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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.
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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
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 Source: The EPICure studies
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 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
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 post-menstrual 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
