International Neonatal Immunotherapy Study INIS What is

International Neonatal Immunotherapy Study (INIS)

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

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

BACKGROUND

Incidence & mortality • Annual incidence 6. 6/1000 live births (Isaacs et al. MJA 1995) • ~ 25% early onset sepsis (< 48 hrs), 75% late 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

Current evidence that IVIG reduces mortality In neonates, IVIG treatment demonstrated a 30% - 37% reduction in all-cause mortality Cochrane reviews (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];

Problems encountered in Cochrane reviews (1) • The confidence intervals were wide and the studies included in the analyses were small and not of high methodological quality. • Problems identified by the reviewers were lack of allocation concealment, lack of blinding of outcome assessment and high levels of post-randomisation exclusions in some of the trials.

Problems encountered in Cochrane reviews (2) 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.

Cochrane reviewers’ conclusions “Large, multi-centre studies are needed to confirm the effectiveness of polyclonal IVIG in reducing mortality in patients with sepsis. These are particularly indicated for neonatal sepsis, where evidence for benefit is still conflicting” “The reduced mortality following treatment with IVIG for subsequently proven infection, the imprecise estimate of the effect size, and the borderline statistical significance for the outcome of mortality in neonates with suspected infection justify further research. Researchers should be encouraged to undertake well-designed trials to confirm or refute the effectiveness of IVIG”

Infection and perinatal brain damage

Cerebral Palsy after preterm rupture of membranes • In babies born after p. PROM 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)

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 (Murphy et al, BMJ 1997) • Cohort study in 923 18 month olds who were VLBW infants (Wheater & Rennie, Dev Med Child Neurol 2000)

Brain damage Infection / inflammation is an important proposed pathway in neonatal brain damage Dammann & Leviton, Pediatrics 1999

Infection & inflammation may lead to: • Release of pro-inflammatory cytokines (in peripheral blood & affected areas of the brain) • • • T-cell activation Release of matrix metallo-proteinases Disruption of blood brain barrier Disruption of oligodendrocyte myelination Cellular apoptosis White matter damage / PVL

Evidence that cytokines cause cerebral injury Increased cytokines (e. g. IL-1 , IL-6, TNF ): • in neonatal blood spots are associated with Cerebral Palsy at 3 yrs of age Nelson et al, Ann Neurol 1998 • in amniotic fluid are associated with cerebral white matter lesions, PVL Yoon et al, 1996, 1997 • In transgenic mice which produce excessive IL-6, no Blood Brain Barrier forms, and there is widespread axonal degeneration and CNS parenchymal injury Brett et al, 1995

Which pathogens have been associated with CP following perinatal infection? • A wide range pathogens have been implicated in the pathogenesis of preterm 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

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)

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)?

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

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 (Ig. G) has potent antiinflammatory properties • Preterm infants may lack an adequate endogenous reservoir of anti-inflammatory Ig. G • This may partly explain their increased risk of brain damage and cerebral palsy

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 p. H 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.

RESEARCH PLAN

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 site or - on respiratory support by ETT and Receiving antibiotics Exclusions: already had IVIG or IVIG considered necessary or contraindicated

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

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.

Eligibility Case Scenarios • 28 weeks GA, B Wt 980 g, born after p. PROM of 48 hrs; Day 1, ventilated, poor response to surfactant, on antibiotics for suspected sepsis • Eligible for INIS because of – Suspected neonatal sepsis (after p. PROM, which increases the risk of brain injury/CP) – Birthweight <1500 g – Receiving antibiotics

Eligibility Case Scenarios • 38 weeks GA, B Wt 2700 g, Day 4, Caesarean section for non-progression of labour, fits on postnatal ward, LP yields turbid CSF, latex +ve for pneumococcus, on antibiotics • Eligible for INIS because of –evidence of infection in usually sterile body fluid (CSF)

Eligibility Case Scenarios • 31 weeks GA, B Wt 1450 g, mother had fever >39 C and uterine tenderness, maternal CRP =15 mg/L, antibiotics started before delivery. Day 1: not ventilated, infant pyrexial 38 C, on antibiotics. • Eligible for INIS because of – Suspected neonatal sepsis (after clinical chorioamnionitis, which increases the risk of CP) – Birthweight <1500 g – Receiving antiobiotics

Eligibility Case Scenarios • 40 weeks GA, B Wt 3800 g, vaginal swab +ve for GBS. Day 1: grunting, on CPAP, Fi. O 2 > 60%, ventilated, poor activity, screened for infection, antibiotics started • Eligible for INIS because – Suspected serious infection – Ventilated – Receiving antibiotics

Eligibility Case Scenarios • 24 weeks GA, 580 g, Day 17: 3 rd episode of suspected sepsis - not recruited to INIS before, ventilated, long line - blood culture growing Staph epidermidis, on vancomycin and cefotaxime • Eligible for INIS because of – Proven serious infection (clinical evidence of sepsis with Staph epidermidis, which is associated with increased duration of hospitalisation and morbidity) – Birthweight <1500 g – Receiving antiobiotics

Eligibility Case Scenarios • 32 weeks GA, no chorio-amnionitis, no p. PROM, B Wt 1600 g, in air, day 1, on antibiotics pending results of blood cultures • NOT eligible for INIS because – no evidence of suspected clinical sepsis with potentially serious sequelae – birth weight > 1500 g, no evidence of infection, not ventilated

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.

Sample size • • 5, 000 infants will be recruited to INIS • 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 This will provide over 90% power (2 p = 0. 05) to detect a difference from 25% versus 21% in the rate of primary outcome between IVIG & control groups > 80% power to detect important treatment differences stratified by initial mortality risk

Economic evaluation • An economic evaluation will be performed in Australia and New Zealand. • If hypothesis is confirmed, INIS is likely to be cost-saving

PRACTICALITIES

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

Central Coordination INIS Coordinating Centre (A&NZ) NHMRC Clinical Trials Centre University of Sydney Ph: 02 9562 5335 Fax: 02 9565 1863 Email: inis@ctc. usyd. edu. au Project Coordinator: Anne Cust Clinical Trials Research Assistant: Megan Hay

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 arrange 2 year follow-up appointments • All other study costs are covered by INIS

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

Recruitment Procedures (1) • • Information Sheet on admission or when eligible • • Contact pharmacy • • Ensure 2 nd infusion is given 48 hrs later If baby becomes eligible, seek parental consent in person or by telephone if necessary Caregiver completes Entry Form booklet & administers 1 st infusion Fill in simple Drug Accountability Form and Enrolment Log

Recruitment Procedures (2) • Fax copy of Entry Form to INIS Coordinating Centre ASAP • Local INIS research coordinator completes remaining CRFs, and ensures complete data until discharge home from this or another hospital • No further IVIG can be given

Serious Adverse Events (SAEs) • If a serious adverse event is unexpected, then an SAE form must be completed and sent to the INIS Coordinating Centre (NHMRC Clinical Trials Centre, Uni of Sydney) within 24 hours of identification • The Coordinating Centre will ensure that the regulatory authorities are informed • The local investigator should inform their own hospital’s ethics committee of SAEs • The SDMC will evaluate interim data in strict confidence to ensure the safety of patients

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.

Follow-up is very important!! • • 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)

Conclusion • • INIS is a simple, pragmatic study that will address an issue of fundamental public health and strategic importance in neonatal care Assessment of neuro-developmental status in survivors is essential if neonatal trials are to contribute fully to evidence-based policy