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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BVT.BSSL-030

ISRCTN number

US NCT number

NCT01413581

WHO universal trial number (UTN)

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

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?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

06 Aug 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 May 2014

Was the trial ended prematurely?

Yes

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

Independent data monitoring committee (IDMC) involvement?

Yes

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

Preterm newborn - gestational age < 37 wk

415

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

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 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

Are arms mutually exclusive

Yes

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.

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 title

Extended f-u to 24 months corrected age

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

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

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

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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Reporting group title

rhBSSL Full Analysis Set

Reporting group description

Reporting group title

Placebo Full Analysis Set

Reporting group description

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 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

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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Reporting group title

rhBSSL Full Analysis Set

Reporting group description

Reporting group title

Placebo Full Analysis Set

Reporting group description

Reporting group title

rhBSSL EES

Reporting group description

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

Subject analysis set title

Placebo Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

rhBSSL Full Analysis Set, PBM Strata

Subject analysis set type

Full analysis

Subject analysis set description

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

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

ANCOVA

Statistical analysis description

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

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

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

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

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

Top of page

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

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

Secondary: Body Weight: Change from Baseline at 3 Months

Top of page

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

ANCOVA

Statistical analysis description

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

Top of page

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

ANCOVA

Statistical analysis description

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

Top of page

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

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

Top of page

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

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

Top of page

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

ANCOVA

Statistical analysis description

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

Top of page

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

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

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.27

Secondary: Body Length: Change from Baseline at 3 Months

Top of page

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

ANCOVA

Statistical analysis description

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

Top of page

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

ANCOVA

Statistical analysis description

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

Top of page

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

Top of page

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

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

Top of page

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

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

Top of page

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

ANOVA

Statistical analysis description

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

Top of page

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

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

Top of page

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

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

Top of page

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

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

Top of page

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

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

Top of page

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

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

Top of page

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

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

Top of page

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

Top of page

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

Top of page

End point title

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

End point description

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

Top of page

End point title

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

End point description

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

Top of page

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

Top of page

End point title

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

End point description

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

Top of page

End point title

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

End point description

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

Top of page

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

Top of page

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

Top of page

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

Top of page

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

Top of page

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

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

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

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

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

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

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

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

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

Top of page

End point title

Levels of Urea 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	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

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

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

Top of page

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

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

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

Top of page

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

ANOVA

Statistical analysis description

Comparison groups

rhBSSL EES v Placebo EES

Number of subjects included in analysis

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

Top of page

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

ANOVA

Statistical analysis description

Comparison groups

rhBSSL EES v Placebo EES

Number of subjects included in analysis

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

Top of page

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

Top of page

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 name

MedDRA

Dictionary version

16.1

Reporting group title

rhBSSL Safety Analysis Set: Baseline to week 4

Reporting group description

Reporting group title

Placebo Safety Analysis Set: Baseline to week 4

Reporting group description

Reporting group title

rhBSSL Safety Analysis Set: 4 weeks to 3 months

Reporting group description

Reporting group title

Placebo Safety Analysis Set: 4 weeks to 3 months

Reporting group description

Reporting group title

rhBSSL Safety Analysis Set: 3 months to 12 months CA

Reporting group description

Reporting group title

Placebo Safety Analysis Set: 3 months to 12 months CA

Reporting group description

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
subjects affected / exposed	10 / 212 (4.72%)	12 / 200 (6.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	10	12	0	0	0	0
Eye disorders
Retinopathy of prematurity
subjects affected / exposed	34 / 212 (16.04%)	29 / 200 (14.50%)	10 / 212 (4.72%)	4 / 200 (2.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	34	30	10	5	0	0
Conjunctivitis
subjects affected / exposed	23 / 212 (10.85%)	20 / 200 (10.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	23	20	0	0	0	0
Gastrointestinal disorders
Gastrooesophageal reflux disease
subjects affected / exposed	7 / 212 (3.30%)	5 / 200 (2.50%)	6 / 212 (2.83%)	8 / 200 (4.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	7	5	6	8	0	0
Flatulence
subjects affected / exposed	7 / 212 (3.30%)	3 / 200 (1.50%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	7	3	0	0	0	0
Abdominal distension
subjects affected / exposed	7 / 212 (3.30%)	1 / 200 (0.50%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	8	1	0	0	0	0
Umbilical hernia
subjects affected / exposed	5 / 212 (2.36%)	7 / 200 (3.50%)	11 / 212 (5.19%)	10 / 200 (5.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	5	7	11	10	0	0
Inguinal hernia
subjects affected / exposed	0 / 212 (0.00%)	0 / 200 (0.00%)	7 / 212 (3.30%)	8 / 200 (4.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	0	0	7	9	0	0
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary dysplasia
subjects affected / exposed	17 / 212 (8.02%)	11 / 200 (5.50%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	17	11	0	0	0	0
Apnoea
subjects affected / exposed	17 / 212 (8.02%)	8 / 200 (4.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	17	15	0	0	0	0
Musculoskeletal and connective tissue disorders
Osteopenia
subjects affected / exposed	3 / 212 (1.42%)	8 / 200 (4.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	3	8	0	0	0	0
Infections and infestations
Rhinitis
subjects affected / exposed	13 / 212 (6.13%)	7 / 200 (3.50%)	5 / 212 (2.36%)	8 / 200 (4.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	13	9	6	8	0	0
Urinary tract infection
subjects affected / exposed	7 / 212 (3.30%)	2 / 200 (1.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	8	2	0	0	0	0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	5 / 212 (2.36%)	6 / 200 (3.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)	0 / 212 (0.00%)	0 / 200 (0.00%)
occurrences all number	5	6	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

07 Jul 2011

Amendment 1 was completed before the first patient entered the study and included mostly clarifications and corrections.

15 Feb 2013

Amendment 2 was prepared to prolong the study from 12 to 24 months corrected age to study health economy and effect on neurodevelopment.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Based on the limited number of patients expected to complete the 24 month CA visit due to the sponsors decision to terminate the study early, only a subset of the pre-planned analyses and data presentations for the extension were performed.

http://www.ncbi.nlm.nih.gov/pubmed/27244221

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Growth Velocity during 4 weeks of treatment

Primary: Growth Velocity during 4 weeks of treatment

Secondary: Body Weight: Change from Baseline at 4 Weeks

Secondary: Body Weight: Change from Baseline at 4 Weeks

Secondary: Body Weight: Change from Baseline at 3 Months

Secondary: Body Weight: Change from Baseline at 3 Months

Secondary: Body Weight at 12 Months Corrected Age

Secondary: Body Weight at 12 Months Corrected Age

Secondary: Head Circumference: Change from Baseline at 4 Weeks

Secondary: Head Circumference: Change from Baseline at 4 Weeks

Secondary: Head Circumference: Change from Baseline at 3 Months

Secondary: Head Circumference: Change from Baseline at 3 Months

Secondary: Head Circumference at 12 Months Corrected Age

Secondary: Head Circumference at 12 Months Corrected Age

Secondary: Body Length: Change from Baseline at 4 Weeks

Secondary: Body Length: Change from Baseline at 4 Weeks

Secondary: Body Length: Change from Baseline at 3 Months

Secondary: Body Length: Change from Baseline at 3 Months

Secondary: Body Length at 12 Months Corrected Age

Secondary: Body Length at 12 Months Corrected Age

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

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

Secondary: Growth Restriction

Secondary: Growth Restriction

Secondary: Time to Discharge

Secondary: Time to Discharge

Secondary: Time to Readiness for Discharge

Secondary: Time to Readiness for Discharge

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

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

Secondary: Feeding Utilization

Secondary: Feeding Utilization

Secondary: DHA Concentration in S-TG at 4 weeks

Secondary: DHA Concentration in S-TG at 4 weeks

Secondary: DHA Concentration in S-PC at 4 weeks

Secondary: DHA Concentration in S-PC at 4 weeks

Secondary: AA Concentration in S-TG at 4 weeks

Secondary: AA Concentration in S-TG at 4 weeks

Secondary: AA Concentration in S-PC in 4 weeks

Secondary: AA Concentration in S-PC in 4 weeks

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Mean number of vomiting episodes/day

Secondary: Mean number of vomiting episodes/day

Secondary: Systolic Blood Pressure at Baseline

Secondary: Systolic Blood Pressure at Baseline

Secondary: Systolic Blood Pressure at 4 weeks

Secondary: Systolic Blood Pressure at 4 weeks

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

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

Secondary: Diastolic Blood Pressure at Baseline

Secondary: Diastolic Blood Pressure at Baseline

Secondary: Diastolic Blood Pressure at 4 weeks

Secondary: Diastolic Blood Pressure at 4 weeks

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

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

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