1. International Neonatal Immunotherapy Study (INIS)

2. An international, placebo-controlled, multi-centre randomised trial Aust / NZ Coordinating Centre at the NHMRC Clinical Trials Centre, University of Sydney Main INIS Coordinating Centre is at the National Perinatal Epidemiology Unit, Oxford, UK What is INIS?

3. Primary hypothesis that adding non-specific polyclonal intravenous immunoglobulin (IVIG) to standard antibiotic therapy in suspected or proven serious infection of early or late onset reduces death and/or major disability at two years of age

4. Incidence & mortality Annual incidence 6.6/1000 live births (Isaacs et al. MJA 1995) ~ 25% early onset sepsis ( 48 hrs) ANZNN 2000 Report: 14% of cohort had clinically proven systemic infection, with 15% all-cause mortality & 6% mortality due to infection Sepsis is often undiagnosed, so incidence & sepsis-specific mortality rates may be unreliable

5. (1) Intravenous immunoglobulin for suspected or subsequently proven infection in neonates; Ohlsson A, Lacy JB; Issue 2, 2003 6 studies, N = 318, RR = 0.63 [95% CI 0.40 – 1.00] (2) Intravenous immunoglobulin for treating sepsis & septic shock; Alejandria M, Issue 2, 2003 Adults: 6 studies, N = 251, RR = 0.62 [95% CI 0.49 – 0.79]; Neonates: 5 studies, N=241, RR = 0.70 [95% CI 0.42 – 1.18]; In neonates, IVIG treatment demonstrated a 30% - 37% reduction in all-cause mortality Current evidence that IVIG reduces mortality Cochrane reviews

6. Disability in survivors: an unanswered question No comparisons of morbidity or disability in survivors were available in the Cochrane Reviews. Without such data, it may not be ethical to introduce IVIG into routine practice. Follow-up?

7. Cerebral Palsy after preterm rupture of membranes In babies born after pPROM and before 32 weeks gestation, cerebral palsy was twice as likely, after adjusting for gestation RR 2.3 [ 1.3 - 4.2 ] If the mother had clinical chorio-amnionitis, cerebral palsy was four times more likely, after adjusting for gestation RR 4.2 [ 1.4 - 12.0 ] (Murphy et al, Lancet 1995) (Wu et al, JAMA, 2000)

8. CP after neonatal sepsis Cerebral palsy was four times more likely after neonatal sepsis in preterm infants Population-based case control study in 293 3-5 year olds born before 32 weeks gestation Cohort study in 923 18 month olds who were VLBW infants (Wheater & Rennie, Dev Med Child Neurol 2000) (Murphy et al, BMJ 1997)

9. Which pathogens have been associated with CP following perinatal infection? A wide range pathogens have been implicated in the pathogenesis of pre- term brain injury and Cerebral Palsy These include Coagulase Negative Staphylocci which were associated with subsequent CP in a preliminary study by Mittendorf et al Lancet 1999

10. IVIG in other conditions Widely used in inflammatory and autoimmune conditions to improve clinical function (e.g. Kawasaki Disease, Idiopathic Thrombocytopenic Purpura, chronic demyelinating inflammatroy polyneuropathy etc.) Multiple Sclerosis: IVIG reduced number and size of inflammatory cerebral lesions, including existing lesions Sorensen et al. Neurology 1998 Beneficial effect on clinical disability (Fazekas et al, Lancet, 1997) and relapses (Clegg et al, Health Tech Assess 2000)

11. Duggan et al, Lancet 2001 36% of babies born before 30 weeks gestation had MRI cerebral lesions on scans done at a median 2 days after birth The risk of cerebral lesions increased after – raised maternal CRP – preterm rupture of membranes Could postnatal IVIG benefit pre-existing cerebral inflammation (as in adult MS)?

12. IVIG: Mechanisms of action IVIG has multiple anti- inflammatory properties & mechanisms of action (indicated by purple arrows on the next slide)

14. Safety of IVIG Intragam® P (IVIG in Aust & NZ) uses plasma from non-remunerated Australian/NZ donors. 2 specific viral inactivation steps, pasteurisation and low pH incubation. No transmitted infections have ever been recorded using Intragam® P, or its predecessor Intragam®. The risk of transmission of a virus is estimated by CSL as less than 1 in 10 million (which is 100 times safer than a blood transfusion). In trials of prophylactic IVIG involving more than 5000 infants, no serious adverse effects were reported.

15. Summary Neonatal sepsis causes significant mortality and morbidity Cerebral injury may be caused, in part, by an excessive inflammatory response to bacterial, viral or fungal antigens Immunoglobulin (IgG) has potent anti- inflammatory properties Preterm infants may lack an adequate endogenous reservoir of anti-inflammatory IgG This may partly explain their increased risk of brain damage and cerebral palsy

16. Eligibility criteria Proven or suspected serious infection and - less than 1500 g birth weight or - has evidence of infection in blood or CSF or a normally sterile siteor - on respiratory support by ETT and Receiving antibiotics Exclusions: already had IVIG or IVIG considered necessary or contraindicated

17. A pragmatic approach inactivity unresponsiveness poor perfusion prolonged bleeding ileus bowel perforation or definite NEC [ SEVERE SIGNS, HIGH RISK GROUP ] pneumonia white cells < 5000/  l platelets < 50,000/  l CRP > 15 mg/l pathogen in blood or CSF [ MODERATE SIGNS, MEDIUM RISK GROUP ] clinical chorioamnionitis, PROM or maternal CRP > 8 mg/ L very likely to need, or has had, 5 days antibiotics As a guide, serious infection may include any of:

18. What is serious infection ? Sepsis is a systemic inflammatory response of the body to severe infection caused by various micro-organisms such as bacteria, fungi or viruses. … Alejandria, Lansang, Dans, Mantaring. Cochrane Library, Issue 1, 2002 Over 50 clinical and laboratory criteria have been used to describe neonatal sepsis, so a precise definition is not practical.

19. Statistical analyses Intention-to-treat analysis of all babies randomised to IVIG vs placebo Subgroup analyses will stratify by birthweight, gestation, clinical severity, clinical chorioamnionitis, small for gestation, elevated maternal CRP, duration of membrane rupture, type of infection, and type of IVIG.

20. Sample size 5,000 infants will be recruited to INIS This will provide over 90% power (2p = 0.05) to detect a difference from 25% versus 21% in the rate of primary outcome between IVIG & control groups This would give a ‘Number needed to treat’ (NNT) to prevent one case of death or major disability, of 25 1500 recruited in Australia and New Zealand > 80% power to detect important treatment differences stratified by initial mortality risk

21. Funding & support Funding: UK Medical Research Council New Zealand Health Research Council NHMRC - pending Financial Markets Foundation for Children Telstra Foundation Ian Potter travel grant INIS has the additional support of: Australian Red Cross Blood Service & New Zealand Blood Service (who distribute the IVIG) the Commonwealth (who have given us a free and reserved supply of IVIG for the study in Australia) CSL (who make Intragam® P) NHMRC Clinical Trials Centre

22. Local Coordination Each participating hospital nominates a Principal Investigator and a Research Nurse Coordinator to help locally coordinate INIS The INIS research nurse is funded to work several hours a week on INIS, to help identify eligible babies discuss the study with parents & medical staff complete the data forms and data queries help maintain contact with families help with follow-up until 2 years of age All other study costs are covered by INIS

23. Intervention Prepared by pharmacist [Pharmacy play a key role in the team] Intravenous infusion of 500 mg/ kg (8.3 ml/ kg) Intragam  P or placebo solution over 4 – 6 hours, repeated after 48 hours Pharmacist primes line, yellow contact mask Double-blind No more IVIG can be given

24. Outcomes PRIMARY Death or major disability at 2 years corrected for gestational age SECONDARY hospital mortality, chronic lung disease or major cerebral abnormality before hospital discharge, significant positive culture after trial entry, pneumonia, necrotising enterocolitis, duration of respiratory support, mortality before two years, major disability at 2 years, non-major disability at 2 years, length of hospital stay and number of hospital admissions.

25. Follow-up Parents receive a Discharge letter (with contact numbers, change of address slip & Reply Paid envelope) & optional letter for their GP Local research coordinator & central INIS Coordinator keep in touch with parents Parent Newsletters, birthday cards, 1 st year questionnaire 2 year follow-up corrected for GA includes parent questionnaire, paediatrician questionnaire, (& Bayley II Scales at many ANZ centres)