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    Clinical Trial Results:
    Follow-Up Study to Assess Long-Term Safety and Outcomes in Infants and Children Born to Mothers Participating in Retosiban Treatment Studies

    Summary
    EudraCT number
    		 2014-000499-24
    Trial protocol
    		 BE   GB   ES   SE   DE   IT   FR  
    Global end of trial date
    02 Sep 2019

    Results information
    Results version number
    		 v1
    This version publication date
    23 May 2020
    First version publication date
    23 May 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    200722
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001359-PIP01-12
    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
    11 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study objective is to assess the safety and outcomes in infants and children who were exposed to retosiban or comparator in the Phase III treatment studies.
    Protection of trial subjects
    To minimize inconvenience to parents of the infants enrolled, this study did not require medical interventions or study visits to an investigational site. Instead, parents or legal guardians were prompted at certain timepoints to complete developmental questionnaires and other data regarding their child’s health status via an electronic device.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Israel: 32
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Japan: 6
    Worldwide total number of subjects
    98
    EEA total number of subjects
    22
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    4
    Infants and toddlers (28 days-23 months)
    94
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized, long-term follow-up study to evaluate the safety and outcomes of infants and children born to women who received retosiban or comparator in the Phase III spontaneous preterm labor (SPTL) treatment studies:200719 (NCT02377466) and 200721 (NCT02292771). Current study was referred as a retosiban infant outcome study (ARIOS).

    Pre-assignment
    Screening details
    		 A total of 101 participants were screened and 98 participants were enrolled and randomized in this study.

    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
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (200719 study)
    Arm description
    		 All infants and children born to women who received the placebo (0.9 percent sodium chloride infusion matched for retosiban volume, intravenous [IV] loading dose over 5 minutes and continuous infusion rate including dose increase in participants with an inadequate response any time after first hour of treatment) in 200719 study. Current study did not require any medical interventions or study visits to an investigational site.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was available as 0.9 percent sodium chloride infusion matched for retosiban volume, intravenous (IV) loading dose over 5 minutes and continuous infusion rate including dose increase in participants with an inadequate response any time after first hour of treatment.

    Arm title
    		 Atosiban (200721 study)
    Arm description
    		 All infants and children born to women who received atosiban (in 3 successive stages; an initial bolus dose of 6.75 milligram [mg] using atosiban 6.75 mg per 0.9 milliliter [mL] solution for injection, followed by continuous high dose infusion at 18 mg per hour for 3 hours, then a lower 6 mg per hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg per 5 mL concentrate for solution) in 200721 study. Current study did not require any medical interventions or study visits to an investigational site.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atosiban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atosiban was available as an initial bolus dose of 6.75 milligram (mg) using 6.75 mg per 0.9 milliliter (mL) solution for injection, followed by continuous high dose infusion at 18 mg per hour for 3 hours, then a lower 6 mg per hour infusion for the remainder of the 48-hour using 37.5 mg per 5 mL concentrate for solution.

    Arm title
    		 Retosiban (200719 and 200721 study)
    Arm description
    		 All infants and children born to women who received retosiban (6 mg IV loading dose of retosiban over 5 minutes followed by a 6 mg per hour continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg per hour continuous infusion for remainder of 48-hour treatment period) in 200719 study or 200721 study. Current study did not require any medical interventions or study visits to an investigational site.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Retosiban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Retosiban was available as 6 mg IV loading dose over 5 minutes followed by a 6 milligram per hour continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg per hour continuous infusion for remainder of 48-hour treatment period

    Number of subjects in period 1
    		Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Started
    5
    44
    49
    Completed
    4
    24
    28
    Not completed
    1
    20
    21
         Consent withdrawn by subject
    -
    3
    3
         Lost to follow-up
    1
    17
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (200719 study)
    Reporting group description
    		 All infants and children born to women who received the placebo (0.9 percent sodium chloride infusion matched for retosiban volume, intravenous [IV] loading dose over 5 minutes and continuous infusion rate including dose increase in participants with an inadequate response any time after first hour of treatment) in 200719 study. Current study did not require any medical interventions or study visits to an investigational site.

    Reporting group title
    Atosiban (200721 study)
    Reporting group description
    		 All infants and children born to women who received atosiban (in 3 successive stages; an initial bolus dose of 6.75 milligram [mg] using atosiban 6.75 mg per 0.9 milliliter [mL] solution for injection, followed by continuous high dose infusion at 18 mg per hour for 3 hours, then a lower 6 mg per hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg per 5 mL concentrate for solution) in 200721 study. Current study did not require any medical interventions or study visits to an investigational site.

    Reporting group title
    Retosiban (200719 and 200721 study)
    Reporting group description
    		 All infants and children born to women who received retosiban (6 mg IV loading dose of retosiban over 5 minutes followed by a 6 mg per hour continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg per hour continuous infusion for remainder of 48-hour treatment period) in 200719 study or 200721 study. Current study did not require any medical interventions or study visits to an investigational site.

    Reporting group values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study) Total
    Number of subjects
    		 5 44 49 98
    Age categorical
    Units: Subjects
        Total Participants
    		 5 44 49 98
    Age Continuous
    Units: Months
        arithmetic mean (standard deviation)
    		 2.16 ( 1.479 ) 2.18 ( 1.158 ) 2.12 ( 0.932 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 1 18 21 40
        Male
    		 4 26 28 58
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African (Afr) Heritage
    		 0 1 1 2
        American Indian or Alaskan Native
    		 0 5 6 11
        Asian-Central/South Asian Heritage
    		 0 0 1 1
        Asian-East Asian Heritage
    		 1 4 8 13
        Asian-Japanese Heritage
    		 4 0 2 6
        White-Arabic/North Afr/Caucasian/European Heritage
    		 0 34 31 65

    End points

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    End points reporting groups
    Reporting group title
    Placebo (200719 study)
    Reporting group description
    		 All infants and children born to women who received the placebo (0.9 percent sodium chloride infusion matched for retosiban volume, intravenous [IV] loading dose over 5 minutes and continuous infusion rate including dose increase in participants with an inadequate response any time after first hour of treatment) in 200719 study. Current study did not require any medical interventions or study visits to an investigational site.

    Reporting group title
    Atosiban (200721 study)
    Reporting group description
    		 All infants and children born to women who received atosiban (in 3 successive stages; an initial bolus dose of 6.75 milligram [mg] using atosiban 6.75 mg per 0.9 milliliter [mL] solution for injection, followed by continuous high dose infusion at 18 mg per hour for 3 hours, then a lower 6 mg per hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg per 5 mL concentrate for solution) in 200721 study. Current study did not require any medical interventions or study visits to an investigational site.

    Reporting group title
    Retosiban (200719 and 200721 study)
    Reporting group description
    		 All infants and children born to women who received retosiban (6 mg IV loading dose of retosiban over 5 minutes followed by a 6 mg per hour continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg per hour continuous infusion for remainder of 48-hour treatment period) in 200719 study or 200721 study. Current study did not require any medical interventions or study visits to an investigational site.

    Primary: Number of infants and children with newly diagnosed chronic medical conditions (after 28 days post estimated date of delivery)

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    End point title
    		 Number of infants and children with newly diagnosed chronic medical conditions (after 28 days post estimated date of delivery) [1]
    End point description
    The parents of the infants filled in an online child health inventory (CHI) questionnaire, which asked them about each condition. If they reported anything, it was then verified by a healthcare professional. ARIOS Safety Population was a subset of the Infant Safety Population (all the infants whose mothers were randomized and received retosiban or comparator in any of the Phase III treatment trials) for which the mother/infant pairs were enrolled into the ARIOS study. Number of infants and children with newly diagnosed chronic medical conditions are presented.
    End point type
    Primary
    End point timeframe
    From 28 days post estimated date of delivery up to 24 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [2]
    44 [3]
    49 [4]
    Units: Participants
    0
    1
    3
    Notes
    [2] - ARIOS Safety Population
    [3] - ARIOS Safety Population
    [4] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants and children with newly diagnosed congenital anomalies (after 28 days post estimated date of delivery)

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    End point title
    		 Number of infants and children with newly diagnosed congenital anomalies (after 28 days post estimated date of delivery) [5]
    End point description
    A congenital anomaly is a condition present at birth that results from malformation, deformation, or disruption in 1 or more parts of the body, a chromosomal abnormality, or a known clinical syndrome. Congenital anomaly serious adverse events (SAEs) were examined by the birth defect evaluator. Events were coded per centers for disease control and prevention (CDC) Metropolitan Atlanta congenital defects program (MACDP) criteria and/or European surveillance of congenital anomalies (EUROCAT) criteria. Predefined defect codes specified whether the defect was face and neck, a cleft lip or palate, cardiovascular, respiratory, upper gastrointestinal, female genitalia, male genitalia, renal and urinary system, other musculoskeletal defects, skin, a chromosome anomaly, other organ systems, or a specified syndrome. Number of infants and children with newly diagnosed congenital anomalies reported up to 1 year of chronological age and reported after 1 year of chronological age are presented.
    End point type
    Primary
    End point timeframe
    From 28 days post estimated date of delivery up to 24 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [6]
    44 [7]
    49 [8]
    Units: Participants
        Up to 1 year of chronological age
    0
    0
    2
        After 1 year of chronological age
    0
    0
    0
    Notes
    [6] - ARIOS Safety Population
    [7] - ARIOS Safety Population
    [8] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infant and child death (after 28 days post estimated date of delivery)

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    End point title
    		 Number of infant and child death (after 28 days post estimated date of delivery) [9]
    End point description
    Number of infant and child death that occurred after 28 days post estimated date of delivery and up to 24 months are presented.
    End point type
    Primary
    End point timeframe
    From 28 days post estimated date of delivery up to 24 months
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [10]
    44 [11]
    49 [12]
    Units: Participants
    0
    0
    0
    Notes
    [10] - ARIOS Safety Population
    [11] - ARIOS Safety Population
    [12] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for any domain at 9 months

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for any domain at 9 months [13]
    End point description
    The ASQ-3 included 6 questions in each area, designed to assess: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes(10 points), sometimes(5 points) or not yet(0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for communication was 13.97,gross motor was 17.82,fine motor was 31.32, problem solving was 28.72 and personal social skills was 18.91. Total score was derived by taking mean of all 5 components. Any infant who scored below the cut-off,a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for any domains in the black zone at 9 months is presented. Only those participants with data available at the specified data points were analyzed.
    End point type
    Primary
    End point timeframe
    At 9 months
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    3 [14]
    17 [15]
    20 [16]
    Units: Participants
    0
    4
    4
    Notes
    [14] - ARIOS Safety Population
    [15] - ARIOS Safety Population
    [16] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for any domain at 18 months

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for any domain at 18 months [17]
    End point description
    The ASQ-3 included 6 questions in each area, designed to assess: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes(10 points), sometimes(5 points) or not yet(0 points) to each question to complete ASQ-3. At 18 months, the pre-defined cut-off score for communication was 13.06,gross motor was 37.38,fine motor was 34.32, problem solving was 25.74 and personal social skills was 27.19. Total score was derived by taking mean of all 5 components. Any infant who scored below the cut-off,a score more than or equal to 2 standard deviations below the mean score(that is Black zone in the score chart)in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for any domains in the black zone at 18 months is presented. Only those participants with data available at the specified data points were analyzed.
    End point type
    Primary
    End point timeframe
    At 18 months
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    3 [18]
    19 [19]
    18 [20]
    Units: Participants
    2
    5
    0
    Notes
    [18] - ARIOS Safety Population
    [19] - ARIOS Safety Population
    [20] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for any domain at 24 months

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for any domain at 24 months [21]
    End point description
    The ASQ-3 included 6 questions in each area, designed to assess: communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes(10 points), sometimes(5 points) or not yet(0 points) to each question to complete ASQ-3. At 24 months, the pre-defined cut-off score for communication was 25.17,gross motor was 38.07,fine motor was 35.16, problem solving was 29.78 and personal social skills was 31.54. Total score was derived by taking mean of all 5 components. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score(that is Black zone in the score chart)in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment. Number of infants with ASQ-3 scores for any domains in the black zone at 24 months is presented. Only those participants with data available at the specified data points were analyzed
    End point type
    Primary
    End point timeframe
    At 24 months
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    2 [22]
    19 [23]
    25 [24]
    Units: Participants
    1
    2
    2
    Notes
    [22] - ARIOS Safety Population
    [23] - ARIOS Safety Population
    [24] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for gross motor skills

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for gross motor skills [25]
    End point description
    The ASQ-3 included 6 questions in each area; communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for gross motor skills was 17.82. At 18 months, it was 37.38. At 24 months, it was 38.07. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist. Number of infants with ASQ-3 scores for gross motor skills in the black zone at 9, 18 and 24 months is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [26]
    44 [27]
    49 [28]
    Units: Participants
        9 months, n=3,17,20
    0
    1
    0
        18 months, n=3,19,18
    1
    1
    0
        24 months, n=2,19,25
    0
    1
    0
    Notes
    [26] - ARIOS Safety Population
    [27] - ARIOS Safety Population
    [28] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for fine motor skills

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for fine motor skills [29]
    End point description
    The ASQ-3 included 6 questions in each area; communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for fine motor skills was 31.32. At 18 months, it was 34.32. At 24 months, it was 35.16. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist. Number of infants with ASQ-3 scores for fine motor skills in the black zone at 9, 18 and 24 months is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [30]
    44 [31]
    49 [32]
    Units: Participants
        9 months, n=3,17,20
    0
    0
    2
        18 months, n=3,19,18
    1
    2
    0
        24 months, n=2,19,25
    0
    0
    0
    Notes
    [30] - ARIOS Safety Population
    [31] - ARIOS Safety Population
    [32] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for communication skills

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for communication skills [33]
    End point description
    The ASQ-3 included 6 questions in each area; communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for communication skills was 13.97. At 18 months, it was 13.06. At 24 months, it was 25.17. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist. Number of infants with ASQ-3 scores for communication skills in the black zone at 9, 18 and 24 months is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [34]
    44 [35]
    49 [36]
    Units: Participants
        9 months, n=3,17,20
    0
    1
    1
        18 months, n=3,19,18
    1
    0
    0
        24 months, n=2,19,25
    1
    1
    2
    Notes
    [34] - ARIOS Safety Population
    [35] - ARIOS Safety Population
    [36] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for problem solving skills

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for problem solving skills [37]
    End point description
    The ASQ-3 included 6 questions in each area; communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for problem solving skills was 28.72. At 18 months, it was 25.74. At 24 months, it was 29.78. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist. Number of infants with ASQ-3 scores for problem solving skills in the black zone at 9, 18 and 24 months is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants),but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [38]
    44 [39]
    49 [40]
    Units: Participants
        9 months, n=3,17,20
    0
    1
    2
        18 months, n=3,19,18
    0
    1
    0
        24 months, n=2,19,25
    0
    1
    0
    Notes
    [38] - ARIOS Safety Population
    [39] - ARIOS Safety Population
    [40] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for personal social skills

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    End point title
    		 Number of infants with ages and stages questionnaire-3 (ASQ-3) score in the black zone for personal social skills [41]
    End point description
    The ASQ-3 included 6 questions in each area; communication skills, gross motor skills, fine motor skills, problem solving skills, and personal social skills. Parents answered either yes (10 points), sometimes (5 points) or not yet (0 points) to each question to complete ASQ-3. At 9 months, the pre-defined cut-off score for personal social skills was 18.91. At 18 months, it was 27.19. At 24 months, it was 31.54. Any infant who scored below the cut-off, a score more than or equal to 2 standard deviations below the mean score (that is Black zone in the score chart) in any of the 5 areas of the ASQ-3 was to be referred to a developmental specialist. Number of infants with ASQ-3 scores for personal social skills in the black zone at 9, 18 and 24 months is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants),but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [41] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [42]
    44 [43]
    49 [44]
    Units: Participants
        9 months, n=3,17,20
    0
    2
    0
        18 months, n=3,19,18
    0
    1
    0
        24 months, n=2,19,25
    0
    1
    0
    Notes
    [42] - ARIOS Safety Population
    [43] - ARIOS Safety Population
    [44] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants referred for developmental evaluation using Bayley scales of infant development, third edition (BSID-III)

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    End point title
    		 Number of infants referred for developmental evaluation using Bayley scales of infant development, third edition (BSID-III) [45]
    End point description
    Any infant who scored below the cut-off i.e., a score greater than or equal to 2 Standard Deviations (SDs) below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was evaluated using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Total score was derived by taking mean of all the components. Number of infants referred for developmental evaluation using BSID-III is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [45] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [46]
    44 [47]
    49 [48]
    Units: Participants
        9 months, n=0,4,4
    0
    1
    3
        18 months, n=2,5,0
    2
    3
    0
        24 months, n=1,2,2
    0
    2
    1
    Notes
    [46] - ARIOS Safety Population
    [47] - ARIOS Safety Population
    [48] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the cognitive scale (less than 4)

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    End point title
    		 Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the cognitive scale (less than 4) [49]
    End point description
    Any infant who scored below the cut-off i.e., a score greater than or equal to 2 Standard Deviations (SDs) below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was evaluated using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the cognitive scale (less than 4) is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [49] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [50]
    44 [51]
    49 [52]
    Units: Participants
        9 months, n=0,0,1
    0
    0
    0
        18 months, n=0,2,0
    0
    2
    0
        24 months, n=0,0,1
    0
    0
    1
    Notes
    [50] - ARIOS Safety Population
    [51] - ARIOS Safety Population
    [52] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the gross motor scale (less than 4)

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    End point title
    		 Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the gross motor scale (less than 4) [53]
    End point description
    Any infant who scored below the cut-off i.e., a score greater than or equal to 2 Standard Deviations (SDs) below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was evaluated using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the gross motor scale (less than 4) is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [53] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [54]
    44 [55]
    49 [56]
    Units: Participants
        9 months, n=0,0,1
    0
    0
    0
        18 months, n=0,2,0
    0
    2
    0
        24 months, n=0,0,1
    0
    0
    1
    Notes
    [54] - ARIOS Safety Population
    [55] - ARIOS Safety Population
    [56] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the fine motor scale (less than 4)

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    End point title
    		 Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the fine motor scale (less than 4) [57]
    End point description
    Any infant who scored below the cut-off i.e., a score greater than or equal to 2 Standard Deviations (SDs) below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was evaluated using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the fine motor scale (less than 4) is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [57] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [58]
    44 [59]
    49 [60]
    Units: Participants
        9 months, n=0,0,1
    0
    0
    0
        18 months, n=0,2,0
    0
    2
    0
        24 months, n=0,0,1
    0
    0
    1
    Notes
    [58] - ARIOS Safety Population
    [59] - ARIOS Safety Population
    [60] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the language scale (less than 70)

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    End point title
    		 Number of infants with Bayley Scales of Infant Development, third edition score greater than 2 standard deviation below the mean score for the language scale (less than 70) [61]
    End point description
    Any infant who scored below the cut-off i.e., a score greater than or equal to 2 Standard Deviations (SDs) below the mean score (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was evaluated using the BSID-III. It scaled scores for cognitive, language (receptive and expressive), motor (fine and gross motor). The language and motor areas each have a composite score, with a mean of 100, a SD of 15 and a range of 40 to 160. Scores lower than 70 indicated moderate or severe impairment. In the cognitive area, the infant scored "1" if they could do an activity and "0" if they could not. Number of infants with BSID-III score greater than 2 SD below the mean score for the language scale (less than 70) is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    9, 18 and 24 months
    Notes
    [61] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [62]
    44 [63]
    49 [64]
    Units: Participants
        9 months, n=0,0,1
    0
    0
    0
        18 months, n=0,2,0
    0
    2
    0
        24 months, n=0,0,1
    0
    0
    1
    Notes
    [62] - ARIOS Safety Population
    [63] - ARIOS Safety Population
    [64] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with a child behavior checklist for ages 1.5 to 5 years (CBCL/1.5 to 5) score above the 97th percentile for a subset of prespecified questions that relate to attention and hyperactivity problems

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    End point title
    		 Number of infants with a child behavior checklist for ages 1.5 to 5 years (CBCL/1.5 to 5) score above the 97th percentile for a subset of prespecified questions that relate to attention and hyperactivity problems [65]
    End point description
    The CBCL/1.5 to 5 questionnaire is a parent-completed questionnaire used for assessing behavioral and social competencies. It included approximately 100 items that characterized preschool children between the ages of 1.5 and 5 years. Each question could be answered as “not true scored as"0",somewhat or sometimes true scored as"1"or very true or often true scored as "2”. There were 6 questions related to attention and hyperactivity problems. The responses to those 6 questions were summed (ranged 0 to 12). Total score of 0 to 9 indicated normal,10 indicated borderline and 11 to 12 indicated significant attention and hyperactivity problems. Scores above the 97th percentile are in the significant range of clinical concern. Number of infants with CBCL/1.5 to 5 score above 97th percentile for subset of pre-specified questions related to attention and hyperactivity problems at 24 months is reported. Only those participants with data available at the specified data points were analyzed.
    End point type
    Primary
    End point timeframe
    At 24 months
    Notes
    [65] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    2 [66]
    12 [67]
    14 [68]
    Units: Participants
    0
    1
    0
    Notes
    [66] - ARIOS Safety Population
    [67] - ARIOS Safety Population
    [68] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants indicated as needing further evaluation after completion of the modified checklist for autism in toddlers- revised with follow-up (M-CHAT-R/F)

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    End point title
    		 Number of infants indicated as needing further evaluation after completion of the modified checklist for autism in toddlers- revised with follow-up (M-CHAT-R/F) [69]
    End point description
    The M-CHAT-R/F is a parent-reported autism screening tool designed to identify children 16 to 30 months of age who received a more thorough assessment for possible early signs of autism spectrum disorder (ASD) or developmental delay. The M-CHAT-R/F consisted of 20 questions that were answered with either “yes, scored as 0” or “no, scored as 1”. Total scores (ranged 0 to 20) on the M-CHAT-R/F between 0 and 2 indicated a low risk, scores between 3 and 7 indicated a medium risk and triggered administration of the follow-up questionnaire, and scores between 8 and 20 indicated a high risk. Number of infants who needed further evaluation as per the M-CHAT-R/F at 18 and 24 months is presented. All 98 participants in the study were included in the analysis (5, 44 and 49 Participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    18 and 24 months
    Notes
    [69] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    5 [70]
    44 [71]
    49 [72]
    Units: Participants
        18 months,n=2,10,7
    0
    0
    0
        24 months,n=2,11,13
    0
    0
    0
    Notes
    [70] - ARIOS Safety Population
    [71] - ARIOS Safety Population
    [72] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants referred for neurological evaluation to determine diagnosis of cerebral palsy

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    End point title
    		 Number of infants referred for neurological evaluation to determine diagnosis of cerebral palsy [73]
    End point description
    Parents reported in CHI questionnaire if their infant had cerebral palsy. If the infant was not diagnosed with cerebral palsy, then this was detected as part of the ASQ-3 assessment, based on the results of the gross motor scale. To confirm the diagnosis of cerebral palsy, the healthcare practitioner referred the infant for further neurological tests if they scored in the black zone of the ASQ-3 at the month 24 assessment. Number of infants referred for neurological evaluation to determine diagnosis of cerebral palsy at 24 months is presented. Only those participants with data available at the specified data points were analyzed.
    End point type
    Primary
    End point timeframe
    At 24 months
    Notes
    [73] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    2 [74]
    19 [75]
    25 [76]
    Units: Participants
    0
    0
    0
    Notes
    [74] - ARIOS Safety Population
    [75] - ARIOS Safety Population
    [76] - ARIOS Safety Population
    No statistical analyses for this end point

    Primary: Number of infants with the indicators of neurodevelopmental impairment

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    End point title
    		 Number of infants with the indicators of neurodevelopmental impairment [77]
    End point description
    The indicators of neurodevelopmental impairment were 'hearing impaired, uncorrected even with aids'; 'blindness in 1 or both eyes, or sees light only'; 'cerebral palsy-moderate and severe (moderate: Grade 2 or 3 using the gross motor functional classification system [GMFCS] and severe: Grade 4 or 5 using the GMFCS)'; 'cognitive impairment: BSID-III cognitive scale score of less than 2 SDs below mean score (less than 4)'; 'motor impairment: BSID-III motor composite scale score of greater than 2 SDs below mean score (less than 70)'; 'diagnosis of ASD, attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD)'. Number of infants having any 1 of these indicators is presented. Only those participants with data available at the specified data points were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 24 months
    Notes
    [77] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Placebo (200719 study) Atosiban (200721 study) Retosiban (200719 and 200721 study)
    Number of subjects analysed
    4 [78]
    30 [79]
    36 [80]
    Units: Participants
        Hearing impaired, uncorrected even with aids
    0
    0
    0
        Blindness in 1 or both eyes, or sees light only
    0
    0
    0
        Cerebral palsy (moderate and severe)
    0
    0
    0
        Cognitive impairment
    0
    1
    1
        Motor impairment
    0
    1
    1
        Diagnosis of ASD,ADD or ADHD
    0
    1
    0
    Notes
    [78] - ARIOS Safety Population
    [79] - ARIOS Safety Population
    [80] - ARIOS Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) were collected for infants from after 28 days post estimated due date until maximum of 24 months chronological age. Non-SAEs were not collected, since all the adverse events that occurred in infants were considered as SAEs
    Adverse event reporting additional description
    SAEs were reported for ARIOS Safety Population which comprised of a subset of Infant Safety Population (all the infants whose mothers were randomized and received retosiban or comparator in any of the Phase III treatment trials) for which the mother/infant pairs were enrolled into the ARIOS study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo (200719 study)
    Reporting group description
    		 All infants and children born to women who received the placebo (0.9 percent sodium chloride infusion matched for retosiban volume, intravenous [IV] loading dose over 5 minutes and continuous infusion rate including dose increase in participants with an inadequate response any time after first hour of treatment) in 200719 study. Current study did not require any medical interventions or study visits to an investigational site.

    Reporting group title
    Retosiban (200719 and 200721 study)
    Reporting group description
    		 All infants and children born to women who received retosiban (6 mg IV loading dose of retosiban over 5 minutes followed by a 6 mg per hour continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg per hour continuous infusion for remainder of 48-hour treatment period) in 200719 study or 200721 study. Current study did not require any medical interventions or study visits to an investigational site.

    Reporting group title
    Atosiban (200721 study)
    Reporting group description
    		 All infants and children born to women who received atosiban (in 3 successive stages; an initial bolus dose of 6.75 milligram [mg] using atosiban 6.75 mg per 0.9 milliliter [mL] solution for injection, followed by continuous high dose infusion at 18 mg per hour for 3 hours, then a lower 6 mg per hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg per 5 mL concentrate for solution) in 200721 study. Current study did not require any medical interventions or study visits to an investigational site.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Non-SAEs were not collected, since all the adverse events that occurred in infants were considered as SAEs
    Serious adverse events
    		 Placebo (200719 study) Retosiban (200719 and 200721 study) Atosiban (200721 study)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 49 (6.12%)
    6 / 44 (13.64%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Injury of genitals
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cataract
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital hydrocoele
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Circumoral cyanosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 49 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Cervical lymphadenitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 49 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute bronchiolitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 49 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 49 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 49 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 49 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo (200719 study) Retosiban (200719 and 200721 study) Atosiban (200721 study)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 49 (0.00%)
    0 / 44 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2015
    Amendment 01: Extended the study duration from 24 months to 5 years; added an assessment using a modified version of the child health inventory questionaire; added an additional assessment of modified checklist for autism in toddlers- revised with follow-up (M-CHAT-R/F); revised child behavior checklist (CBCl/1.5 to 5) per American academy of pediatrics guidelines, deletion of neurodevelopment endpoint for an additional behaviour assessment using M-CHAT-R/F and CBCl/1.5 to 5; revised the subgroups to reflect study design of Phase III spontaneous preterm labour Study 200719 (NEWBORN-1); clarified unblinding text; incorporation of other administrative changes
    01 Nov 2018
    Amendment 02: Reduction of study duration from 5 years to 24 months; termination of retosiban development program; low recruitment for 200719 (NEWBORN-1) and 200721 (ZINN) studies; modification in the recommendation of independent data monitoring committee; reclassification of all resource utilization endpoints as exploratory endpoints due to the reduced sample size; correction of an error in the mean Bayley Scales of Infant Development, third edition (BSID-III) score; incorporation of other administrative changes

    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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