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    Clinical Trial Results:
    The probiotic Bifidobacterium breve strain BBG-01 admistered early to preterm infants to prevent infection, necrotising enterocolitis and death.

    Summary
    EudraCT number
    		 2006-003445-17
    Trial protocol
    		 GB  
    Global end of trial date
    04 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Mar 2017
    First version publication date
    10 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BBG001
    Additional study identifiers
    ISRCTN number
    		 ISRCTN05511098
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    Mile End Road, London, United Kingdom, E1 4NS
    Public contact
    Joint R&D Office, Queen Mary University of London, m.rickard@qmul.ac.uk
    Scientific contact
    Joint R&D Office, Queen Mary University of London, m.rickard@qmul.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether early administration of B breve BBG to preterm infants reduces the incidence of episodes of infection, necrotising enterocolitis and death.
    Protection of trial subjects
    N/A
    Background therapy
    		 Standard neonatal care
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1315
    Worldwide total number of subjects
    1315
    EEA total number of subjects
    1315
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    1315
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place in 24 hospitals within 60 miles of London between July 1, 2010, and July 31, 2013 Multiple births were randomised individually.

    Pre-assignment
    Screening details
    		 Inclusions: Gestational age >= 23 weeks and 0 days and <= 30 weeks and 6 days, less than 48 hours old, with written informed parental consent, babies already on antibiotics for suspected or proven infection. Exclusions: lethal congenital abnormality, gastrointestinal malformation, no realistic prospect of survival.

    Period 1
    Period 1 title
    Trial entry
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject, Monitor, Carer, Assessor
    Blinding implementation details
    The investigational product was supplied freeze dried with corn starch; the placebo was corn starch alone. Both products were manufactured in Japan at the Yakult Fujisusono Pharmaceutical Plant by the Yakult Honsha Co. Ltd., and provided in identical foil sachets each containing 1 gram of product. In order that the products could not be distinguished both were suspended in 3 ml 1/8 strength (1 scoop to 240 ml sterile water) of the elemental infant formula Neocate and allowed to settle.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 B. breve BBG
    Arm description
    		 The product is a probiotic supplied freeze dried with corn starch.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BBG-001 (Bifidobacterium breve)
    Investigational medicinal product code
    Other name
    B breve BBG
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    The powder is suspended in 3 ml 1/8 strength (1 scoop to 240 ml sterile water) of the elemental infant formula Neocate and the corn starch is allowed to settle for 30 minutes. 1 ml of supernatant is withdrawn to be given to the baby; this contains 6.7 x 107 - 6.7 x 109 colony forming organisms. The products are administered via a naso-gastric or oro-gastric tube or, for babies no longer tube fed, directly into the mouth using a syringe. The intervention will be given once daily starting as soon as possible after randomisation and continuing until 36 completed weeks of post-menstrual age (36 weeks + 0 days) or death or discharge from hospital if sooner.

    Arm title
    		 Placebo
    Arm description
    		 Freeze dried corn starch
    Arm type
    		 Placebo

    Investigational medicinal product name
    BBG-001 (Placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    The powder is suspended in 3 ml 1/8 strength (1 scoop to 240 ml sterile water) of the elemental infant formula Neocate and the corn starch is allowed to settle for 30 minutes. 1 ml of supernatant is withdrawn to be given to the baby. The products are administered via a naso-gastric or oro-gastric tube or, for babies no longer tube fed, directly into the mouth using a syringe. The intervention will be given once daily starting as soon as possible after randomisation and continuing until 36 completed weeks of post-menstrual age (36 weeks + 0 days) or death or discharge from hospital if sooner.

    Number of subjects in period 1
    		B. breve BBG Placebo
    Started
    654
    661
    Completed
    650
    660
    Not completed
    4
    1
         Consent withdrawn by subject
    4
    1
    Period 2
    Period 2 title
    Discharge
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The investigational product was supplied freeze dried with corn starch; the placebo was corn starch alone. Both products were manufactured in Japan at the Yakult Fujisusono Pharmaceutical Plant by the Yakult Honsha Co. Ltd., and provided in identical foil sachets each containing 1 gram of product. In order that the products could not be distinguished both were suspended in 3 ml 1/8 strength (1 scoop to 240 ml sterile water) of the elemental infant formula Neocate and allowed to settle.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 B. breve BBG
    Arm description
    		 The product is a probiotic supplied freeze dried with corn starch.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bifidobacterium breve strain BBG freeze dried with corn starch
    Investigational medicinal product code
    Other name
    B breve BBG
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Nasogastric use , Oral use, Other use
    Dosage and administration details
    The powder is suspended in 3 ml 1/8 strength (1 scoop to 240 ml sterile water) of the elemental infant formula Neocate and allowed to settle for 30 minutes. 1 ml of supernatant is withdrawn to be given to the baby; this contains 6.7 x 107 - 6.7 x 109 colony forming organisms. The products are administered via a naso-gastric or oro-gastric tube or, for babies no longer tube fed, directly into the mouth using a syringe. The intervention will be given once daily starting as soon as possible after randomisation and continuing until 36 completed weeks of post-menstrual age (36 weeks + 0 days) or death or discharge from hospital if sooner.

    Arm title
    		 Placebo
    Arm description
    		 Freeze dried corn starch
    Arm type
    		 Placebo

    Investigational medicinal product name
    BBG-01 DT (Placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Nasogastric use , Oral use, Other use
    Dosage and administration details
    The powder is suspended in 3 ml 1/8 strength (1 scoop to 240 ml sterile water) of the elemental infant formula Neocate and allowed to settle for 30 minutes. 1 ml of supernatant is withdrawn to be given to the baby; this contains 6.7 x 107 - 6.7 x 109 colony forming organisms. The products are administered via a naso-gastric or oro-gastric tube or, for babies no longer tube fed, directly into the mouth using a syringe. The intervention will be given once daily starting as soon as possible after randomisation and continuing until 36 completed weeks of post-menstrual age (36 weeks + 0 days) or death or discharge from hospital if sooner.

    Number of subjects in period 2
    		B. breve BBG Placebo
    Started
    650
    660
    Completed
    650
    660

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    B. breve BBG
    Reporting group description
    		 The product is a probiotic supplied freeze dried with corn starch.

    Reporting group title
    Placebo
    Reporting group description
    		 Freeze dried corn starch

    Reporting group values
    		 B. breve BBG Placebo Total
    Number of subjects
    		 654 661 1315
    Age categorical
    Postnatal age at randomisation
    Units: Subjects
        <24 hrs
    		 167 172 339
        24 to <=48 hrs
    		 482 487 969
        >48 hrs
    		 1 1 2
        Excluded from analysis
    		 4 1 5
    Gender categorical
    Units: Subjects
        Female
    		 276 290 566
        Male
    		 374 370 744
        Excluded from analysis
    		 4 1 5

    End points

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    End points reporting groups
    Reporting group title
    B. breve BBG
    Reporting group description
    		 The product is a probiotic supplied freeze dried with corn starch.

    Reporting group title
    Placebo
    Reporting group description
    		 Freeze dried corn starch
    Reporting group title
    B. breve BBG
    Reporting group description
    		 The product is a probiotic supplied freeze dried with corn starch.

    Reporting group title
    Placebo
    Reporting group description
    		 Freeze dried corn starch

    Primary: Sepsis

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    End point title
    		 Sepsis
    End point description
    Blood stream infection with non-skin commensals
    End point type
    Primary
    End point timeframe
    After 72 hours postnatal age and <46 weeks post menstrual age
    End point values
    		 B. breve BBG Placebo
    Number of subjects analysed
    650
    660
    Units: Babies
        Yes
    73
    77
        No
    577
    583
    Statistical analysis title
    		 Adjusted risk ratio
    Statistical analysis description
    Adjusted for sex, gestational age at birth, randomisation<24 hours of age. Allowances for correlations between multiple births are accounted for.
    Comparison groups
    B. breve BBG v Placebo
    Number of subjects included in analysis
    1310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.29

    Primary: NEC

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    End point title
    		 NEC
    End point description
    Necrotising Enterocolitis (Bell stage II or higher)
    End point type
    Primary
    End point timeframe
    Between randomisation and discharge
    End point values
    		 B. breve BBG Placebo
    Number of subjects analysed
    650
    660
    Units: Babies
        Yes
    61
    66
        No
    589
    594
    Statistical analysis title
    		 Adjusted risk ratio
    Statistical analysis description
    Adjusted for sex, gestational age at birth, randomisation<24 hours of age. Allowances for correlations between multiple births are accounted for.
    Comparison groups
    Placebo v B. breve BBG
    Number of subjects included in analysis
    1310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.27

    Primary: Death before discharge home

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    End point title
    		 Death before discharge home
    End point description
    End point type
    Primary
    End point timeframe
    Between randomisation and discharge home
    End point values
    		 B. breve BBG Placebo
    Number of subjects analysed
    650
    660
    Units: Babies
        Yes
    54
    56
        No
    596
    604
    Statistical analysis title
    		 Adjusted risk ratio
    Statistical analysis description
    Adjusted for sex, gestational age at birth, randomisation<24 hours of age. Allowances for correlations between multiple births are accounted for.
    Comparison groups
    B. breve BBG v Placebo
    Number of subjects included in analysis
    1310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.3

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Safety was assessed continuously during each baby’s stay in the neonatal unit, between randomisation and discharge home.
    Adverse event reporting additional description
    Adverse events are foreseeable due to the nature of the patient population, their routine care and treatment. No adverse drug reactions are expected from BBG. Consequently, only those adverse events (or reactions) identified as serious will be recorded for this trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None used
    Dictionary version
    1
    Reporting groups
    Reporting group title
    B. breve BBG
    Reporting group description
    		 The product is a probiotic supplied freeze dried with corn starch.

    Reporting group title
    Placebo
    Reporting group description
    		 Freeze dried corn starch

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Due to the nature of the patient population, neonates in intensive care, a high incidence of adverse events is foreseeable during their routine care and treatment. Consequently, only those adverse events identified as serious were recorded for the trial.
    Serious adverse events
    		 B. breve BBG Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 654 (0.15%)
    1 / 661 (0.15%)
         number of deaths (all causes)
    54
    56
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 654 (0.15%)
    0 / 661 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxic epidermal necrolysis
         subjects affected / exposed
    0 / 654 (0.00%)
    1 / 661 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 B. breve BBG Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 654 (0.00%)
    0 / 661 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26628328
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