PiPS Background: the evidence so far

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Plan
 Background
 The evidence so far
 Gaps in our knowledge
 PiPS
The problem
 As survival increases so the proportion
of deaths attributed to NEC and infection
rises
National data: trends
US ‘linked’ data : singletons
Lucaks SL et al 2004. Peds Inf Dis J.
 As survival increases so the proportion
of deaths attributed to NEC and infection
rises
Primary cause
of death
1995
2006
p
RR (95% CI)
Infection
8%
16%
<0.001
1.4 (1.2 – 1.6)
NEC
4%
12%
<0.0001
1.7 (1.5 – 1.9)
Source: The EPICure studies
Why probiotics?
Normal development of bowel flora
 Sterile at birth …..
 Healthy babies colonised rapidly by
maternal faecal flora
 Flora of breast fed babies dominated by
Bifidobacteria
Benefits of the microbial-host interaction
Benefit
Mechanism
Maintain mucosal
barrier integrity
•Reduce mucosal permeability
•Increase mucus production
•Strengthen tight junctions
•Inhibit bacterial translocation
Regulate appropriate
bacterial colonisation
•Modulate microflora growth and adherence
•Produce toxins to aerobic bacteria
•Reduce intraluminal pH
•Compete with pathogens for binding sites
Activate intestinal
immune defences
•Increase faecal IgA and enhance IgA response
•Produce short chain fatty acids
•Increase leucocyte phagocytosis
Modulate intestinal
inflammation
•Increase T-cell &macrophage cytokine production
•Decrease production of anti-inflammatory cytokines
•Decrease proinflammatory cytokines
•Promote Th1 cytokine profile
Martin CR & Walker WA: Seminars in Perinat 2008;
Gut flora in preterm babies
 Slower acquisition, further delayed by
antibiotics
 Less diversity
 Fewer commensals
 More potentially pathogenic strains
Gewolb IH et al Arch Dis Childh 1999
Probiotic
 A live micro-organism which when
administered in adequate amounts confers
a health benefit on the host (World Health
Organisation, 2010)
Systematic reviews:
 Barclay AR et al., JPGN 2007
 Deshpande G et al., Lancet 2007
 AlFaleh KM & Bassler D, Cochrane 2008
 Mihatsch., 2008
 Guthmann., 2010
 Deshpande G et al., Pediatrics 2010
 AlFaleh et al., Cochrane 2011
Systematic reviews:
 Barclay AR et al., JPGN 2007
 Deshpande G et al., Lancet 2007
 AlFaleh KM & Bassler D, Cochrane 2008
 Mihatsch., 2008
 Guthmann., 2010
 Deshpande G et al., Pediatrics 2010
 AlFaleh et al., Cochrane 2011
Outcome: ‘Definite’ NEC
Deshpande et al. 2010
Outcome: Blood culture positive sepsis
Deshpande et al. 2010
Outcome: Death
Deshpande et al. 2010
Summary of outcomes
 Significant reduction of ‘definite’ NEC
 No effect on blood culture positive sepsis
 Significant reduction ‘all cause’ mortality
 No reported problems with safety
A closer look at those trials
designed to study clinical outcomes
 Dani C et al 2002
 Lin H-C et al 2005
 Bin-Nun A et al 2005
 Samanta M et al 2008
 Lin H-C et al 2008
These studies account for 85% of the babies included in
the updated systematic review
Characteristics of clinical studies <2008
Authors
Year
Population
Exclusions
Dani et al
2002
Multicentre
<33w or<1500g
n=585
Mean wt >1300g
Lin et al
2005
Single centre
Deaths or
NEC in 1st
<1500g &>7d
week
Lines out>24h
n=367
Mean wt c.1100g
Intervention
Primary
outcome
Incidence in
comparator
group
Lactobacillus
GG
To discharge
UTI
NEC ≥stage2
Sepsis
all after 7d
5.2%
2.8%
4.1%
L acidophilus
B infantis
To discharge
Death or
NEC ≥stage
2
12.8%
(powered at
23%)
B infantis
Any NEC
16.4%
(other than
anomalies &
refusals)
Bin-Nun et Single centre
al
<1500g starting
2005
milk on weekday
n=147 (3 not
analysed)
Mean wt >1100g
Death <14d
No
information
Str thermophilus
B bifidus
To 36w
Characteristics of clinical studies <2008
Authors
Year
Population
Dani et al
2002
Multicentre
<33w or<1500g
n=585
Mean wt >1300g
Lin et al
2005
Single centre
<1500g &>7d
Lines out>24h
n=367
Mean wt c.1100g
Exclusions
Intervention
Primary
outcome
Incidence in
comparator
group
Death <14d
100/685
Lactobacillus
GG
To discharge
UTI
NEC ≥stage2
Sepsis
all after 7d
5.2%
2.8%
4.1%
Deaths or
NEC in 1st
week
48/417
L acidophilus
B infantis
To discharge
Death or
NEC ≥stage
2
12.8%
(powered at
23%)
No
information
B infantis
Any NEC
16.4%
(other than
anomalies &
refusals)
Bin-Nun et Single centre
al
<1500g starting
2005
milk on weekday
n=147 (3 not
analysed)
Mean wt >1100g
Str thermophilus
B bifidus
To 36w
Characteristics of 2 recent studies
Authors
Year
Population
Samanta
et al
2008
Single centre
<32w &<1500g
Survived 48h
Mean wt >1100g
Lin et al
2008
Multicentre
<34w &<1500g
& enterally fed
Exclusions
Intervention
Primary
outcome
Incidence in
comparator
group
Deaths due
to ‘other
neonatal
illness’:
B infantis
B bifidum
B longum
L acidophilus
To discharge
NEC ≥2
Sepsis
Death due to
NEC or
sepsis
15.8%
29.5%
14.7%
Asphyxia
Formula fed
Comg
anolmaly
NBM >3w
L acidophilus
B bifidum
For 6w
Death or
NEC≥2 in the
6w study
period
9.2% (was
powered at
25%)
(other than
anomalies &
refusals)
Characteristics of 2 recent studies
Authors
Year
Population
Samanta
et al
2008
Single centre
<32w &<1500g
Survived 48h
Mean wt >1100g
Lin et al
2008
Multicentre
<34w &<1500g
& enterally fed
Exclusions
Intervention
Primary
outcome
Incidence in
comparator
group
Deaths due
to ‘other
neonatal
illness’:
88/274
B infantis
B bifidum
B longum
L acidophilus
To discharge
NEC ≥2
Sepsis
Death due to
NEC or
sepsis
15.8%
29.5%
14.7%
Asphyxia
Formula fed
Comg
anolmaly
NBM >3w
137/580 , 98
of whom
died
L acidophilus
B bifidum
For 6w
Death or
NEC≥2 in the
6w study
period
9.2% (was
powered at
25%)
(other than
anomalies &
refusals)
Published studies: general comments
 Only 5 of 11 trials were designed to study clinical
outcomes
 Have only recruited babies receiving milk feeds
 Not easy to separate out the smaller more immature
babies
 No study has undertaken stool microbiology to
determine whether the babies are successfully
colonised and how much cross-contamination is
occurring
 All use different products none of which is quality
controlled
Safety
 None of the published studies reports any
complications
 Published reports of lactobacilli and one
case report of B breve septicaemia
 Increased mortality associated with
probiotic use in adults with acute
pancreatitis, Besselink MGH et al., Lancet 2008.
 The babies at highest risk of NEC and
possibly of adverse effects have been
excluded from the studies.
Major outstanding questions
 Will probiotics reduce NEC and death in an
unselected group of very preterm babies?
 Why are probiotics apparently ineffective at
preventing sepsis?
 Is it necessary to give a multi-strain
preparation to gain benefit?
 Is it safe to give probiotics to the babies at
highest risk of NEC?
Objective
To determine whether early administration
of Bifidobacterium breve strain BBG to
preterm infants reduces the incidence of
infection, necrotising enterocolitis and
death.
Why is PiPS different?
 It is statistically powered to study all three
outcomes
 Uses a more stringent definition of sepsis for the
primary outcome
 It has few exclusions and includes babies at high
risk of NEC
 The intervention is started early whether or not
milk feeds have been started
 The intervention is a single bacterial strain
manufactured to high specification and with a CTA
 Stool colonisation with the probiotic bacterium and
the effect on intestinal flora will be studied
What will PiPS deliver?
 Clarity as to whether B breve BBG prevents death,
NEC and blood culture positive sepsis and whether
it is safe in a high risk population of babies
 Unique insight into the importance of ‘colonisation’
as opposed to simple ‘administration’ of probiotic
on efficacy
 Unique insight into the implications of probiotic
usage on a Neonatal Unit for those babies for
whom it is not prescribed
Trial design
Double blind placebo controlled
randomised trial
Primary outcomes
 Any baby with an episode of blood stream
infection, with any organism other than a
skin commensal, diagnosed on a sample
drawn more than 72h after birth and
before death or discharge.
 NEC, Bell stage II or III
 Death before discharge
Secondary outcomes
 A range of infective outcomes including CONs
and numbers of septic screens and stool
colonisation
 Use of antimicrobials
 Time to full feeds and growth
 BPD, ROP, IVH etc.
 Length of stay
 Economic evaluation
Eligibility criteria
 ≤30w +6d at birth
 <48h after birth
 Written informed consent
Exclusion criteria
 Lethal congenital malformation known at
trial entry
 Any known g-i malformation
 No realistic chance of survival
 Babies on antibiotics for suspected or proven infection
are eligible for recruitment
Interventions
Active
 Bifidobacterium breve strain BBG freeze
dried with corn starch re-suspended in 3ml
1/8th strength Neocate: Iml (2.7± 0.5x109 cfu)
to be given once a day starting ASAP after
randomisation and continued to 36w postmenstrual age.
Placebo
 Freeze dried corn starch alone prepared
and administered in the same way.
 Participating staff receive training about
the trial, making up the intervention and
completing the data collection forms
 There is emphasis on avoiding cross
colonisation of the placebo group with the
administered probiotic strain
Clinical management
 Feeding and all aspects of management,
including the decision to omit a dose of the
intervention, are at the discretion of the
local clinicians
Data collection
 Data collection is paper based and
continues till discharge from hospital
 Details of microbiology samples, positive
cultures and details of antibiotic
sensitivities are collected directly from
laboratories
Sample collection
 2 stool samples; as close as possible to
2w post-natal and 36w post-menstrual age
 These samples are posted in a special
container to the microbiology laboratory at
the Royal London Hospital
 No other additional samples are required
Power calculations and statistical significance
 The incidence of all 3 primary outcome
measures is estimated at around 15%
 A trial of 1,300 babies will have 90% power to
detect a 40% reduction in relative risk from 15 to
9%. Likewise if the incidence is nearer 12% we
will still have 90% power to detect a 44% RR
reduction from 12 to 6.7% and from 10 to 5.6%
 For the primary outcomes a 95% Confidence
Interval will be calculated; because there are a
number of secondary outcomes 99% will be
used
Analyses
 Comparative analyses will be by Intention to Treat
 The following pre-specified sub-groups will be
analysed: gestation as per minimisation, male v.
female, whether randomised in the first or second
24h
 A secondary analysis of all clinical and
microbiological outcomes will be conducted by
whether the baby was colonised with B breve BBG
 Logistic regression analysis will be used to study
determinants of successful colonisation with B breve
BBG in the active intervention group
Time-line
 The aim is to recruit 1300 babies over
a 2.5 year period
Practicalities of achieving target
recruitment rates
 NHS R&D approval
 Adequate numbers of staff on the ground
with GCP training who can take consent
 Approvals in ‘networked’ hospitals so that
babies can continue the intervention until
36w pma after returning to the referring
hospital
Summary
 Probiotics are the current best bet for a
preventive intervention against NEC and are
probably safe
 We do not know which organism to use and
which babies to give it to
 PiPS is designed to fill some of the important
gaps in our current knowledge
Thank you
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