Clinical Trial Results:
The probiotic Bifidobacterium breve strain BBG-01 admistered early to preterm infants to prevent infection, necrotising enterocolitis and death.
Summary
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EudraCT number |
2006-003445-17 |
Trial protocol |
GB |
Global end of trial date |
04 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Mar 2017
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First version publication date |
10 Mar 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BBG001
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Additional study identifiers
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ISRCTN number |
ISRCTN05511098 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Queen Mary University of London
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Sponsor organisation address |
Mile End Road, London, United Kingdom, E1 4NS
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Public contact |
Joint R&D Office, Queen Mary University of London, m.rickard@qmul.ac.uk
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Scientific contact |
Joint R&D Office, Queen Mary University of London, m.rickard@qmul.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Nov 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Sep 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Sep 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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Protection of trial subjects |
N/A
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Background therapy |
Standard neonatal care | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jul 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 1315
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Worldwide total number of subjects |
1315
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EEA total number of subjects |
1315
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
1315
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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
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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
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Period 1 title |
Trial entry
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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)
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Investigational medicinal product code |
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Other name |
B breve BBG
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Nasogastric use , Oral use
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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.
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Arm title
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Placebo | |||||||||||||||
Arm description |
Freeze dried corn starch | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
BBG-001 (Placebo)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Nasogastric use , Oral use
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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.
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Period 2
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Period 2 title |
Discharge
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Is this the baseline period? |
No | |||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
B breve BBG
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Nasogastric use , Oral use, Other use
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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.
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Arm title
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Placebo | |||||||||||||||
Arm description |
Freeze dried corn starch | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
BBG-01 DT (Placebo)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Nasogastric use , Oral use, Other use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
B. breve BBG
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Reporting group description |
The product is a probiotic supplied freeze dried with corn starch. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Freeze dried corn starch | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
B. breve BBG
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Reporting group description |
The product is a probiotic supplied freeze dried with corn starch. | ||
Reporting group title |
Placebo
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Reporting group description |
Freeze dried corn starch | ||
Reporting group title |
B. breve BBG
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Reporting group description |
The product is a probiotic supplied freeze dried with corn starch. | ||
Reporting group title |
Placebo
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Reporting group description |
Freeze dried corn starch |
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End point title |
Sepsis | |||||||||||||||
End point description |
Blood stream infection with non-skin commensals
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End point type |
Primary
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End point timeframe |
After 72 hours postnatal age and <46 weeks post menstrual age
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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.
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Comparison groups |
B. breve BBG v Placebo
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Number of subjects included in analysis |
1310
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
Method |
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Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
0.97
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.73 | |||||||||||||||
upper limit |
1.29 |
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End point title |
NEC | |||||||||||||||
End point description |
Necrotising Enterocolitis (Bell stage II or higher)
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End point type |
Primary
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End point timeframe |
Between randomisation and discharge
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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.
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Comparison groups |
Placebo v B. breve BBG
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Number of subjects included in analysis |
1310
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
Method |
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Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
0.93
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.68 | |||||||||||||||
upper limit |
1.27 |
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End point title |
Death before discharge home | |||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Between randomisation and discharge home
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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.
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Comparison groups |
B. breve BBG v Placebo
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Number of subjects included in analysis |
1310
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
Method |
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Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
0.93
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.67 | |||||||||||||||
upper limit |
1.3 |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Safety was assessed continuously during each baby’s stay in the neonatal unit, between randomisation and discharge home.
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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.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
None used | |||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
B. breve BBG
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Reporting group description |
The product is a probiotic supplied freeze dried with corn starch. | |||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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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. |
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/26628328 |