1. International Neonatal Immunotherapy Study

2. Co-ordinating Centre National Perinatal Epidemiology Unit Oxford www.npeu.ox.ac.uk/inis

3. INIS is funded by the Medical Research Council

4. INIS - hypothesis The addition of non-specific polyclonal immunoglobulin reduces death and major disability in infants receiving antibiotics for serious sepsis

5. International randomised controlled trial evaluating the use of intravenous immunoglobulin (IVIG) for the reduction of death or disability in infants with sepsis INIS – the reality

6. Current Status 5th year of study 3286 babies recruited (at 27/03/07) 48 centres in UK 21 Argentina 17 Australia 2 New Zealand 8 Europe

7. Future MRC funding awarded to extend recruitment until Summer 2007 97 centres worldwide Target of at least 3500 babies

8. Background

9. Neonatal sepsis Incidence6.6 per 1000 live births 1 15.4 per 1000 VLBW 2 Death VLBW 14% -21% 3 All 10 -14%

10. Sepsis and neurodevelopment Studies show a strong association between intrauterine sepsis and both cPVL and cerebral palsy 5 In addition there is evidence to show a link between postnatal infection and cerebral palsy 6

11. Intrauterine sepsis and neurodevelopment Babies born to mothers with clinical chorioamnionitis have a statistically significant higher risk of developing cerebral palsy 5 –Term infants – RR 4.7 (1.3,16.2) –Preterm infants – RR 1.9 (1.4-2.5)

12. Postnatal sepsis and neurodevelopment Postnatal infection is associated with an increased risk of cerebral palsy (after adjustment for gestational age) 6 OR 3.6 (1.8, 7.4)

13. Treatment for sepsis Newborn infants, especially if small or preterm, may be deficient in immunoglobulin (IgG) IVIG provides IgG which has potent anti- inflammatory and immuno-modulatory properties This makes it an attractive adjunctive treatment for sepsis in all babies, not just the preterm population

14. Evidence

15. Systematic Reviews Intravenous immunoglobulin for preventing infection in preterm and low birth weight infants Ohlsson A, Lacy JB. In: The Cochrane Library, Issue 1, 2003. Intravenous immunoglobulin for suspected or subsequently proven infection in neonate Ohlsson A, Lacy JB. In: The Cochrane Library, Issue 1, 2003. Intravenous immunoglobulin for treating sepsis and septic shock Alejandria MM, Lansang MA, Dans LF, Mantanng JBV. In The Cochrane Library, 2003.

16. Cochrane systematic review– IVIG for prevention of infection 19 RCTs, 5054 infants Results: –Reduction in sepsis - RR 0.85 (0.74-0.98) –No effect on death No major adverse effects from immunoglobulin

17. Cochrane systematic review– IVIG for treatment of infection Suspected infection 6 RCTs, n=318 Reduction in death not statistically significant RR 0.63 (0.4,1.00) Proven infection 7 RCTS, n=262 Statistically significant reduction in death RR 0.55 (0.31,0.98)

18. Cochrane systematic review– IVIG for treatment of infection Criticisms of RCTs based on : –Small size; 22-82 infants per study –Poor study designs –Lack of placebo group –Absence of blinding

19. Cochrane SR – suspected infection

20. Cochrane SR– proven infection

21. Cochrane systematic review – IVIG for treatment of sepsis or septic shock 11 RCTs, 492 patients (any age) Results: –All ages - reduction in all cause death –RR 0.64 (95% CI 0.51-0.80) –Neonates – no statistically significant difference –RR 0.70 (0.42,1.18)

22. Summary of evidence Insufficient and weak evidence to support use of immunoglobulin for prevention or treatment of sepsis Large RCT needed to test hypothesis

23. Study Design

24. Study design ‘The randomised double-blind controlled trial is usually taken as the ‘gold standard’ against which to judge the quality of the design of a trial.’ The design of INIS adheres to these principles

25. Study design Randomisation: –Controls for known and unknown confounders –Ensures treatment allocation is unbiased at the start of the trial

26. Study design Randomisation –Drug packs are pre-randomised and kept on unit –So no phone calls to randomise an eligible baby! –Selecting the lowest numbered drug pack will ensure randomisation is intact

27. Study design Placebo-controlled –The placebo is a weak solution of albumin –It is identical in appearance to the IVIG both in its reconstituted form and in its packaging

28. Study design Blindness –INIS is a double-blind trial –Neither the attending medical staff nor those evaluating outcomes will know which treatment has been given –This avoids any bias whilst the study is being run

29. Eligibility Criteria Receiving antibiotics and suspected or proven serious sepsis AND At least one of the following:  birth weight less than 1500g  receiving respiratory support via an endotracheal tube  evidence of infection in blood culture, CSF or usually sterile body fluid

30. AND There is substantial uncertainty that IVIG is indicated Eligibility

31. Exclusion criteria IVIG already given* IVIG thought to be needed or contraindicated * Specific IVIG

32. IVIG for specific indications should be given as per hospital policy and these infants will still be eligible –Hepatitis B immunoglobulin –Varicella-Zoster immunoglobulin

33. Eligibility - age Babies at any age whilst resident on NICU After discharge babies are eligible until EDD plus 28 days

34. Consent Consent must be fully informed and obtained before randomisation Use the Patient Information Leaflet –This is for relevant for all parents whose baby is admitted to NICU –It gives a simple and accurate description of the study Direct parents to website or INIS contact

35. Intervention IVIG group Intravenous infusion of IVIG 500 mg / kg (10ml/kg) over 4 - 6 hours, repeated 48 hours later Control group Intravenous infusion of 10 ml / kg of placebo (0.2% albumin solution), repeated 48 hours later

36. IVIG Plasma from non-UK donors Produced by Scottish National Blood Transfusion Service Tested for HIV 1,2 and Hepatitis A,B,C Excellent safety record Few adverse reactions

37. Placebo 0.2% albumin Identical appearance to IVIG Safety record as for IVIG

38. Death or Major disability at 2 years corrected age Primary Outcome

39. Secondary Outcomes Short term –Death, chronic lung disease or major cerebral abnormality before hospital discharge –Significant positive culture after trial entry –Pneumonia –NEC –Duration of respiratory support

40. Secondary Outcomes Long term –Death before 2 years –Major disability at 2yrs –Non-major disability at 2yrs

41. Parent questionnaire Paediatrician questionnaire Completed at 2 year appointment Follow-up

42. If you have any queries please contact : Clare Shakeshaft INIS Study Co-ordinator 01865 289741 inis@npeu.ox.ac.uk www.npeu.ox.ac.uk/inis