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    Clinical Trial Results:
    A randomised controlled trial comparing the effect of the faster-acting insulin analog - insulin Fiasp® – versus insulin Novorapid® in the treatment of women with type 1 or type 2 diabetes during pregnancy and lactation

    Summary
    EudraCT number
    		 2018-004680-31
    Trial protocol
    		 DK  
    Global end of trial date
    23 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2023
    First version publication date
    30 Oct 2023
    Other versions
    Summary report(s)
    		 Published study results Lancet Diabetes Endocrinology

    Trial information

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    Trial identification
    Sponsor protocol code
    2018-004680-31
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03770767
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet University Hospital of Copenhagen
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Principal investigator, Lene Ringholm, 45 35451336, lene.ringholm.02@regionh.dk
    Scientific contact
    Principal investigator, Lene Ringholm, 45 35451336, lene.ringholm.02@regionh.dk
    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 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective is to evaluate the effect of insulin Fiasp® compared to insulin NovoRapid®, both in combination with usual long-acting insulin when indicated, on postprandial glucose levels, HbA1c, prevalence of fetal overgrowth in women with type 1 or type 2 diabetes during pregnancy. Infant growth and health up to 3 months of age will also be evaluated. The incidence of mild and severe hypoglycemia and the potential of blinded CGM to predict fetal overgrowth will be evaluated. The most appropriate insulin pump settings during pregnancy and lactation will be explored.
    Protection of trial subjects
    The trial protocol was approved by The Danish Medicines Agency (2018-004680-31) and the Regional Ethics Committee (H-19029966), and was published before completed enrollment. The trial was conducted in accordance with the Good Clinical Practice guidelines and monitored by the local GCP unit. Written informed consent was obtained by all participants prior to trial participation and by the participants’ partners regarding data collection of the infant prior to delivery.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 2019
    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
    Denmark: 216
    Worldwide total number of subjects
    216
    EEA total number of subjects
    216
    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)
    216
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first contact with the women with type 1 or type 2 diabetes refered to our center took place in early pregnancy at the first antenatal visit at our center. The women with type 1 or type 2 diabetes were contacted by a diabetes caregiver and invited orally and in writing to participate in this trial. The women had time to consider participation.

    Pre-assignment
    Screening details
    		 Eligibility assessment with regards to inclusion and exclusion criteria was performed. If any inclusion criterion was answered “no” or any exclusion criterion answered “yes” the woman was a screening failure and no further assessment was done. Re-screening was not allowed if the woman had failed one of the inclusion or exclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 Women randomized to intervention with faster-acting insulin aspart
    Arm type
    		 Experimental

    Investigational medicinal product name
    Faster aspart
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Faster aspart (100 U/mL) was continued from before pregnancy in those using insulin before pregnancy. For participants initiating insulin at randomization, 0.3 U/kg body weight was given. The dose of faster aspart was titrated based on blood glucose monitoring. During pregnancy all participants were encouraged to adjust mealtime insulin dose every 3-5 days between the routine visits, when appropriate, to obtain BGM targets 4-5.5 mmol/L pre-prandially, 4-7 mmol/L postprandially and 5-7 mmol/L before bedtime. Post-delivery the BGM targets were 4.0-7.0 mmol/L pre-prandially and 6.0-10.0 mmol/L before bedtime.

    Arm title
    		 Control
    Arm description
    		 Women randomized to active comparator insulin aspart
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aspart
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin aspart (100 U/mL) was continued from before pregnancy in those using insulin before pregnancy. For participants initiating insulin at randomization 0.3 U/kg body weight was given. The insulin aspart dose was titrated based on blood glucose monitoring. During pregnancy all participants were encouraged to adjust mealtime insulin dose every 3-5 days between the routine visits, when appropriate, to obtain BGM targets 4-5.5 mmol/L pre-prandially, 4-7 mmol/L postprandially and 5-7 mmol/L before bedtime. Post-delivery the BGM targets were 4.0-7.0 mmol/L pre-prandially and 6.0-10.0 mmol/L before bedtime.

    Number of subjects in period 1
    		Intervention Control
    Started
    109
    107
    Completed
    101
    102
    Not completed
    8
    5
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    7
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Women randomized to intervention with faster-acting insulin aspart

    Reporting group title
    Control
    Reporting group description
    		 Women randomized to active comparator insulin aspart

    Reporting group values
    		 Intervention Control Total
    Number of subjects
    		 109 107 216
    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)
    		 109 107 216
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        18-64
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.7 ± 5.1 31.6 ± 5.3 -
    Gender categorical
    Pregnant women
    Units: Subjects
        Female
    		 109 107 216
        Male
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Intervention
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary data analyses included all randomised participants according to the intention-to-treat principle.

    Subject analysis set title
    Control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary data analyses included all randomised participants according to the intention-to-treat principle.

    Subject analysis sets values
    		 Intervention Control
    Number of subjects
    101
    102
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    101
    102
        From 65-84 years
    0
    0
        85 years and over
    0
    0
        18-64
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.6 ± 5.2
    31.8 ± 5.3
    Gender categorical
    Pregnant women
    Units: Subjects
        Female
    101
    102
        Male
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Women randomized to intervention with faster-acting insulin aspart

    Reporting group title
    Control
    Reporting group description
    		 Women randomized to active comparator insulin aspart

    Subject analysis set title
    Intervention
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary data analyses included all randomised participants according to the intention-to-treat principle.

    Subject analysis set title
    Control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary data analyses included all randomised participants according to the intention-to-treat principle.

    Primary: Offspring birthweight standard deviation score

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    End point title
    		 Offspring birthweight standard deviation score
    End point description
    End point type
    Primary
    End point timeframe
    Participants were randomized between November 11 2019 and May 10 2022. Primary end point was collected when participants delivered mean 37 weeks after randomization.
    End point values
    		 Intervention Control Intervention Control
    Number of subjects analysed
    101
    102
    101
    102
    Units: gram(s)
        arithmetic mean (standard deviation)
    1.0 ± 1.4
    1.2 ± 1.3
    1.0 ± 1.4
    1.2 ± 1.3
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The primary outcome was analyzed by multiple linear regression adjusted for the stratification variable.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.5
    Method
    		 Regression, Linear
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From November 11 2019 to March 23 2023.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 -

    Reporting group title
    Comparator
    Reporting group description
    		 -

    Serious adverse events
    		 Intervention Comparator
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 109 (30.28%)
    25 / 107 (23.36%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    Congenital malformations
         subjects affected / exposed
    8 / 109 (7.34%)
    6 / 107 (5.61%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    pregnancy
         subjects affected / exposed
    25 / 109 (22.94%)
    19 / 107 (17.76%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Intervention Comparator
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 109 (75.23%)
    85 / 107 (79.44%)
    Reproductive system and breast disorders
    Pregnancy
         subjects affected / exposed
    82 / 109 (75.23%)
    85 / 107 (79.44%)
         occurrences all number
    82
    85

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2020
    From March 12 to May 1 2020: Inclusion paused due to COVID-19 pandemic.
    01 Sep 2020
    Participants were planned to be offered blinded continuous glucose monitoring (CGM, Envision Pro Sensor, Medtronic MiniMed) for seven days following randomisation, at 21 and 33 weeks, and in the morning for planned induction of labour or caesarean section. However, this blinded CGM was withdrawn from the market during the trial. Participants using continuous glucose monitoring (CGM) routinely continued their use regardless type of CGM device. The remaining participants with type 1 diabetes were offered intermittently scanned CGM from early pregnancy as part of routine care
    27 Apr 2021
    The pre-planned inclusion period of two years was extended by six months to meet the prespecified 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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37804858
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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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