Comparison of rhBSSL With Placebo When Added to Infant Formula or Pasteurized Breast Milk During 4 Weeks of Treatment in Preterm Infants (LAIF)

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

The purpose of this study is to demonstrate that rhBSSL improves growth in preterm infants as compared with placebo.

Study Overview

• Status: Terminated
• Conditions: Prevention of Growth Restriction
• Intervention / Treatment: Drug: rhBSSL (recombinant human bile-salt-stimulated lipase); Drug: Placebo

Detailed Description

The purpose of this study is to demonstrate that rhBSSL improves growth in preterm infants as compared with placebo. The infants should be born before week 32 of gestational age.

The study drug, rhBSSL or placebo, will be administered during a 4 week treatment period by adding it to either infant formula or pasteurized breast milk.

The study will also evaluate the safety and tolerability of rhBSSL.

Eligible patients will be randomized in a ratio of 1:1 (rhBSSL:placebo). The study consists of maximum 1 week screening period, a 4-week treatment period and a 2 year follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 415
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruges, Belgium
    • Swedish Orphan Biovitrum Investigational Site
  • Leuven, Belgium
    • Swedish Orphan Biovitrum Investigational Site
  • Liege, Belgium
    • Swedish Orphan Biovitrum Investigational Site
  • Rocourt, Belgium
    • Swedish Orphan Biovitrum Investigational Site
  • Wilrijk, Belgium
    • Swedish Orphan Biovitrum Investigational Site
• Czech Republic
  • Hradec Kralove, Czech Republic
    • Swedish Orphan Biovitrum Investigational Site
  • Olomouc, Czech Republic
    • Swedish Orphan Biovitrum Investigational Site
  • Prague, Czech Republic
    • Swedish Orphan Biovitrum Investigational Site
  • Zlin, Czech Republic
    • Swedish Orphan Biovitrum Investigational Site
• France
  • Amiens, France
    • Swedish Orphan Biovitrum Investigational Site
  • Lille, France
    • Swedish Orphan Biovitrum Investigational Site
  • Nancy, France
    • Swedish Orphan Biovitrum Investigational Site
  • Paris, France
    • Swedish Orphan Biovitrum Investigational Site
  • Rouen, France
    • Swedish Orphan Biovitrum Investigational Site
  • Strasbourg, France
    • Swedish Orphan Biovitrum Investigational Site
  • Toulouse, France
    • Swedish Orphan Biovitrum Investigational Site
• Germany
  • Berlin, Germany
    • Swedish Orphan Biovitrum Investigational Site
  • Freiburg, Germany
    • Swedish Orphan Biovitrum Investigational Site
  • Heidelberg, Germany
    • Swedish Orphan Biovitrum Investigational Site
  • Wiesbaden, Germany
    • Swedish Orphan Biovitrum Investigational Site
• Hungary
  • Budapest, Hungary
    • Swedish Orphan Biovitrum Investigational Site
  • Gyula, Hungary
    • Swedish Orphan Biovitrum Investigational Site
  • Miskolc, Hungary
    • Swedish Orphan Biovitrum Investigational Site
  • Nyíregyháza, Hungary
    • Swedish Orphan Biovitrum Investigational Site
  • Pécs, Hungary
    • Swedish Orphan Biovitrum Investigational Site
  • Veszprem, Hungary
    • Swedish Orphan Biovitrum Investigational Site
• Italy
  • Ancona, Italy
    • Swedish Orphan Biovitrum Investigational Site
  • Bari, Italy
    • Swedish Orphan Biovitrum Investigational Site
  • Foggia, Italy
    • Swedish Orphan Biovitrum Investigational Site
  • Milano, Italy
    • Swedish Orphan Biovitrum Investigational Site
  • Padova, Italy
    • Swedish Orphan Biovitrum Investigational Site
  • Roma, Italy
    • Swedish Orphan Biovitrum Investigational Site
• Poland
  • Bydgoszcz, Poland
    • Swedish Orphan Biovitrum Investigational Site
  • Gdansk, Poland
    • Swedish Orphan Biovitrum Investigational Site
  • Lodz, Poland
    • Swedish Orphan Biovitrum Investigational Site
  • Poznan, Poland
    • Swedish Orphan Biovitrum Investigational Site
  • Warszawa, Poland
    • Swedish Orphan Biovitrum Investigational Site
• Russian Federation
  • Ivanovo, Russian Federation
    • Swedish Orphan Biovitrum Investigational Site
  • Nizhniy Novgorod, Russian Federation
    • Swedish Orphan Biovitrum Investigational Site
• Spain
  • Almería, Spain
    • Swedish Orphan Biovitrum Investigational Site
  • Cádiz, Spain
    • Swedish Orphan Biovitrum Investigational Site
  • Córdoba, Spain
    • Swedish Orphan Biovitrum Investigational Site
  • Madrid, Spain
    • Swedish Orphan Biovitrum Investigational Site
  • Málaga, Spain
    • Swedish Orphan Biovitrum Investigational Site
  • Oviedo, Spain
    • Swedish Orphan Biovitrum Investigational Site
  • Salamanca, Spain
    • Swedish Orphan Biovitrum Investigational Site
  • Santiago de Compostela, Spain
    • Swedish Orphan Biovitrum Investigational Site
• Sweden
  • Stockholm, Sweden
    • Swedish Orphan Biovitrum Investigational Site
  • Umeå, Sweden
    • Swedish Orphan Biovitrum Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Preterm infants born before week 32 of gestation.
• Preterm infant who is less than 33 weeks postmenstrual age at the time of randomization.
• Preterm infant who is appropriate for gestational age (AGA) or small for gestational age (SGA) at birth.
• Preterm infant who is receiving food enterally (bottle or gavage tube) at a level of at least 100 ml/kg/day at randomization.
• Preterm infant whose enteral feeding consists of only infant formula or only pasteurized breast milk at the time of inclusion, and who are expected to remain on only infant formula for 4 weeks, or only pasteurized breast milk for at least 2 weeks following treatment initiation.
• Preterm infant who is expected not to receive any fresh breast milk for 4 weeks following treatment initiation.
• Informed consent is obtained.

Exclusion Criteria:

• Expected stay in the hospital is less than 4 weeks from the first dose of study drug.
• Criteria to ensure no disease or treatment affecting growth or development, e.g. brain disease, necrotizing enterocolitis.
• Enrolled in another concurrent clinical intervention study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo added to infant formula/pasteurized breast milk during a 4 week treatment period.
Experimental: rhBSSL; rhBSSL (recombinant human bile-salt-stimulated lipase)	Drug: rhBSSL (recombinant human bile-salt-stimulated lipase); rhBSSL added to infant formula/pasteurized breast milk during a 4 week treatment period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Growth velocity in grams per kilogram per day during 4 weeks of treatment.	Baseline and Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in body weight (g) at 3 months		Baseline and Month 3
Body weight (g) at 12 months' corrected age		12 months´ corrected age
Body weight (g) at 24 months' corrected age		24 months´ corrected age
Change from baseline in total body length (mm) at 4 weeks		Baseline and Day 29
Change from baseline in total body length (mm) at 3 months		Baseline and Month 3
Total body length (mm) at 12 months' corrected age		12 months' corrected age
Total body height (cm) at 24 months' corrected age		24 months' corrected age
Growth restriction	Defined as growth velocity <15 gram per kilogram bodyweight per day during 4 weeks of treatment	Day 29
Time to readiness for discharge	Time until each of the following are fulfilled; sustained weight gain (weight of 1800 g sustained for three days); ability to maintain normal body temperature; ability to suckle feed; ability to maintain stable cardiorespiratory function	Baseline and date of readiness for discharge
Time to discharge		Baseline and date of discharge
Change from baseline in head circumference (mm) at 4 weeks.		Baseline and Day 29
Change from baseline in head circumference (mm) at 3 months.		Baseline and Month 3
Head circumference (mm) at 12 months' corrected age.		12 months´ corrected age
Head circumference (mm) at 24 months' corrected age.		24 months´ corrected age
Time from baseline to 150 mL/kg/day of enteral feeding		Date of first dose and date 150 mL/kg/day of enteral feeding achieved (or exceeded)
Re-admission to hospital within 1 month of discharge		Date of discharge and date of re-admission
Bayley Scale of Infant and Toddler Development, third edition: Cognitive domain composite score 12 months' corrected age		12 months' corrected age
Bayley Scale of Infant and Toddler Development, third edition: Cognitive domain composite score at 24 months' corrected age		24 months' corrected age
Bayley Scale of Infant and Toddler Development, third edition: Language domain composite score at 12 months' corrected age		12 months' corrected age
Bayley Scale of Infant and Toddler Development, third edition: Language domain composite score at 24 months' corrected age		24 months' corrected age
Bayley Scale of Infant and Toddler Development, third edition: Motor domain composite score at 12 months' corrected age		12 months' corrected age
Bayley Scale of Infant and Toddler Development, third edition: Motor domain composite score at 24 months' corrected age		24 months' corrected age
Bayley Scale of Infant and Toddler Development, third edition: Social-emotional domain composite score at 24 months' corrected age		24 months' corrected age
Bayley Scale of Infant and Toddler Development, third edition: Adaptive behavior domain composite score at 24 months' corrected age		24 months' corrected age
Neurodevelopment Disability Composite	Presence of : Composite score of less than 70 on any of the cognitive, language or motor domains of Bayley scale of infant and toddler development, third edition; Bilateral deafness; Bilateral blindness; Cerebral palsy	24 months' corrected age
Child Behavior Checklist total problem score at 24 months' corrected age		24 months' corrected age visit
Number of patients with at least one treatment emergent Adverse Event	Total and by system organ class and preferred term (coded by MedDRA)	Baseline and Day 29
Number of patients with at least one treatment emergent Adverse Event	Total and by system organ class and preferred term (coded by MedDRA)	Day 29 and Month 3
Number of patients with at least one treatment emergent Serious Adverse Event	Total and by system organ class and preferred term (coded by MedDRA)	Baseline and Day 29
Number of patients with at least one treatment emergent Serious Adverse Event	Total and by system organ class and preferred term (coded by MedDRA)	Day 29 and Month 3
Number of patients with at least one Serious Adverse Drug Reaction	Total and by system organ class and preferred term (coded by MedDRA)	12 months' corrected age and 24 months' corrected age
Level of Vitamin A (nmol/L) at 4 weeks		Day 29
Level of Vitamin D (nmol/L) at 4 weeks		Day 29
Number of outpatient visits from the time of initial hospital discharge to home up to 24 months' corrected age		Date of initial hospital discharge to home to date of 24 months' corrected age
Number of inpatient visits from the time of initial hospital discharge to home up to 24 months' corrected age		Date of initial hospital discharge to home to date of 24 months' corrected age
Number of days of hospitalization from the time of initial hospital discharge to home up to 24 months' corrected age		Date of initial hospital discharge to home to date of 24 months' corrected age
Number of days in intensive care unit from the time of initial hospital discharge to home up to 24 months' corrected age		Date of initial hospital discharge to home to date of 24 months' corrected age
Number of days lost from work related to the child's condition from the time of initial hospital discharge to home up to 24 months' corrected age		Date of initial hospital discharge to home to date of 24 months' corrected age
Presence of chronic medical conditions/diagnoses at 24 months' corrected age		24 months' corrected age
Docosahexaenoic acid (% of total fatty acids) in the serum triglyceride fraction at 4 weeks		Day 29
Docosahexaenoic acid (% of total fatty acids) in the serum phosphatidylcholine fraction at 4 weeks		Day 29
Arachidonic acid (% of total fatty acids) in the serum triglyceride fraction at 4 weeks		Day 29
Arachidonic acid (% of total fatty acids) in the serum phosphatidylcholine fraction at 4 weeks		Day 29
Number of patients with antibodies to rhBSSL at 4 weeks		Day 29
Number of patients with antibodies to rhBSSL at Month 3		Month 3
Number of patients with antibodies to rhBSSL at 12 months' corrected age		12 months' corrected age

Collaborators and Investigators

• Sponsor: Swedish Orphan Biovitrum
• Investigators: Study Director: Kristina Timdahl, MD, Swedish Orphan Biovitrum

Publications and helpful links

General Publications

• Casper C, Carnielli VP, Hascoet JM, Lapillonne A, Maggio L, Timdahl K, Olsson B, Vagero M, Hernell O. rhBSSL improves growth and LCPUFA absorption in preterm infants fed formula or pasteurized breast milk. J Pediatr Gastroenterol Nutr. 2014 Jul;59(1):61-9. doi: 10.1097/MPG.0000000000000365.
• Casper C, Hascoet JM, Ertl T, Gadzinowski JS, Carnielli V, Rigo J, Lapillonne A, Couce ML, Vagero M, Palmgren I, Timdahl K, Hernell O. Recombinant Bile Salt-Stimulated Lipase in Preterm Infant Feeding: A Randomized Phase 3 Study. PLoS One. 2016 May 31;11(5):e0156071. doi: 10.1371/journal.pone.0156071. eCollection 2016.

Helpful Links

• Results are available on the European Union Clinical Trials Register

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: June 8, 2011
• First Submitted That Met QC Criteria: August 9, 2011
• First Posted (Estimate): August 10, 2011

Study Record Updates

• Last Update Posted (Estimate): July 30, 2015
• Last Update Submitted That Met QC Criteria: July 29, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: preterm infants; growth velocity; rhBSSL; Swedish Orphan Biovitrum; Prevention of growth restriction
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Gastrointestinal Agents; Bile Acids and Salts
• Other Study ID Numbers: BVT.BSSL-030