ≤ 6.0% HbA1c whereas ‘No’ infers number of subjects who have not achieved ≤ 6.0% HbA1c. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: from randomization to date of trial completion. The date of trial completion is the date of the final scheduled follow-up visit V92 (delivery + 58 days). For subjects not attending the follow-up visit V92, the date of trial completion is the date of the last subject-investigator contact. FASpregnant included all randomised women who were pregnant during the trial. In the report data, Number of Subjects Analysed = number of subjects who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    After gestational week 16
    End point values
    		 IDeg IDet
    Number of subjects analysed
    84
    84
    Units: Subjects
        Yes
    36
    31
        No
    48
    53
    No statistical analyses for this end point

    Secondary: Last planned average post-prandial glucose prior to delivery. Average of three main meals

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    End point title
    		 Last planned average post-prandial glucose prior to delivery. Average of three main meals
    End point description
    Mean of last planned average post-prandial glucose (PPG) prior to delivery after GW 16 is presented. Average PPG is defined as the average of the available blood glucouse (BG) measurements 90 minutes after breakfast, lunch and main evening meal respectively. The endpoint was evaluated based on the data from in-trial and on-treatment observation periods. The in-trial observation period starts at randomization and ends at the date of trial completion. The date of trial completion is the date of the final scheduled follow-up visit V92. For subjects not attending the follow-up visit V92, the date of trial completion is the date of the last subject-investigator contact. On-treatment observation period starts at the date of first dose of trial product and ended at the date of the last day on trial product. FASpregnant included all randomised women who were pregnant during the trial. In the report data, Number of Subjects Analysed = number of subjects who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    After gestational week 16
    End point values
    		 IDeg IDet
    Number of subjects analysed
    82
    83
    Units: mmol/L
    arithmetic mean (standard deviation)
        in-trial
    7.37 ( 1.35 )
    6.96 ( 1.63 )
        on-treatment
    7.37 ( 1.35 )
    6.96 ( 1.64 )
    No statistical analyses for this end point

    Secondary: Last planned fasting plasma glucose prior to delivery

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    End point title
    		 Last planned fasting plasma glucose prior to delivery
    End point description
    Mean of last planned fasting plasma glucose (FPG) prior to delivery after GW 16 is presented. The endpoint was evaluated based on the data from in-trial and on-treatment observation periods. The in-trial observation period starts at randomization and ends at the date of trial completion. The date of trial completion is the date of the final scheduled follow-up visit V92 (delivery + 58 days). For subjects not attending the follow-up visit V92, the date of trial completion is the date of the last subject-investigator contact. On-treatment observation period starts at the date of first dose of trial product and ended at the date of the last day on trial product. FASpregnant included all randomised women who were pregnant during the trial. In the report data, Number of Subjects Analysed = number of subjects who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    After gestational week 16
    End point values
    		 IDeg IDet
    Number of subjects analysed
    82
    83
    Units: mmol/L
    arithmetic mean (standard deviation)
        in-trial
    6.17 ( 2.05 )
    6.79 ( 2.47 )
        on-treatment
    6.19 ( 2.06 )
    6.78 ( 2.48 )
    No statistical analyses for this end point

    Secondary: Number of hypoglycaemic episodes

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    End point title
    		 Number of hypoglycaemic episodes
    End point description
    Hypoglycaemic episode (plasma glucose <= 3.9 mmol/L (70 mg/dL) Or > 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms) is defined as treatment emergent if the onset of the episode occurs on or after the first day of trial product administration, and no later than 7 days from the last day on trial product. Number of treatment emergent hypoglycaemic episodes during the pregnancy period is presented. The endpoint was evaluated based on the data from pregnancy period. Pregnancy period started from first day of pregnancy (date of conception corresponding to the first day in GW 2) or randomisation (whichever comes last) to the date of delivery. Safety analysis set for pregnant women (SASpregnant) included all randomised women exposed to at least one dose of trial product and who are pregnant during the trial.
    End point type
    Secondary
    End point timeframe
    During the pregnancy period (from first day of pregnancy (date of conception) or randomisation (whichever comes last) to delivery)
    End point values
    		 IDeg IDet
    Number of subjects analysed
    91
    94
    Units: Episodes
        number (not applicable)
    5431
    5982
    No statistical analyses for this end point

    Secondary: Development of sight-threatening retinopathy defined as proliferative retinopathy or maculopathy (yes/no)

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    End point title
    		 Development of sight-threatening retinopathy defined as proliferative retinopathy or maculopathy (yes/no)
    End point description
    Sight-threatening retinopathy is defined as proliferative retinopathy or maculopathy. Eye examination was performed by fundus photography or pharmacologically dilated fundoscopy to identify if pregnant subjects have developed sight-threatening retinopathy. Number of subjects who developed sight-threatening retinopathy from treatment baseline as well as from pregnancy baseline to the end of treatment (EOT) visit is presented. In the reported data, ‘Yes’ infers number of subjects who developed sight-threatening retinopathy whereas ‘No’ infers number of subjects who have not developed sight-threatening retinopathy. For subjects randomised pregnant the pregnancy baseline is same as treatment baseline. For subjects randomised nonpregnant and becoming pregnant in the conception period of trial, pregnancy baseline corresponds to data from visit 55 (week 53+30 days). SASpregnant included all randomised women exposed to at least one dose of trial product and who are pregnant during the trial.
    End point type
    Secondary
    End point timeframe
    From treatment baseline as well as from pregnancy baseline to the end of treatment visit
    End point values
    		 IDeg IDet
    Number of subjects analysed
    91
    94
    Units: Subjects
        From treatment baseline to EOT: Left eye: Yes
    2
    2
        From treatment baseline to EOT: Left eye: No
    79
    79
        From treatment baseline to EOT: Left eye: Missing
    10
    13
        From treatment baseline to EOT: Right eye: Yes
    2
    2
        From treatment baseline to EOT: Right eye: No
    79
    79
        From treatment baseline to EOT: Right eye: Missing
    10
    13
        From pregnancy baseline to EOT: Left eye: Yes
    2
    2
        From pregnancy baseline to EOT: Left eye: No
    79
    79
        From pregnancy baseline to EOT: Left eye: Missing
    10
    13
        From pregnancy baseline to EOT: Right eye: Yes
    2
    2
        From pregnancy baseline to EOT:Right eye: No
    79
    79
        From pregnancy baseline to EOT: Right eye: Missing
    10
    13
    No statistical analyses for this end point

    Secondary: Number of adverse events during the pregnancy period

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    End point title
    		 Number of adverse events during the pregnancy period
    End point description
    Number of adverse events (AEs) during pregnancy period is reported. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All AEs presented are treatment-emergent AEs (TEAEs). The TEAE is defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. SASpregnant included all randomised women exposed to at least one dose of trial product and who are pregnant during the trial.
    End point type
    Secondary
    End point timeframe
    From first day of pregnancy (date of conception) or randomisation (whichever comes last) to delivery
    End point values
    		 IDeg IDet
    Number of subjects analysed
    91
    94
    Units: Events
        number (not applicable)
    429
    328
    No statistical analyses for this end point

    Secondary: Pre-eclampsia defined as new-onset hypertension and simultaneous proteinuria or presence of eclampsia, haemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, or other severe organ involvement (yes/no)

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    End point title
    		 Pre-eclampsia defined as new-onset hypertension and simultaneous proteinuria or presence of eclampsia, haemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, or other severe organ involvement (yes/no)
    End point description
    Number of subjects with one or more events of pre-eclampsia during pregnancy period is reported. Pre-eclampsia was defined as new-onset hypertension (BP greater than or equal to (≥) 140 mmHg systolic or ≥ 90 mmHg diastolic, based on at least 2 measurements taken at least 4 hours apart) occurring from GW 20 to delivery and simultaneous proteinuria (defined as ≥ 300 mg protein in a 24 hours urine sample, a protein-to-creatinine ratio of ≥ 300 mg/g in a urine sample or a urine dipstick protein of 1+) or presence of eclampsia, HELLP syndrome, or other severe organ involvement. In the reported data, ‘Yes’ infers number of subjects who had pre-eclampsia events whereas ‘No’ infers number of subjects who have not had pre-eclampsia events. SASpregnant included all randomised women exposed to at least one dose of trial product and who are pregnant during the trial.
    End point type
    Secondary
    End point timeframe
    occurring from gestational week 20 to delivery
    End point values
    		 IDeg IDet
    Number of subjects analysed
    91
    94
    Units: Subjects
        Yes
    12
    7
        No
    79
    87
    No statistical analyses for this end point

    Secondary: Birth weight in gram (g)

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    End point title
    		 Birth weight in gram (g)
    End point description
    Mean birth weight for live birth infants is presented. The endpoint was evaluated based on the data from in-trial observation period which started at randomization and ended at the date of trial completion. The date of trial completion was the date of the final scheduled follow-up visit (delivery + 58 days). For subjects who had not attended the follow-up visit, the date of trial completion was the date of the last subject-investigator contact. FASpregnant included all randomised women who were pregnant during the trial. In the report data, Number of Subjects Analysed = number of subjects who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 IDeg IDet
    Number of subjects analysed
    86
    84
    Units: gram
        arithmetic mean (standard deviation)
    3691.0 ( 628.01 )
    3490.2 ( 629.94 )
    No statistical analyses for this end point

    Secondary: Pre-term delivery (delivery < 37 completed gestational weeks) (yes/no)

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    End point title
    		 Pre-term delivery (delivery < 37 completed gestational weeks) (yes/no)
    End point description
    Number of pregnant women who had pre-term delivery is presented. Pre-term delivery refers to delivery in less than 37 completed gestational weeks. In reported data, ‘Yes’ infers number of subjects who had pre-term delivery whereas ‘No’ infers number of subjects who has not had pre-term delivery. Unaddressed category refers to cases where either parents of infant had not given consent to share information after delivery or subjects who were withdrawn from trial and they did not give any further information or if subjects did not fill pregnancy outcome form. Endpoint was evaluated based on data from in-trial observation period which started at randomisation and ended at date of trial completion. Date of trial completion was date of final scheduled follow-up visit (delivery + 58 days). For subjects who had not attended follow-up visit, date of trial completion was date of last subject-investigator contact. FASpregnant included all randomised women who were pregnant during the trial.
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 IDeg IDet
    Number of subjects analysed
    92
    96
    Units: Subjects
        Yes
    34
    26
        No
    57
    66
        Unaddressed
    1
    4
    No statistical analyses for this end point

    Secondary: Presence of major abnormalities (classified according to European Concerted Action on Congenital Anomalies and Twins (EUROCAT)) (yes/no)

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    End point title
    		 Presence of major abnormalities (classified according to European Concerted Action on Congenital Anomalies and Twins (EUROCAT)) (yes/no)
    End point description
    Number of subjects who delivered foetuses/infants with abnormalities (classified according to EUROCAT) is presented. Presence of major abnormalities were based on adjudicated data, as after adjudication congenital anomalies were classified into major abnormalities or minor anomalies or in other categories. In reported data, ‘Yes’ infers presence of major abnormalities whereas ‘No’ infers no presence of major abnormalities. FASpregnant included all randomised women who were pregnant during the trial.
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 IDeg IDet
    Number of subjects analysed
    92
    96
    Units: Subjects
        Yes
    8
    8
        No
    84
    88
    No statistical analyses for this end point

    Secondary: Live born infants (yes/no)

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    End point title
    		 Live born infants (yes/no)
    End point description
    Number of subjects with live born infants is presented. In the reported data, ‘Yes’ infers number of live infants whereas 'No’ infers early foetal death or termination of pregnancy (induced/elective abortion). Unaddressed category refers to the cases where either the parents of the infant had not given consent to share information after delivery or the subjects who were withdrawn from trial and they did not give any further information or if the subjects did not fill the pregnancy outcome form. FASpregnant included all randomised women who were pregnant during the trial.
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 IDeg IDet
    Number of subjects analysed
    92
    96
    Units: Subjects
        Yes
    86
    85
        No
    5
    7
        Unaddressed
    1
    4
    No statistical analyses for this end point

    Secondary: Number of adverse events in the infant

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    End point title
    		 Number of adverse events in the infant
    End point description
    AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. AEs in foetus/infant with particular focus on the AEs from delivery to follow-up are presented.
    End point type
    Secondary
    End point timeframe
    From delivery to final follow-up
    End point values
    		 IDeg IDet
    Number of subjects analysed
    91
    94
    Units: Events
        number (not applicable)
    164
    150
    No statistical analyses for this end point

    Secondary: Neonatal hypoglycaemic episodes defined as plasma glucose ≤ 1.7 mmol/L (31 Milligrams per decilitre (mg/dL)) during the first 24 hours after birth or ≤ 2.5 mmol/L (45 mg/dL) between 24 hours and 48 hours after birth (yes/no)

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    End point title
    		 Neonatal hypoglycaemic episodes defined as plasma glucose ≤ 1.7 mmol/L (31 Milligrams per decilitre (mg/dL)) during the first 24 hours after birth or ≤ 2.5 mmol/L (45 mg/dL) between 24 hours and 48 hours after birth (yes/no)
    End point description
    Number of infants with neonatal hypoglycaemic episodes during the first 24 hours and between 24 hours and 48 hours after birth is presented. If plasma glucose was ≤ 1.7 mmol/L (31 mg/dL) during the first 24 hours and ≤ 2.5 mmol/L (45 mg/dL) between 24 hours and 48 hours after birth, it was called as neonatal hypoglycaemic episode. In the reported data, ‘Yes’ infers number of infants with neonatal hypoglycaemic episodes whereas ‘No’ infers number of infants with no neonatal hypoglycaemic episodes. Unaddressed category refers to the cases where either the parents of the infant had not given consent to share information after delivery or the subjects who were withdrawn from trial and they did not give any further information or if the subjects did not fill the pregnancy outcome form. FASpregnant included all randomised women who were pregnant during the trial. In the report data, Number of Subjects Analysed = number of subjects who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    During the first 24 hours after birth or between 24 hours and 48 hours after birth
    End point values
    		 IDeg IDet
    Number of subjects analysed
    86
    85
    Units: Subjects
        First 24 hours after birth: Yes
    20
    19
        First 24 hours after birth: No
    64
    65
        First 24 hours after birth: Unaddressed
    2
    1
        24 - 48 hours after birth: Yes
    4
    5
        24 - 48 hours after birth: No
    77
    78
        24 - 48 hours after birth: Unaddressed
    5
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first day of study drug administration until final follow-up (maximum 25 months)
    Adverse event reporting additional description
    All adverse events are TEAEs. A TEAE is defined as event that has onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomized treatment. SAS all included all randomised women exposed to at least one dose of trial product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    IDet
    Reporting group description
    		 Individually adjusted IDet injected subcutaneously as basal insulin once daily or twice daily + individually adjusted IAsp injected subcutaneously as bolus insulin 2-4 times daily with meals from randomization (gestational week 8-13 + 6 days) and continued until 28 days after delivery. If a subject was not pregnant at randomization, treatment was given up to a maximum of 53 weeks. For subjects who became pregnant, randomized treatment was continued throughout the pregnancy until end of treatment 28 days after delivery. Subjects who were not pregnant at 53 weeks after randomization were withdrawn.

    Reporting group title
    IDeg
    Reporting group description
    		 Individually adjusted IDeg injected subcutaneously as basal insulin once daily + individually adjusted IAsp injected subcutaneously as bolus insulin 2-4 times daily with meals from randomization (gestational week 8-13 + 6 days) and continued until 28 days after delivery. If a subject was not pregnant at randomization, treatment was given up to a maximum of 53 weeks. For subjects who became pregnant, randomized treatment was continued throughout the pregnancy until end of treatment 28 days after delivery. Subjects who were not pregnant at 53 weeks after randomization were withdrawn.

    Serious adverse events
    		 IDet IDeg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 112 (33.93%)
    41 / 110 (37.27%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Diabetes mellitus management
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maternal therapy to enhance foetal lung maturity
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    2 / 112 (1.79%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anembryonic gestation
         subjects affected / exposed
    1 / 112 (0.89%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical incompetence
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eclampsia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal hypokinesia
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational hypertension
         subjects affected / exposed
    6 / 112 (5.36%)
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational oedema
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HELLP syndrome
         subjects affected / exposed
    0 / 112 (0.00%)
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage in pregnancy
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Placental insufficiency
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyhydramnios
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum haemorrhage
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    2 / 112 (1.79%)
    6 / 110 (5.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature rupture of membranes
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature separation of placenta
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Preterm premature rupture of membranes
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Threatened labour
         subjects affected / exposed
    4 / 112 (3.57%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine contractions abnormal
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine hypotonus
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (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
    Injection site hypersensitivity
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (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
    Pelvic pain
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shortened cervix
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haematoma
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood ketone body increased
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (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
    Accidental overdose
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medication error
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (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
    Dizziness postural
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia of pregnancy
         subjects affected / exposed
    2 / 112 (1.79%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diabetic retinal oedema
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis of pregnancy
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial vaginosis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (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 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (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
    1 / 112 (0.89%)
    0 / 110 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 112 (1.79%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    6 / 112 (5.36%)
    4 / 110 (3.64%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IDet IDeg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 112 (54.46%)
    76 / 110 (69.09%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 112 (8.93%)
    8 / 110 (7.27%)
         occurrences all number
    16
    18
    Pregnancy, puerperium and perinatal conditions
    Placental insufficiency
         subjects affected / exposed
    5 / 112 (4.46%)
    7 / 110 (6.36%)
         occurrences all number
    5
    7
    Polyhydramnios
         subjects affected / exposed
    8 / 112 (7.14%)
    6 / 110 (5.45%)
         occurrences all number
    8
    6
    Pre-eclampsia
         subjects affected / exposed
    6 / 112 (5.36%)
    4 / 110 (3.64%)
         occurrences all number
    7
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 112 (14.29%)
    22 / 110 (20.00%)
         occurrences all number
    16
    22
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 112 (0.89%)
    8 / 110 (7.27%)
         occurrences all number
    1
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 112 (0.89%)
    6 / 110 (5.45%)
         occurrences all number
    1
    9
    Abdominal pain upper
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 110 (1.82%)
         occurrences all number
    8
    2
    Diarrhoea
         subjects affected / exposed
    1 / 112 (0.89%)
    8 / 110 (7.27%)
         occurrences all number
    1
    9
    Nausea
         subjects affected / exposed
    7 / 112 (6.25%)
    7 / 110 (6.36%)
         occurrences all number
    10
    7
    Vomiting
         subjects affected / exposed
    6 / 112 (5.36%)
    8 / 110 (7.27%)
         occurrences all number
    8
    8
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    5 / 112 (4.46%)
    7 / 110 (6.36%)
         occurrences all number
    5
    12
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    7 / 112 (6.25%)
    5 / 110 (4.55%)
         occurrences all number
    10
    5
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    4 / 112 (3.57%)
    6 / 110 (5.45%)
         occurrences all number
    4
    7
    Infections and infestations
    Influenza
         subjects affected / exposed
    7 / 112 (6.25%)
    5 / 110 (4.55%)
         occurrences all number
    10
    6
    Nasopharyngitis
         subjects affected / exposed
    23 / 112 (20.54%)
    21 / 110 (19.09%)
         occurrences all number
    45
    30
    Pharyngitis
         subjects affected / exposed
    2 / 112 (1.79%)
    7 / 110 (6.36%)
         occurrences all number
    2
    7
    Sinusitis
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 110 (1.82%)
         occurrences all number
    6
    2
    Urinary tract infection
         subjects affected / exposed
    9 / 112 (8.04%)
    11 / 110 (10.00%)
         occurrences all number
    11
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2018
    Discontinuation of the glycaemic data collection system (i.e. the combined use of a blood glucose (BG)-meter and eDiary). Instead a paper diary solution was implemented.
    30 Apr 2019
    Reduction in sample size

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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