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    Clinical Trial Results:
    A Prospective, Randomized, Double-Blind, Phase 3 Study Comparing rhBSSL and Placebo Added to Infant Formula or Pasteurized Breast Milk During 4 Weeks of Treatment in Preterm Infants Born Before Week 32 of Gestational Age

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2010-023909-35
    Trial protocol
    GB   BE   SE   DE   HU   FR   CZ   PL   ES   IT   Outside EU/EEA  
    Global end of trial date
    15 May 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    14 Jul 2016
    First version publication date
    27 Jun 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • New data added to full data set
    1) Results for the period 12-24 months corrected age has been added as analysis of these endpoints has now been finalized. 2) Link to publication added. 3) Correction of wrongful allocation of data within the “Adverse Events” section caused by EudraCT software issues.

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    BVT.BSSL-030
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01413581
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Swedish Orphan Biovitrum AB (publ)
    Sponsor organisation address
    Tomtebodavägen 23A, Solna, Stockholm, Sweden, SE-112 76
    Public contact
    Anna Olsson, Swedish Orphan Biovitrum AB (publ), 46 8 697 20 00, anna.olsson@sobi.com
    Scientific contact
    Kristina Timdahl, Swedish Orphan Biovitrum AB (publ), 46 8 697 20 00, kristina.timdahl@sobi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000822-PIP01-09
    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
    06 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to demonstrate that rhBSSL improves growth in preterm infants as compared with placebo when administered in infant formula or PBM.
    Protection of trial subjects
    The study will be conducted according to the International Conference on Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice ensuring that the rights, safety and well-being of patients are protected, consistent with the principles that have their origin in the Declaration of Helsinki. The conduct of the study in neonatology intensive care units allowed for the continuous monitoring of patient safety and the accessibility to any necessary therapeutic measures. Furthermore the blood volume to be drawn from the preterm infants was strictly controlled. Serum levels of possible rhBSSL antibodies was determined at Baseline, at the end of treatment (Day 29), and 3 months after the start of treatment and followed further if antibodies were detected. Each individual patient with a positive anti-drug antibody response was checked for immune related adverse events (and vice versa).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Jun 2011
    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
    Poland: 87
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Belgium: 42
    Country: Number of subjects enrolled
    Czech Republic: 49
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 108
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Russian Federation: 3
    Worldwide total number of subjects
    415
    EEA total number of subjects
    412
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    415
    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)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    74 study centres in Europe participated in the trial and patients were randomised at 54 of them. First patient was screened on July 26 2011 and last patient randomised on 3 June 2013.

    Pre-assignment
    Screening details
    After informed consent was collected from the parents/legally authorised representatives, patients entered a screening period of a maximum of seven days. The screening and baseline visit could also take place on the same date. A total of 415 patients were randomized and treatment was initiated in 412 patients.

    Period 1
    Period 1 title
    Overall study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    rhBSSL Full Analysis Set
    Arm description
    Patients received rhBSSL Day 1 (Baseline) as soon as possible after randomization (either on the day of randomization or the day after). The administration of rhBSSL continued for 4 weeks. Follow-up visits occurred at 3 months after the first dose of study drug and at 12 months corrected age. The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant Human Bile-Salt-Stimulated Lipase
    Investigational medicinal product code
    rhBSSL
    Other name
    Recombinant Human Bile-Salt-Stimulated Lipase (rhBSSL)
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Enteral use
    Dosage and administration details
    15 mg of rhBSSL (sterile powder for oral solution) will be reconstituted in 1mL of sterile water before addition to 100 mL pasteurised breast milk of infant formula. The food volume should be in the range of 150-180 mL/kg/day. Each feeding during the 4 week treatment period should contain study drug.

    Arm title
    Placebo Full Analysis Set
    Arm description
    Patients received placebo Day 1 (Baseline) as soon as possible after randomization (either on the day of randomization or the day after). The administration of placebo continued for 4 weeks. Follow-up visits occurred at 3 months after the first dose of study drug and at 12 months corrected age. The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Enteral use , Oral use
    Dosage and administration details
    Placebo will be reconstituted in 1mL of sterile water before addition to 100 mL pasteurised breast milk of infant formula. The food volume should be in the range of 150-180 mL/kg/day. Each feeding during the 4 week treatment period should contain study drug.

    Number of subjects in period 1 [1]
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Started
    206
    204
    Initiated Treatment
    206
    204
    In the study at Day 29
    204
    204
    Completed
    179
    186
    Not completed
    27
    18
         Adverse event, serious fatal
    2
    1
         Parents decision
    -
    1
         Consent withdrawn by subject
    7
    7
         Not possible for parents to come to visit
    -
    1
         Adverse event, non-fatal
    2
    -
         Patient moved
    1
    -
         Lost to follow-up
    14
    7
         Not possible to schedule visit with parents
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 415 patients were randomly assigned to treatment (rhBSSL=207, placebo=208). Treatment was initiated in 412 patients (rhBSSL=207, placebo=205). The full analysis set (FAS) was used as the primary population for the analyses of the primary and secondary efficacy variables and it is the FAS that baseline characteristics are described for. 410 patients were included in the FAS (rhBSSL=206, placebo=204). Exclusion from the FAS was due to lack of body weight data post baseline.
    Period 2
    Period 2 title
    Extended f-u to 24 months corrected age
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    rhBSSL EES
    Arm description
    At the 12 months corrected age visit the parents/primary caregivers were to be asked to consent to an extended follow-up to 24 months corrected age. The extended follow-up included telephone visits at 15, 18 and 21 months corrected age and a visit at 24 months corrected age. The extension efficacy set (EES) was the primary analysis set and consisted of all patients who signed an ICF to have data collected in the extension portion of the study, and had at least one efficacy assessment at the 24-months CA visit. Of the 179 patients treated with rhBSSL who performed the 12-months CA visit, 133 consented to continue with the extended follow-up and 35 of these completed the 24-months CA visit. The remaining 98 were withdrawn from the study upon request from the sponsor
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant Human Bile-Salt-Stimulated Lipase
    Investigational medicinal product code
    rhBSSL
    Other name
    Recombinant Human Bile-Salt-Stimulated Lipase (rhBSSL)
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Enteral use
    Dosage and administration details
    15 mg of rhBSSL (sterile powder for oral solution) will be reconstituted in 1mL of sterile water before addition to 100 mL pasteurised breast milk of infant formula. The food volume should be in the range of 150-180 mL/kg/day. Each feeding during the 4 week treatment period should contain study drug.

    Arm title
    Placebo EES
    Arm description
    At the 12 months corrected age visit the parents/primary caregivers were to be asked to consent to an extended follow-up to 24 months corrected age. The extended follow-up included telephone visits at 15, 18 and 21 months corrected age and a visit at 24 months corrected age. The extension efficacy set (EES) was the primary analysis set and consisted of all patients who signed an ICF to have data collected in the extension portion of the study, and had at least one efficacy assessment at the 24-months CA visit. Of the 186 patients treated with placebo who performed the 12-months CA visit, 133 consented to continue with the extended follow-up and 37 of these completed the 24-months CA visit. One patient reached the 24 months CA but did not perform the visit. The remaining 95 were withdrawn from the study; 1 was lost to follow-up, 1 withdrew consent and 93 upon request from the sponsor
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Enteral use , Oral use
    Dosage and administration details
    Placebo will be reconstituted in 1mL of sterile water before addition to 100 mL pasteurised breast milk of infant formula. The food volume should be in the range of 150-180 mL/kg/day. Each feeding during the 4 week treatment period should contain study drug.

    Number of subjects in period 2 [2]
    rhBSSL EES Placebo EES
    Started
    35
    37
    Completed
    35
    37
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 365 pts performing the 12-months CA visit, 266 consented to an extended fu to 24 months CA, one pt reached the 24 months CA but did not perform the visit, 72 completed the 24-months CA visit and 193 were withdrawn (1 lost to follow-up, 1 consent withdrawn, 101 sponsor request). The extension efficacy set (EES) was the primary analysis set for efficacy and consisted of all pts who consented to the extended fu and had at least one efficacy assessment at the 24-months CA visit (72 pts)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rhBSSL Full Analysis Set
    Reporting group description
    Patients received rhBSSL Day 1 (Baseline) as soon as possible after randomization (either on the day of randomization or the day after). The administration of rhBSSL continued for 4 weeks. Follow-up visits occurred at 3 months after the first dose of study drug and at 12 months corrected age. The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data.

    Reporting group title
    Placebo Full Analysis Set
    Reporting group description
    Patients received placebo Day 1 (Baseline) as soon as possible after randomization (either on the day of randomization or the day after). The administration of placebo continued for 4 weeks. Follow-up visits occurred at 3 months after the first dose of study drug and at 12 months corrected age. The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data.

    Reporting group values
    rhBSSL Full Analysis Set Placebo Full Analysis Set Total
    Number of subjects
    206 204 410
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    206 204 410
        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)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Age at time of randomization
    Units: weeks
        arithmetic mean (standard deviation)
    3.18 ( 1.528 ) 3.23 ( 1.457 ) -
    Gender categorical
    Units: Subjects
        Female
    104 117 221
        Male
    102 87 189
    Feeding regimen
    Number of patients receiving their study medication together with PBM and formula respectively
    Units: Subjects
        Pasteurized breast milk
    79 76 155
        Formula
    127 128 255
    Size for gestational age
    An infant who had a birth weight that was above the 10th percentile for the gestational age on the gender-specific intrauterine growth curves was defined as AGA. An infant with a birth weight at or below the 10th percentile was defined as SGA (Olsen, Groveman et al. 2010).
    Units: Subjects
        Small for gestational age (SGA)
    32 30 62
        Appropriate for gestational age (AGA)
    174 174 348
    Gestational Age at Time of Birth
    Units: Weeks
        arithmetic mean (standard deviation)
    28.75 ( 1.666 ) 28.83 ( 1.729 ) -
    Baseline Body Weight
    Units: gram(s)
        arithmetic mean (standard deviation)
    1384.9 ( 265.19 ) 1387.6 ( 263 ) -
    Baseline Body Length
    Units: cm
        arithmetic mean (standard deviation)
    39.76 ( 2.727 ) 39.49 ( 2.374 ) -
    Head Circumference at Baseline
    Units: cm
        arithmetic mean (standard deviation)
    27.85 ( 1.61 ) 27.78 ( 1.663 ) -
    Subject analysis sets

    Subject analysis set title
    rhBSSL Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Subject analysis set title
    Placebo Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Subject analysis set title
    rhBSSL Full Analysis Set, PBM Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 79 patients treated with rhBSSL and included in the FAS received PBM (Pasteurized breast milk)

    Subject analysis set title
    Placebo Full Analysis Set, AGA strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 174 patients treated with placebo and included in the FAS were classified as appropriate for gestational age (AGA)

    Subject analysis set title
    rhBSSL Full Analysis Set, Formula Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 127 patients treated with rhBSSL and included in the FAS received Infant Formula

    Subject analysis set title
    Placebo Full Analysis Set, PBM strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 76 patients treated with placebo and included in the FAS received PBM (Pasteurized breast milk)

    Subject analysis set title
    Placebo Full Analysis Set, Formula strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 128 patients treated with placebo and included in the FAS received Infant Formula

    Subject analysis set title
    rhBSSL Full Analysis Set, SGA Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 32 patients treated with rhBSSL and included in the FAS were classified as small for gestational age (SGA)

    Subject analysis set title
    rhBSSL Full Analysis Set, AGA Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 174 patients treated with rhBSSL and included in the FAS were classified as appropriate for gestational age (AGA)

    Subject analysis set title
    Placebo Full Analysis Set, SGA strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 30 patients treated with placebo and included in the FAS were classified as small for gestational age (SGA)

    Subject analysis set title
    rhBSSL Extension safety set: 12 to 24 months CA
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The extension safety set (ESAF) consisted of all patients who signed an ICF to have data collected in the extension portion of the study and who were included in the safety set in the main study. Patients in the placebo group that incorrectly received two or more kits with rhBSSL were included in the rhBSSL group.

    Subject analysis set title
    Placebo Extension safety set: 12 to 24 months CA
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The extension safety set (ESAF) consisted of all patients who signed an ICF to have data collected in the extension portion of the study and who were included in the safety set in the main study. Patients in the rhBSSL group that incorrectly received no kit with rhBSSL were included in the placebo group.

    Subject analysis sets values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set rhBSSL Full Analysis Set, PBM Strata Placebo Full Analysis Set, AGA strata rhBSSL Full Analysis Set, Formula Strata Placebo Full Analysis Set, PBM strata Placebo Full Analysis Set, Formula strata rhBSSL Full Analysis Set, SGA Strata rhBSSL Full Analysis Set, AGA Strata Placebo Full Analysis Set, SGA strata rhBSSL Extension safety set: 12 to 24 months CA Placebo Extension safety set: 12 to 24 months CA
    Number of subjects
    212
    200
    79
    174
    127
    76
    128
    32
    174
    30
    135
    131
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    212
    200
    79
    174
    127
    76
    128
    32
    174
    30
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Age at time of randomization
    Units: weeks
        arithmetic mean (standard deviation)
    3.21 ( 1.552 )
    3.18 ( 1.429 )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    107
    115
        Male
    105
    85
    Feeding regimen
    Number of patients receiving their study medication together with PBM and formula respectively
    Units: Subjects
        Pasteurized breast milk
    80
    77
        Formula
    132
    123
    Size for gestational age
    An infant who had a birth weight that was above the 10th percentile for the gestational age on the gender-specific intrauterine growth curves was defined as AGA. An infant with a birth weight at or below the 10th percentile was defined as SGA (Olsen, Groveman et al. 2010).
    Units: Subjects
        Small for gestational age (SGA)
    34
    30
        Appropriate for gestational age (AGA)
    178
    170
    Gestational Age at Time of Birth
    Units: Weeks
        arithmetic mean (standard deviation)
    28.74 ( 1.675 )
    28.86 ( 1.731 )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Baseline Body Weight
    Units: gram(s)
        arithmetic mean (standard deviation)
    1386.8 ( 268.9 )
    1383.1 ( 258.85 )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Baseline Body Length
    Units: cm
        arithmetic mean (standard deviation)
    39.75 ( 2.718 )
    39.48 ( 2.364 )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Head Circumference at Baseline
    Units: cm
        arithmetic mean (standard deviation)
    27.86 ( 1.605 )
    27.77 ( 1.664 )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    rhBSSL Full Analysis Set
    Reporting group description
    Patients received rhBSSL Day 1 (Baseline) as soon as possible after randomization (either on the day of randomization or the day after). The administration of rhBSSL continued for 4 weeks. Follow-up visits occurred at 3 months after the first dose of study drug and at 12 months corrected age. The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data.

    Reporting group title
    Placebo Full Analysis Set
    Reporting group description
    Patients received placebo Day 1 (Baseline) as soon as possible after randomization (either on the day of randomization or the day after). The administration of placebo continued for 4 weeks. Follow-up visits occurred at 3 months after the first dose of study drug and at 12 months corrected age. The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data.
    Reporting group title
    rhBSSL EES
    Reporting group description
    At the 12 months corrected age visit the parents/primary caregivers were to be asked to consent to an extended follow-up to 24 months corrected age. The extended follow-up included telephone visits at 15, 18 and 21 months corrected age and a visit at 24 months corrected age. The extension efficacy set (EES) was the primary analysis set and consisted of all patients who signed an ICF to have data collected in the extension portion of the study, and had at least one efficacy assessment at the 24-months CA visit. Of the 179 patients treated with rhBSSL who performed the 12-months CA visit, 133 consented to continue with the extended follow-up and 35 of these completed the 24-months CA visit. The remaining 98 were withdrawn from the study upon request from the sponsor

    Reporting group title
    Placebo EES
    Reporting group description
    At the 12 months corrected age visit the parents/primary caregivers were to be asked to consent to an extended follow-up to 24 months corrected age. The extended follow-up included telephone visits at 15, 18 and 21 months corrected age and a visit at 24 months corrected age. The extension efficacy set (EES) was the primary analysis set and consisted of all patients who signed an ICF to have data collected in the extension portion of the study, and had at least one efficacy assessment at the 24-months CA visit. Of the 186 patients treated with placebo who performed the 12-months CA visit, 133 consented to continue with the extended follow-up and 37 of these completed the 24-months CA visit. One patient reached the 24 months CA but did not perform the visit. The remaining 95 were withdrawn from the study; 1 was lost to follow-up, 1 withdrew consent and 93 upon request from the sponsor

    Subject analysis set title
    rhBSSL Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Subject analysis set title
    Placebo Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Subject analysis set title
    rhBSSL Full Analysis Set, PBM Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 79 patients treated with rhBSSL and included in the FAS received PBM (Pasteurized breast milk)

    Subject analysis set title
    Placebo Full Analysis Set, AGA strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 174 patients treated with placebo and included in the FAS were classified as appropriate for gestational age (AGA)

    Subject analysis set title
    rhBSSL Full Analysis Set, Formula Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 127 patients treated with rhBSSL and included in the FAS received Infant Formula

    Subject analysis set title
    Placebo Full Analysis Set, PBM strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 76 patients treated with placebo and included in the FAS received PBM (Pasteurized breast milk)

    Subject analysis set title
    Placebo Full Analysis Set, Formula strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 128 patients treated with placebo and included in the FAS received Infant Formula

    Subject analysis set title
    rhBSSL Full Analysis Set, SGA Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 32 patients treated with rhBSSL and included in the FAS were classified as small for gestational age (SGA)

    Subject analysis set title
    rhBSSL Full Analysis Set, AGA Strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. All 207 patients randomized to the rhBSSL group started treatment but one patient was excluded from the FAS due to lack of body weight data. 174 patients treated with rhBSSL and included in the FAS were classified as appropriate for gestational age (AGA)

    Subject analysis set title
    Placebo Full Analysis Set, SGA strata
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all patients randomly assigned to treatment who had at least one dose of study medication, an assessment of body weight at baseline, and at least one body weight assessment post baseline. The patients were grouped according to randomized treatment. Of the 208 patients that was randomized to the placebo group, 3 did not start treatment and one patient was excluded from the FAS due to lack of body weight data. 30 patients treated with placebo and included in the FAS were classified as small for gestational age (SGA)

    Subject analysis set title
    rhBSSL Extension safety set: 12 to 24 months CA
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The extension safety set (ESAF) consisted of all patients who signed an ICF to have data collected in the extension portion of the study and who were included in the safety set in the main study. Patients in the placebo group that incorrectly received two or more kits with rhBSSL were included in the rhBSSL group.

    Subject analysis set title
    Placebo Extension safety set: 12 to 24 months CA
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The extension safety set (ESAF) consisted of all patients who signed an ICF to have data collected in the extension portion of the study and who were included in the safety set in the main study. Patients in the rhBSSL group that incorrectly received no kit with rhBSSL were included in the placebo group.

    Primary: Growth Velocity during 4 weeks of treatment

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    End point title
    Growth Velocity during 4 weeks of treatment
    End point description
    The primary efficacy variable is growth velocity in grams per kilogram per day during 4 weeks of treatment. The primary efficacy measurement (growth velocity) was made by frequent (at least 3 times per week) measurements of the infant’s weight during treatment. If a patient withdrew before Day 29 then growth velocity was derived using weight assessments up to their last available assessment. In order to calculate growth velocity, the natural log-transformed value of the baseline and all post baseline weight assessments for each patient was calculated. A linear regression model was then fitted for each patient with a response variable of log(weight) and a predictor variable of time. Growth velocity for each patient was estimated as the slope arising from the regression model, and needed to be multiplied by 1000 for conversion into the desired unit.
    End point type
    Primary
    End point timeframe
    Baseline to Week 4
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set rhBSSL Full Analysis Set, PBM Strata Placebo Full Analysis Set, AGA strata rhBSSL Full Analysis Set, Formula Strata Placebo Full Analysis Set, PBM strata Placebo Full Analysis Set, Formula strata rhBSSL Full Analysis Set, SGA Strata rhBSSL Full Analysis Set, AGA Strata Placebo Full Analysis Set, SGA strata
    Number of subjects analysed
    206
    204
    206
    204
    206
    204
    204
    206
    206
    204
    Units: g/kg/day
        arithmetic mean (standard deviation)
    17.394 ( 3.53 )
    17.201 ( 3.3579 )
    16.333 ( 3.0247 )
    17.302 ( 3.3092 )
    18.054 ( 3.6694 )
    15.875 ( 2.7538 )
    17.989 ( 3.4448 )
    18.547 ( 3.7442 )
    17.182 ( 3.4588 )
    16.615 ( 3.6314 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.493
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.214
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.828
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA) and the interaction between treatment and feeding regimen, with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    Placebo Full Analysis Set, PBM strata v rhBSSL Full Analysis Set, PBM Strata
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.371
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.629
         upper limit
    1.37
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA) and the interaction between treatment and feeding regimen, with baseline weight included as a covariate PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set, Formula Strata v Placebo Full Analysis Set, Formula strata
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.119
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.66
         upper limit
    0.898
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA) and the interaction between treatment and size for gestational age, with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set, SGA Strata v Placebo Full Analysis Set, SGA strata
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.951
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.381
         upper limit
    3.521
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA) and the interaction between treatment and size for gestational age, with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set, AGA Strata v Placebo Full Analysis Set, AGA strata
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.095
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.757
         upper limit
    0.567

    Secondary: Body Weight: Change from Baseline at 4 Weeks

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    End point title
    Body Weight: Change from Baseline at 4 Weeks
    End point description
    Change from baseline = post baseline value — baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4. Baseline is defined as last non-missing measurement prior to dosing.
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    204
    204
    Units: gram(s)
        arithmetic mean (standard deviation)
    860.5 ( 226.35 )
    845.4 ( 223.24 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.304
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    18.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.9
         upper limit
    54

    Secondary: Body Weight: Change from Baseline at 3 Months

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    End point title
    Body Weight: Change from Baseline at 3 Months
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Month 3. Baseline is defined as last non-missing measurement prior to dosing.
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    185
    182
    Units: gram(s)
        arithmetic mean (standard deviation)
    2813.5 ( 567.2 )
    2823.8 ( 540.34 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    Placebo Full Analysis Set v rhBSSL Full Analysis Set
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -101.9
         upper limit
    106.6

    Secondary: Body Weight at 12 Months Corrected Age

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    End point title
    Body Weight at 12 Months Corrected Age
    End point description
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age visit
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    169
    169
    Units: gram(s)
        arithmetic mean (standard deviation)
    9077.1 ( 1334.25 )
    8845.9 ( 1239.8 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    197.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -53.3
         upper limit
    448.1

    Secondary: Head Circumference: Change from Baseline at 4 Weeks

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    End point title
    Head Circumference: Change from Baseline at 4 Weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4. Baseline is defined as last non-missing measurement prior to dosing.
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    202
    202
    Units: cm
        arithmetic mean (standard deviation)
    4.09 ( 1.038 )
    4.07 ( 1.075 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Change from baseline = post baseline value — baseline value. Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.655
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.24

    Secondary: Head Circumference: Change from Baseline at 3 Months

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    End point title
    Head Circumference: Change from Baseline at 3 Months
    End point description
    Change from baseline = post baseline value — baseline value
    End point type
    Secondary
    End point timeframe
    Baseline and Month 3. Baseline is defined as last non-missing measurement prior to dosing.
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    183
    180
    Units: cm
        arithmetic mean (standard deviation)
    9.57 ( 1.499 )
    9.54 ( 1.266 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline head circumference included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.21
         upper limit
    0.3

    Secondary: Head Circumference at 12 Months Corrected Age

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    End point title
    Head Circumference at 12 Months Corrected Age
    End point description
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    168
    167
    Units: cm
        arithmetic mean (standard deviation)
    45.63 ( 1.811 )
    45.37 ( 1.724 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.51

    Secondary: Body Length: Change from Baseline at 4 Weeks

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    End point title
    Body Length: Change from Baseline at 4 Weeks
    End point description
    Change from baseline = post baseline value — baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4. Baseline is defined as last non-missing measurement prior to dosing.
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    201
    203
    Units: cm
        arithmetic mean (standard deviation)
    4.44 ( 1.494 )
    4.5 ( 1.442 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline body length included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.982
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.28
         upper limit
    0.27

    Secondary: Body Length: Change from Baseline at 3 Months

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    End point title
    Body Length: Change from Baseline at 3 Months
    End point description
    Change from baseline = post baseline value — baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 3. Baseline is defined as last non-missing measurement prior to dosing.
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    182
    181
    Units: cm
        arithmetic mean (standard deviation)
    13.29 ( 2.406 )
    13.37 ( 2.112 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline body length included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.47
         upper limit
    0.43

    Secondary: Body Length at 12 Months Corrected Age

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    End point title
    Body Length at 12 Months Corrected Age
    End point description
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    169
    169
    Units: cm
        arithmetic mean (standard deviation)
    74.31 ( 4.128 )
    73.49 ( 3.724 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    Placebo Full Analysis Set v rhBSSL Full Analysis Set
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    1.43

    Secondary: Time from First Dose to 150 mL/kg/day of Enteral Feeding Volume

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    End point title
    Time from First Dose to 150 mL/kg/day of Enteral Feeding Volume
    End point description
    Time to 150 mL/kg/day of Enteral Feeding (days) = Date 150 mL/kg/day enteral feeding reached or exceeded — Date of first dose The summary statistics presented are based on a time to event analysis. Patients who do not reach 150 mL/kg/day of enteral feeding are censored at their last day of feeding.
    End point type
    Secondary
    End point timeframe
    Time from First Dose to 150 mL/kg/day of Enteral Feeding Volume
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    206
    204
    Units: day
        median (inter-quartile range (Q1-Q3))
    2 (1 to 7)
    1 (1 to 5)
    No statistical analyses for this end point

    Secondary: Growth Restriction

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    End point title
    Growth Restriction
    End point description
    Growth restriction is defined as a growth velocity of less than 15 g per kilogram bodyweight per day during the 4-week treatment period
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    206
    204
    Units: Patients with growth restriction
    50
    58
    Statistical analysis title
    Logistic regression model
    Statistical analysis description
    Adjusted percentage of patients with growth restriction, odds ratio and p-value obtained from a logistic regression model with treatment, feeding regimen (PBM or infant formula), and size for gestational age category (SGA/AGA) as explanatory variables. Odds ratio is defined as rhBSSL / Placebo. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.312
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.24

    Secondary: Time to Discharge

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    End point title
    Time to Discharge
    End point description
    Time to Discharge (days) = [Date of discharge — Date of first dose]
    End point type
    Secondary
    End point timeframe
    Time to Discharge
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    204
    204
    Units: day
        arithmetic mean (standard deviation)
    41.3 ( 12.82 )
    41.3 ( 19 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula) and size for gestational age category (SGA or AGA). PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.933
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    2.9

    Secondary: Time to Readiness for Discharge

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    End point title
    Time to Readiness for Discharge
    End point description
    Time to Readiness for Discharge (days) = [Date of Readiness for Discharge — Date of First Dose]. In order to have achieved readiness for discharge, a date must be recorded for 'Ability to suckle feed','Ability to self-regulate body temperature', and 'Ability to self-regulate cardiorespiratory function' in the eCRF (missing dates will be replaced by date of discharge), while date of 'Sustained weight gain' is derived. A sustained pattern of weight gain is defined as the first day after the start of treatment when the patient has sustained a weight of 1.8 kg for three days.
    End point type
    Secondary
    End point timeframe
    Time to Readiness for Discharge
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    204
    204
    Units: day
        arithmetic mean (standard deviation)
    31.5 ( 15.29 )
    30.6 ( 18.39 )
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula) and size for gestational age category (SGA or AGA). PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.688
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    3.8

    Secondary: Re-admission to Hospital Within 1 Month of Discharge

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    End point title
    Re-admission to Hospital Within 1 Month of Discharge
    End point description
    Number of patients with re-admission to hospital within 1 month of discharge
    End point type
    Secondary
    End point timeframe
    Discharge unyil 1 month of discharge.
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    206
    204
    Units: Patients
    22
    19
    Statistical analysis title
    Logistic regression
    Statistical analysis description
    Adjusted percentage of patients with re-admission to hospital within 1 month of discharge, odds ratio and p-value obtained from a logistic regression model with treatment, feeding regimen (PBM or infant formula), and size for gestational age category (SGA/AGA) as explanatory variables. Odds ratio is defined as rhBSSL / Placebo.
    Comparison groups
    Placebo Full Analysis Set v rhBSSL Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.659
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    2.21

    Secondary: Feeding Utilization

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    End point title
    Feeding Utilization
    End point description
    Feeding utilization variable (α) which is defined by the differential equation (dm/dt)=αV(t), t>=1 where • α is the efficiency in feeding utilization (g/L) • V(t) is the volume (ml/kg) at time t • m is the weight (g) and • t is the time (day) For each patient all daily feeding volumes between Day 1 and Week 4 and the corresponding body weight values on these days (where missing body weight values will be imputed) will be used to derive nonlinear ordinary least square (OLS) parameter estimates for α, separately for each patient. α will be constrained to be ≥ 0, and the initial value will be set to 0.5. The equation for weight will be fitted by a static model. The model is an appropriate simplification of the mathematical model of weight change with adaption in [Thomas, 2009]. The computed α is an estimate of the metabolic efficiency.
    End point type
    Secondary
    End point timeframe
    Day 1 and Week 4
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    206
    204
    Units: g/L
        arithmetic mean (standard deviation)
    113.94 ( 23.625 )
    109.72 ( 23.286 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Analysis uses analysis of covariance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA), with baseline weight included as a covariate. If a patient withdraws before Day 29 then feeding utilization was derived using weight values and feeding volumes up to their last available assessment. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.044
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    4.347
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.12
         upper limit
    8.574

    Secondary: DHA Concentration in S-TG at 4 weeks

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    End point title
    DHA Concentration in S-TG at 4 weeks
    End point description
    DHA = Docosahexaenoic acid S-TG = Serum triglycerine fraction
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    135
    124
    Units: µg/mL
        arithmetic mean (standard deviation)
    6.41 ( 3.292 )
    6.51 ( 3.738 )
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula) and size for gestational age category (SGA or AGA)
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.952
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    0.83

    Secondary: DHA Concentration in S-PC at 4 weeks

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    End point title
    DHA Concentration in S-PC at 4 weeks
    End point description
    DHA = Docosahexaenoic acid S-PC = Serum phosphatidylcholine fraction
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    143
    133
    Units: µg/mL
        arithmetic mean (standard deviation)
    34.95 ( 10.149 )
    35.15 ( 9.789 )
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula) and size for gestational age category (SGA or AGA).
    Comparison groups
    Placebo Full Analysis Set v rhBSSL Full Analysis Set
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.921
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.48
         upper limit
    2.24

    Secondary: AA Concentration in S-TG at 4 weeks

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    End point title
    AA Concentration in S-TG at 4 weeks
    End point description
    AA = Arachidonic acid. S-TG = Serum triglycerine fraction
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    135
    124
    Units: µg/mL
        arithmetic mean (standard deviation)
    10.41 ( 4.628 )
    10.45 ( 5.665 )
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula) and size for gestational age category (SGA or AGA).
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.34
         upper limit
    1.18

    Secondary: AA Concentration in S-PC in 4 weeks

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    End point title
    AA Concentration in S-PC in 4 weeks
    End point description
    AA = Arachidonic acid S-PC = Serum phosphatidylcholine fraction
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    143
    133
    Units: µg/mL
        arithmetic mean (standard deviation)
    110.68 ( 30.219 )
    108.15 ( 25.678 )
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula) and size for gestational age category (SGA or AGA).
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.519
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.41
         upper limit
    8.72

    Secondary: Bayley III Cognitive Domain at 12 Months Corrected Age: Scaled Scores

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    End point title
    Bayley III Cognitive Domain at 12 Months Corrected Age: Scaled Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Scaled scores represent a child’s performance on a subtest relative to his or her same-age peers. They are derived from the total raw scores (which is the sum of the number of points earned for a subtest) on each of the subtests and are scaled to a metric with a range of 1 to 19, a mean of 10, and a standard deviation of 3.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    181
    179
    Units: Scaled score
        arithmetic mean (standard deviation)
    9.5 ( 2.52 )
    9.3 ( 2.47 )
    No statistical analyses for this end point

    Secondary: Bayley III Cognitive Domain at 12 Months Corrected Age: Composite Scores

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    End point title
    Bayley III Cognitive Domain at 12 Months Corrected Age: Composite Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Composite scores are based on various sums of subtest scaled scores for the Language, Motor , and Adaptive Behaviors composites, and composite equivalents for the scaled scores from the Cognitive and Social-Emotional Scales. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    181
    179
    Units: Composite Scores
        arithmetic mean (standard deviation)
    97.6 ( 12.61 )
    96.6 ( 12.37 )
    No statistical analyses for this end point

    Secondary: Bayley III Language Domain at 12 Months Corrected Age: Receptive Communication: Scaled Scores

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    End point title
    Bayley III Language Domain at 12 Months Corrected Age: Receptive Communication: Scaled Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Scaled scores represent a child’s performance on a subtest relative to his or her same-age peers. They are derived from the total raw scores (which is the sum of the number of points earned for a subtest) on each of the subtests and are scaled to a metric with a range of 1 to 19, a mean of 10, and a standard deviation of 3.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    181
    179
    Units: Scaled Score
        arithmetic mean (standard deviation)
    8.9 ( 3.12 )
    8.7 ( 3.03 )
    No statistical analyses for this end point

    Secondary: Bayley III Language Domain at 12 Months Corrected Age: Expressive Communication: Scaled Scores

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    End point title
    Bayley III Language Domain at 12 Months Corrected Age: Expressive Communication: Scaled Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Scaled scores represent a child’s performance on a subtest relative to his or her same-age peers. They are derived from the total raw scores (which is the sum of the number of points earned for a subtest) on each of the subtests and are scaled to a metric with a range of 1 to 19, a mean of 10, and a standard deviation of 3.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    181
    179
    Units: Scaled Score
        arithmetic mean (standard deviation)
    9.1 ( 2.57 )
    8.9 ( 2.61 )
    No statistical analyses for this end point

    Secondary: Bayley III Language Domain at 12 Months Corrected Age: Composite Scores

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    End point title
    Bayley III Language Domain at 12 Months Corrected Age: Composite Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Composite scores are based on various sums of subtest scaled scores for the Language, Motor , and Adaptive Behaviors composites, and composite equivalents for the scaled scores from the Cognitive and Social-Emotional Scales. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    181
    179
    Units: Composite Score
        arithmetic mean (standard deviation)
    94.5 ( 14.3 )
    93 ( 14.2 )
    No statistical analyses for this end point

    Secondary: Bayley III Motor Domain at 12 Months Corrected Age: Fine Motor: Scaled Scores

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    End point title
    Bayley III Motor Domain at 12 Months Corrected Age: Fine Motor: Scaled Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Scaled scores represent a child’s performance on a subtest relative to his or her same-age peers. They are derived from the total raw scores (which is the sum of the number of points earned for a subtest) on each of the subtests and are scaled to a metric with a range of 1 to 19, a mean of 10, and a standard deviation of 3.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    181
    179
    Units: Scaled score
        arithmetic mean (standard deviation)
    9.2 ( 2.2 )
    9.7 ( 2.34 )
    No statistical analyses for this end point

    Secondary: Bayley III Motor Domain at 12 Months Corrected Age: Gross Motor: Scaled Scores

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    End point title
    Bayley III Motor Domain at 12 Months Corrected Age: Gross Motor: Scaled Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Scaled scores represent a child’s performance on a subtest relative to his or her same-age peers. They are derived from the total raw scores (which is the sum of the number of points earned for a subtest) on each of the subtests and are scaled to a metric with a range of 1 to 19, a mean of 10, and a standard deviation of 3.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    181
    179
    Units: Scaled Score
        arithmetic mean (standard deviation)
    7.7 ( 2.98 )
    8.2 ( 2.85 )
    No statistical analyses for this end point

    Secondary: Bayley III Motor Domain at 12 Months Corrected Age: Composite Scores

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    End point title
    Bayley III Motor Domain at 12 Months Corrected Age: Composite Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Composite scores are based on various sums of subtest scaled scores for the Language, Motor , and Adaptive Behaviors composites, and composite equivalents for the scaled scores from the Cognitive and Social-Emotional Scales. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15.
    End point type
    Secondary
    End point timeframe
    12 Months Corrected Age Visit
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    181
    179
    Units: Composite Score
        arithmetic mean (standard deviation)
    90.7 ( 12.54 )
    93.7 ( 12.74 )
    No statistical analyses for this end point

    Secondary: Mean number of vomiting episodes/day

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    End point title
    Mean number of vomiting episodes/day
    End point description
    Mean number of vomiting episodes per day = total number of vomiting episodes / number of days on treatment. Number of days on treatment = (End of treatment date — treatment start date) + 1. Patients experiencing no vomiting episodes were included in the summary statistics using zero as the mean number of episodes/day.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    212
    200
    Units: Number of vomiting episodes/day
        arithmetic mean (standard deviation)
    0.069 ( 0.1942 )
    0.061 ( 0.1449 )
    No statistical analyses for this end point

    Secondary: Systolic Blood Pressure at Baseline

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    End point title
    Systolic Blood Pressure at Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline. Baseline is defined as last non-missing measurement prior to dosing
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    211
    197
    Units: mmHg
        arithmetic mean (standard deviation)
    69.6 ( 10.64 )
    69.9 ( 10.24 )
    No statistical analyses for this end point

    Secondary: Systolic Blood Pressure at 4 weeks

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    End point title
    Systolic Blood Pressure at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    207
    191
    Units: mmHg
        arithmetic mean (standard deviation)
    74.1 ( 11.32 )
    71.6 ( 11.2 )
    No statistical analyses for this end point

    Secondary: Systolic Blood Pressure: Change from Baseline at 4 Weeks

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    End point title
    Systolic Blood Pressure: Change from Baseline at 4 Weeks
    End point description
    Change from baseline = post baseline value — baseline value
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4. Baseline is defined as last non-missing measurement prior to dosing
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    207
    191
    Units: mmHg
        arithmetic mean (standard deviation)
    4.5 ( 13.88 )
    1.8 ( 13.29 )
    No statistical analyses for this end point

    Secondary: Diastolic Blood Pressure at Baseline

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    End point title
    Diastolic Blood Pressure at Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline. Baseline is defined as last non-missing measurement prior to dosing
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    210
    197
    Units: mmHg
        arithmetic mean (standard deviation)
    39.3 ( 9.12 )
    39.3 ( 8.62 )
    No statistical analyses for this end point

    Secondary: Diastolic Blood Pressure at 4 weeks

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    End point title
    Diastolic Blood Pressure at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    206
    191
    Units: mmHg
        arithmetic mean (standard deviation)
    41.2 ( 9.29 )
    40.4 ( 9.75 )
    No statistical analyses for this end point

    Secondary: Diastolic Blood Pressure: Change from Baseline at 4 Weeks

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    End point title
    Diastolic Blood Pressure: Change from Baseline at 4 Weeks
    End point description
    Change from baseline = post baseline value — baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4. Baseline is defined as last non-missing measurement prior to dosing
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    206
    191
    Units: mmHg
        arithmetic mean (standard deviation)
    2 ( 12.38 )
    1.1 ( 12.02 )
    No statistical analyses for this end point

    Secondary: Heart Rate at Baseline

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    End point title
    Heart Rate at Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline. Baseline is defined as last non-missing measurement prior to dosing
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    212
    200
    Units: bpm
        arithmetic mean (standard deviation)
    153.3 ( 12.75 )
    154.4 ( 12.82 )
    No statistical analyses for this end point

    Secondary: Heart Rate at 4 weeks

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    End point title
    Heart Rate at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    209
    197
    Units: bpm
        arithmetic mean (standard deviation)
    151.5 ( 15.2 )
    151.4 ( 13.65 )
    No statistical analyses for this end point

    Secondary: Heart Rate: Change from Baseline at 4 Weeks

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    End point title
    Heart Rate: Change from Baseline at 4 Weeks
    End point description
    Change from baseline = post baseline value — baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4. Baseline is defined as last non-missing measurement prior to dosing.
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    209
    197
    Units: bpm
        arithmetic mean (standard deviation)
    -1.9 ( 17.64 )
    -3 ( 16.13 )
    No statistical analyses for this end point

    Secondary: Vitamin A Concentration at 4 weeks

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    End point title
    Vitamin A Concentration at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    206
    194
    Units: nmol/L
        arithmetic mean (standard deviation)
    517.8 ( 253.92 )
    528.1 ( 347.33 )
    No statistical analyses for this end point

    Secondary: Vitamin D2 Concentration at 4 weeks

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    End point title
    Vitamin D2 Concentration at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    204
    194
    Units: nmol/L
        arithmetic mean (standard deviation)
    9.813 ( 12.8054 )
    10.428 ( 15.4648 )
    No statistical analyses for this end point

    Secondary: Vitamin D3 Concentration at 4 weeks

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    End point title
    Vitamin D3 Concentration at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    204
    194
    Units: nmol/L
        arithmetic mean (standard deviation)
    96.018 ( 95.4933 )
    96.212 ( 93.0384 )
    No statistical analyses for this end point

    Secondary: Sum Vitamin D2 & D3 Concentrations at week 4

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    End point title
    Sum Vitamin D2 & D3 Concentrations at week 4
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    204
    194
    Units: nmol/L
        arithmetic mean (standard deviation)
    105.831 ( 94.6279 )
    106.64 ( 91.4863 )
    No statistical analyses for this end point

    Secondary: Antibodies to rhBSSL at Baseline

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    End point title
    Antibodies to rhBSSL at Baseline
    End point description
    A positive sample is defined as a sample which when analyzed in a confirmatory batch produces a ratio (ratio of instrument response obtained in the presence of rhBSSL) which is below the confirmatory cut point of 0.598, confirming the presence relative to absence of antibodies specific to rhBSSL.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    210
    198
    Units: number of patients
        Positive
    4
    2
        Negative
    206
    196
    No statistical analyses for this end point

    Secondary: Antibodies to rhBSSL at 4 weeks

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    End point title
    Antibodies to rhBSSL at 4 weeks
    End point description
    A positive sample is defined as a sample which when analyzed in a confirmatory batch produces a ratio (ratio of instrument response obtained in the presence of rhBSSL) which is below the confirmatory cut point of 0.598, confirming the presence relative to absence of antibodies specific to rhBSSL.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    208
    194
    Units: number of patients
        Positive
    196
    193
        Negative
    12
    1
    No statistical analyses for this end point

    Secondary: Antibodies to rhBSSL at 3 months

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    End point title
    Antibodies to rhBSSL at 3 months
    End point description
    A positive sample is defined as a sample which when analyzed in a confirmatory batch produces a ratio (ratio of instrument response obtained in the presence of rhBSSL) which is below the confirmatory cut point of 0.598, confirming the presence relative to absence of antibodies specific to rhBSSL.
    End point type
    Secondary
    End point timeframe
    Month 3
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    202
    189
    Units: number of patients
        Positive
    178
    172
        Negative
    24
    17
    No statistical analyses for this end point

    Secondary: Antibodies to rhBSSL at 6 months

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    End point title
    Antibodies to rhBSSL at 6 months
    End point description
    A positive sample is defined as a sample which when analyzed in a confirmatory batch produces a ratio (ratio of instrument response obtained in the presence of rhBSSL) which is below the confirmatory cut point of 0.598, confirming the presence relative to absence of antibodies specific to rhBSSL. The 6 month sample is only displayed for those patients who have a positive result for the 3 month sample.
    End point type
    Secondary
    End point timeframe
    Month 3
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    22
    15
    Units: number of patients
        Positive
    5
    3
        Negative
    17
    12
    No statistical analyses for this end point

    Secondary: Antibodies to rhBSSL at 12 months

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    End point title
    Antibodies to rhBSSL at 12 months
    End point description
    A positive sample is defined as a sample which when analyzed in a confirmatory batch produces a ratio (ratio of instrument response obtained in the presence of rhBSSL) which is below the confirmatory cut point of 0.598, confirming the presence relative to absence of antibodies specific to rhBSSL. The 12 month sample is only displayed for those patients who have a positive result for the 6 month sample.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    16
    10
    Units: number of patients
        Positive
    6
    1
        Negative
    10
    9
    No statistical analyses for this end point

    Secondary: Levels of Amylase at 4 weeks

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    End point title
    Levels of Amylase at 4 weeks
    End point description
    Blood samples will be collected at the end of treatment for safety analyses unless at least 1 sample had been drawn following a minimum of 2 weeks treatment with study drug. Lab results are analyzed by local laboratories. Week 4 results are included in the summary statistics if the assessment is taken not more than three days after treatment stop. Where multiple samples are taken, the last sample taken during treatment will be used. For laboratory values recorded as less than the limit of quantification (LOQ), the LOQ value * 0.5 was used in the summary statistics.
    End point type
    Secondary
    End point timeframe
    Week 4.
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    176
    165
    Units: ukat/L
        arithmetic mean (standard deviation)
    0.103 ( 0.091 )
    0.096 ( 0.0577 )
    No statistical analyses for this end point

    Secondary: Levels of Alanine Aminotransferase at 4 weeks

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    End point title
    Levels of Alanine Aminotransferase at 4 weeks
    End point description
    Blood samples will be collected at the end of treatment for safety analyses unless at least 1 sample had been drawn following a minimum of 2 weeks treatment with study drug. Lab results are analyzed by local laboratories. Week 4 results are included in the summary statistics if the assessment is taken not more than three days after treatment stop. Where multiple samples are taken, the last sample taken during treatment will be used. For laboratory values recorded as less than the limit of quantification (LOQ), the LOQ value * 0.5 was used in the summary statistics.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    196
    181
    Units: ukat/L
        arithmetic mean (standard deviation)
    0.266 ( 0.2266 )
    0.23 ( 0.1521 )
    No statistical analyses for this end point

    Secondary: Levels of Aspartate Aminotransferase at 4 weeks

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    End point title
    Levels of Aspartate Aminotransferase at 4 weeks
    End point description
    Blood samples will be collected at the end of treatment for safety analyses unless at least 1 sample had been drawn following a minimum of 2 weeks treatment with study drug. Lab results are analyzed by local laboratories. Week 4 results are included in the summary statistics if the assessment is taken not more than three days after treatment stop. Where multiple samples are taken, the last sample taken during treatment will be used. For laboratory values recorded as less than the limit of quantification (LOQ), the LOQ value * 0.5 was used in the summary statistics.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    197
    178
    Units: ukat/L
        arithmetic mean (standard deviation)
    0.447 ( 0.2965 )
    0.428 ( 0.1905 )
    No statistical analyses for this end point

    Secondary: Levels of Bilirubin at week 4

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    End point title
    Levels of Bilirubin at week 4
    End point description
    Blood samples will be collected at the end of treatment for safety analyses unless at least 1 sample had been drawn following a minimum of 2 weeks treatment with study drug. Lab results are analyzed by local laboratories. Week 4 results are included in the summary statistics if the assessment is taken not more than three days after treatment stop. Where multiple samples are taken, the last sample taken during treatment will be used. For laboratory values recorded as less than the limit of quantification (LOQ), the LOQ value * 0.5 was used in the summary statistics.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    191
    178
    Units: umol/L
        arithmetic mean (standard deviation)
    35 ( 32.478 )
    36.03 ( 30.965 )
    No statistical analyses for this end point

    Secondary: Levels of Sodium at 4 weeks

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    End point title
    Levels of Sodium at 4 weeks
    End point description
    Blood samples will be collected at the end of treatment for safety analyses unless at least 1 sample had been drawn following a minimum of 2 weeks treatment with study drug. Lab results are analyzed by local laboratories. Week 4 results are included in the summary statistics if the assessment is taken not more than three days after treatment stop. Where multiple samples are taken, the last sample taken during treatment will be used. For laboratory values recorded as less than the limit of quantification (LOQ), the LOQ value * 0.5 was used in the summary statistics.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    199
    185
    Units: mmol/L
        arithmetic mean (standard deviation)
    138.2 ( 3.3 )
    138.4 ( 3.05 )
    No statistical analyses for this end point

    Secondary: Levels of Urea at 4 weeks

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    End point title
    Levels of Urea at 4 weeks
    End point description
    Blood samples will be collected at the end of treatment for safety analyses unless at least 1 sample had been drawn following a minimum of 2 weeks treatment with study drug. Lab results are analyzed by local laboratories. Week 4 results are included in the summary statistics if the assessment is taken not more than three days after treatment stop. Where multiple samples are taken, the last sample taken during treatment will be used. For laboratory values recorded as less than the limit of quantification (LOQ), the LOQ value * 0.5 was used in the summary statistics.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    rhBSSL Safety Analysis Set Placebo Safety Analysis Set
    Number of subjects analysed
    198
    181
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.04 ( 1.691 )
    3.05 ( 1.856 )
    No statistical analyses for this end point

    Secondary: Growth velocity calculated using a 2-point weight model

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    End point title
    Growth velocity calculated using a 2-point weight model
    End point description
    A sensitivity analysis will be performed for the primary endpoint. Growth velocity (g/kg/day) will be calculated using a 2-Point weight model (Patel, 2009). The net weight gain over time will be divided by the weight at Day 1. For each patient, growth velocity will be calculated using the following formula: GV= (1000 x (Wn x W1)) / (Wn (Dn - D1)) where w1=weight in grams at Day 1 and wn=weight in grams at Day n (Day n being the last available weight assessment during the treatment period, taken on or before Day 29).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    206
    204
    Units: g/kg/day
        arithmetic mean (standard deviation)
    22.353 ( 5.6001 )
    21.938 ( 5.2548 )
    Statistical analysis title
    ANCOVA
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.358
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.448
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.508
         upper limit
    1.404

    Secondary: Growth restriction, 10 percentile

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    End point title
    Growth restriction, 10 percentile
    End point description
    Growth restriction is defined as having a weight below the 10th percentile for the gestational age on the gender specific intrauterine growth curve (based on Olsen et al 2010) during the 4-week treatment period
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    rhBSSL Full Analysis Set Placebo Full Analysis Set
    Number of subjects analysed
    206
    204
    Units: Patients with growth restriction
    68
    74
    Statistical analysis title
    Logistic regression model
    Statistical analysis description
    Adjusted percentage of patients below the 10th percentile, odds ratio and p-value obtained from a logistic regression model with treatment, feeding regimen (PBM or infant formula), and size for gestational age category (SGA/AGA) as explanatory variables. Odds ratio is defined as rhBSSL / Placebo. PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age.
    Comparison groups
    rhBSSL Full Analysis Set v Placebo Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.34
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.29

    Secondary: Bayley III Cognitive Domain at 24 Months Corrected Age: Composite Scores

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    End point title
    Bayley III Cognitive Domain at 24 Months Corrected Age: Composite Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Composite scores are based on various sums of subtest scaled scores for the Language, Motor , and Adaptive Behaviors composites, and composite equivalents for the scaled scores from the Cognitive and Social-Emotional Scales. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15.
    End point type
    Secondary
    End point timeframe
    24 Months Corrected Age Visit
    End point values
    rhBSSL EES Placebo EES
    Number of subjects analysed
    33 [1]
    34 [2]
    Units: Composite Score
        arithmetic mean (standard deviation)
    90.8 ( 14.64 )
    91.5 ( 14.64 )
    Notes
    [1] - Two patients with missing composite score
    [2] - One patient with invalid composite score and two patients with missing composite score
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA). PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age. Invalid composite scores were not included
    Comparison groups
    rhBSSL EES v Placebo EES
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.849
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.91
         upper limit
    6.53

    Secondary: Bayley III Language Domain at 24 Months Corrected Age: Composite Scores

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    End point title
    Bayley III Language Domain at 24 Months Corrected Age: Composite Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Composite scores are based on various sums of subtest scaled scores for the Language, Motor , and Adaptive Behaviors composites, and composite equivalents for the scaled scores from the Cognitive and Social-Emotional Scales. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15.
    End point type
    Secondary
    End point timeframe
    24 Months Corrected Age Visit
    End point values
    rhBSSL EES Placebo EES
    Number of subjects analysed
    33 [3]
    34 [4]
    Units: Composite Scores
        arithmetic mean (standard deviation)
    90.5 ( 17.38 )
    89 ( 14.45 )
    Notes
    [3] - Two patients with missing composite score
    [4] - Three patients with missing composite score
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA). PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age. Invalid composite scores were not included
    Comparison groups
    rhBSSL EES v Placebo EES
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.742
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.57
         upper limit
    9.17

    Secondary: Bayley III Motor Domain at 24 Months Corrected Age: Composite Scores

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    End point title
    Bayley III Motor Domain at 24 Months Corrected Age: Composite Scores
    End point description
    The Bayley-III is an individually administered instrument that assesses the developmental functioning of infants and young children between 1 month and 42 months of age, across five domains: cognitive, motor (including the fine and gross motor subtests), language (including the receptive and expressive communication subtest), social-emotional, and adaptive behavior. Assessments of the cognitive, motor and language domains are conducted using items administered to the child; assessment of the social-emotional and adaptive behavior domains are conducted using parent/primary caregiver response to a questionnaire. Composite scores are based on various sums of subtest scaled scores for the Language, Motor , and Adaptive Behaviors composites, and composite equivalents for the scaled scores from the Cognitive and Social-Emotional Scales. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15.
    End point type
    Secondary
    End point timeframe
    24 Months Corrected Age Visit
    End point values
    rhBSSL EES Placebo EES
    Number of subjects analysed
    33 [5]
    35 [6]
    Units: Composite Scores
        arithmetic mean (standard deviation)
    95.5 ( 10.73 )
    96.3 ( 13.38 )
    Notes
    [5] - Two patients with missing composite score
    [6] - Two patients with missing composite score
    Statistical analysis title
    ANOVA
    Statistical analysis description
    Analysis uses analysis of variance model including factors for treatment, feeding regimen (PBM or Infant formula), size for gestational age category (SGA or AGA). PBM = Pasteurized breast milk; SGA = Small for gestational age; AGA = Appropriate for gestational age. Invalid composite scores were not included
    Comparison groups
    rhBSSL EES v Placebo EES
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.755
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.92
         upper limit
    5.04

    Secondary: Number of Patients with Neurodevelopment Disability at 24 Months Corrected Age Visit

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    End point title
    Number of Patients with Neurodevelopment Disability at 24 Months Corrected Age Visit
    End point description
    The Neurodevelopment Disability Composite is defined as presence of any of the one following: - A composite score of less than 70 on any of the cognitive, language or motor domains of Bayley III - Bilateral deafness, defined as need for bilateral amplification - Bilateral blindness, defined as corrected visual acuity of less than 20/200 (or equivalent) in the better eye - Cerebral palsy, defined as hypotonia, spastic diplegia, hemiplegia or quadriplegia causing functional deficits that require rehabilitation services
    End point type
    Secondary
    End point timeframe
    24 Months Corrected Age Visit
    End point values
    rhBSSL EES Placebo EES
    Number of subjects analysed
    35
    37
    Units: Number of Patients
    3
    3
    No statistical analyses for this end point

    Secondary: Body Weight at 24 Months Corrected Age

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    End point title
    Body Weight at 24 Months Corrected Age
    End point description
    Only includes assessments performed within 24 months corrected age +/- 28 days
    End point type
    Secondary
    End point timeframe
    24 Months Corrected Age Visit
    End point values
    rhBSSL EES Placebo EES
    Number of subjects analysed
    32
    32
    Units: gram(s)
        arithmetic mean (standard deviation)
    11.385 ( 1.4591 )
    11.078 ( 1.3523 )
    No statistical analyses for this end point

    Secondary: Body Height at 24 Months Corrected Age

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    End point title
    Body Height at 24 Months Corrected Age
    End point description
    Only includes assessments performed within 24 months corrected age +/- 28 days
    End point type
    Secondary
    End point timeframe
    24 Months Corrected Age Visit
    End point values
    rhBSSL EES Placebo EES
    Number of subjects analysed
    32
    32
    Units: cm
        arithmetic mean (standard deviation)
    86.45 ( 4.307 )
    85.65 ( 3.709 )
    No statistical analyses for this end point

    Secondary: Head Circumference at 24 Months Corrected Age

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    End point title
    Head Circumference at 24 Months Corrected Age
    End point description
    Only includes assessments performed within 24 months corrected age +/- 28 days
    End point type
    Secondary
    End point timeframe
    24 Months Corrected Age Visit
    End point values
    rhBSSL EES Placebo EES
    Number of subjects analysed
    32
    32
    Units: cm
        arithmetic mean (standard deviation)
    47.77 ( 1.735 )
    47.28 ( 1.379 )
    No statistical analyses for this end point

    Secondary: Serious Adverse Drug Reactions

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    End point title
    Serious Adverse Drug Reactions
    End point description
    Serious Adverse Drug Reactions were to be recorded from the 12 to the 24 months CA visit.
    End point type
    Secondary
    End point timeframe
    12 to 24 months Corrected Age Visits
    End point values
    rhBSSL Extension safety set: 12 to 24 months CA Placebo Extension safety set: 12 to 24 months CA
    Number of subjects analysed
    135
    131
    Units: Number of Patients
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious AEs were recorded from the start of treatment on Day 1 through the 3-month f-u visit. SAEs were recorded from informed consent to the 12 months CA visit. In addition, Serious ADRS were recorded from the 12 to the 24 months CA visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    rhBSSL Safety Analysis Set: Baseline to week 4
    Reporting group description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Reporting group title
    Placebo Safety Analysis Set: Baseline to week 4
    Reporting group description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Reporting group title
    rhBSSL Safety Analysis Set: 4 weeks to 3 months
    Reporting group description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Reporting group title
    Placebo Safety Analysis Set: 4 weeks to 3 months
    Reporting group description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Reporting group title
    rhBSSL Safety Analysis Set: 3 months to 12 months CA
    Reporting group description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Reporting group title
    Placebo Safety Analysis Set: 3 months to 12 months CA
    Reporting group description
    The SAF consisted of a total of 412 patients who received at least one dose of study drug; 212 patients were included in the rhBSSL group and 200 patients were included in the placebo group. Five patients randomized to placebo treatment were included in the rhBSSL group since they incorrectly had received ≥2 vials of rhBSSL

    Serious adverse events
    rhBSSL Safety Analysis Set: Baseline to week 4 Placebo Safety Analysis Set: Baseline to week 4 rhBSSL Safety Analysis Set: 4 weeks to 3 months Placebo Safety Analysis Set: 4 weeks to 3 months rhBSSL Safety Analysis Set: 3 months to 12 months CA Placebo Safety Analysis Set: 3 months to 12 months CA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 212 (9.43%)
    13 / 200 (6.50%)
    46 / 212 (21.70%)
    44 / 200 (22.00%)
    61 / 212 (28.77%)
    55 / 200 (27.50%)
         number of deaths (all causes)
    0
    0
    1
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of liver
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    2 / 200 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    3 / 200 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 200 (0.50%)
    2 / 212 (0.94%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary dysplasia
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    2 / 212 (0.94%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Apparent life threatening event
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neonatal respiratory failure
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Laryngomalacia
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial septal defect
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder congenital
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phenylketonuria
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyloric stenosis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cleft palate
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniosynostosis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Persistent foetal circulation
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic infantile neurological cutaneous and articular syndrome
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac hypertrophy
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral calcification
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periventricular leukomalacia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poor sucking reflex
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White matter lesion
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    6 / 212 (2.83%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy of prematurity
         subjects affected / exposed
    4 / 212 (1.89%)
    6 / 200 (3.00%)
    6 / 212 (2.83%)
    3 / 200 (1.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 6
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    3 / 212 (1.42%)
    8 / 200 (4.00%)
    6 / 212 (2.83%)
    2 / 200 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 8
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising enterocolitis neonatal
         subjects affected / exposed
    4 / 212 (1.89%)
    1 / 200 (0.50%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    2 / 200 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    2 / 212 (0.94%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Growth retardation
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Parotitis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 200 (0.50%)
    8 / 212 (3.77%)
    11 / 200 (5.50%)
    11 / 212 (5.19%)
    7 / 200 (3.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 9
    0 / 11
    0 / 15
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    3 / 212 (1.42%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    3 / 212 (1.42%)
    9 / 200 (4.50%)
    7 / 212 (3.30%)
    12 / 200 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 10
    0 / 12
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    3 / 212 (1.42%)
    3 / 200 (1.50%)
    8 / 212 (3.77%)
    13 / 200 (6.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
    0 / 9
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    1 / 200 (0.50%)
    6 / 212 (2.83%)
    3 / 200 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    2 / 200 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningococcal sepsis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    1 / 200 (0.50%)
    2 / 212 (0.94%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    5 / 200 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    2 / 200 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    6 / 212 (2.83%)
    4 / 200 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermo-hypodermitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exanthema subitum
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    2 / 212 (0.94%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    1 / 200 (0.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    2 / 200 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Feeding disorder
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight gain poor
         subjects affected / exposed
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
    1 / 212 (0.47%)
    1 / 200 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    rhBSSL Safety Analysis Set: Baseline to week 4 Placebo Safety Analysis Set: Baseline to week 4 rhBSSL Safety Analysis Set: 4 weeks to 3 months Placebo Safety Analysis Set: 4 weeks to 3 months rhBSSL Safety Analysis Set: 3 months to 12 months CA Placebo Safety Analysis Set: 3 months to 12 months CA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    174 / 212 (82.08%)
    156 / 200 (78.00%)
    117 / 212 (55.19%)
    104 / 200 (52.00%)
    16 / 212 (7.55%)
    11 / 200 (5.50%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    5 / 212 (2.36%)
    7 / 200 (3.50%)
    7 / 212 (3.30%)
    5 / 200 (2.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences all number
    5
    7
    7
    7
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    114 / 212 (53.77%)
    100 / 200 (50.00%)
    50 / 212 (23.58%)
    49 / 200 (24.50%)
    0 / 212 (0.00%)
    0 / 200 (0.00%)
         occurrences all number
    134
    121
    56
    59
    0
    0
    General disorders and administration site conditions
    Oedema peripheral