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    EudraCT Number:2010-023909-35
    Sponsor's Protocol Code Number:BVT.BSSL-030
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2014-12-08
    Trial results View results
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    A. Protocol Information
    A.2EudraCT number2010-023909-35
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 3 clinical study investigating the effects of rhBSSL (an enzyme to help digestion of fat) added to pasteurized breast milk or formula in babies born prematurely.
    A.4.1Sponsor's protocol code numberBVT.BSSL-030
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/62/2011
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSwedish Orphan Biovitrum AB (publ)
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSwedish Orphan Biovitrum AB (publ)
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD
    B.5.2Functional name of contact pointTracy Roe
    B.5.3 Address:
    B.5.3.1Street AddressFranklin House, Kings Worthy, Winchester
    B.5.3.2Town/ cityHampshire
    B.5.3.4CountryUnited Kingdom
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRecombinant Human Bile Salt-stimulated Lipase
    D.3.2Product code rhBSSL
    D.3.4Pharmaceutical form Powder and solvent for oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor coderhBSSL
    D.3.9.3Other descriptive nameRecombinant Human Bile Salt-stimulated Lipase
    D.3.9.4EV Substance CodeSUB32748
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8700
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder and solvent for oral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Prevention of growth retardation due to lack of bile salt-stimulated lipase in enteral nutrition
    E.1.1.1Medical condition in easily understood language
    Babies born prematurely
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary objectives of the trial
    To determine the effect of rhBSSL treatment in decreasing the risk of growth restriction
    • To determine the effect of rhBSSL treatment in shortening the time of hospital stay
    • To determine the effect of rhBSSL treatment in improving early development
    • To determine the effect of rhBSSL treatment in decreasing readmittance to hospital
    • To determine the effect of rhBSSL treatment in increasing the levels of docosahexaenoic acid (DHA) and arachidonic acid (AA)
    • To compare the safety and tolerability of rhBSSL treatment with that of placebo treatment
    • To determine the effect of rhBSSL treatment on neurodevelopment
    • To determine the long-term effect of rhBSSL treatment on anthropometrics
    • To determine the long-term safety of rhBSSL treatment
    • To assess the effect of rhBSSL treatment on health care utilization
    • To assess the effect of rhBSSL treatment on indirect resource use
    • To assess the effect of rhBSSL treatment on chronic medical conditions/diagnoses
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Preterm infant born before Week 32 of gestation.
    2. Preterm infant who is <33 weeks postmenstrual age at the time of randomization.
    3. Preterm infant who is AGA or SGA at birth.
    4. Preterm infant who is receiving food enterally (bottle or gavage tube) at a level of at least 100 mL/kg/day at randomization.
    5. Preterm infant whose enteral feeding consists of only infant formula or only PBM at the time of inclusion, and who are expected to remain on only infant formula for 4 weeks, or only PBM for at least 2 weeks following treatment initiation.
    6. Preterm infant who is expected not to receive any fresh breast milk for 4 weeks following treatment initiation.
    7. Informed consent is obtained from the patient’s legally acceptable representative. Every effort will be made to ensure informed consent is obtained from both parents. Where this is not possible, the local regulations will be followed in the definition of legally acceptable representative.
    E.4Principal exclusion criteria
    1. Expected stay at the hospital is less than 4 weeks from the first dose of study drug.
    2. Currently receiving mechanical ventilation via endotracheal tube (continuous positive airway pressure [CPAP] or high-flow nasal cannula are not criteria for exclusion).
    3. Require ≥30% oxygen (if on CPAP or in head box) or >0.5 L/min oxygen.
    4. Evidence of severe brain disease or damage, including grade III or IV peri- or intraventricular hemorrhage, meningitis or hydrocephalus, grade III or IV intracranial hemorrhage, or periventricular leukomalacia.
    5. Presence of major dysmorphology or congenital abnormalities that are likely to affect growth and/or development.
    6. Current clinical evidence of hemodynamically significant persistent ductus arteriosus.
    7. Clinical evidence of sepsis (including low or high white blood cell count and/or low platelet count and bacteriologically proven evidence of systemic infection). This should be based on the investigator’s opinion and available local laboratory reference ranges.
    8. Systemic anti-infective treatment within 48 hours prior to randomization, other than prophylactic treatment (eg, antifungal prophylaxis with fluconazole) as per local clinical practice.
    9. Evidence of congenital infection (eg, cytomegalovirus).
    10. Previous or current diagnosis of necrotizing enterocolitis (Bell’s stage 2 or greater).
    11. Prior or current treatment with corticosteroids, except hydrocortisone.
    12. Presence of any condition that in the opinion of the investigator makes the patient unsuitable for inclusion.
    13. Enrolled in another concurrent clinical intervention study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is growth velocity in grams per kilogram per day during 4 weeks of treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary efficacy measurement (growth velocity) will be made by frequent (at least 3 times per week) measurements of the infants’ weight during treatment.
    E.5.2Secondary end point(s)
    • Change from Baseline in body weight (g) at 3 months
    • Body weight (g) at 12 and 24 months corrected age
    • Change from Baseline in total body length (mm) at 4 weeks and 3 months
    • Body length (mm) at 12 months corrected age
    • Body height (cm) at 24 months corrected age
    • Growth restriction, defined as growth velocity <15 g per kilogram bodyweight per day during 4 weeks of treatment
    • Time to readiness for discharge
    • Time to discharge
    • Change from Baseline in head circumference (mm) at 4 weeks and 3 months
    • Head circumference (mm) at 12 and 24 months corrected age
    • Time from Baseline to 150 mL/kg/day of enteral feeding
    • Readmission to hospital within 1 month of discharge
    • Bayley Scale of Infant and Toddler Development III (Bayley-III) scores for the cognitive, language, motor, social-emotional and adaptive behavior domains at 24 months corrected age
    • Neurodevelopment disability composite at 24 months corrected age
    • Child Behavior Checklist (CBCL) scores at 24 months corrected age
    • Adverse events
    • Bayley-III scores for the cognitive, language and motor domains at 12 months corrected age
    • Vomiting (frequency and volume)
    • Vital signs (heart rate, blood pressure, body temperature)
    • Laboratory variables amylase, bilirubin, aminotransferases, sodium, and urea
    • Levels of vitamins A and D
    • Levels of rhBSSL antibodies
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see timepoints in above description of endpoints (section E.5.2)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Russian Federation
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date on which the last patient completes the last visit (includes follow up visits).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 432
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F. of subjects for this age range: 432
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    preterm infants born before week 32 of gestational age
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 432
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: Russian Federation
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