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International Neonatal Immunotherapy Study

International Neonatal Immunotherapy Study. Co-ordinating Centre. National Perinatal Epidemiology Unit Oxford www.npeu.ox.ac.uk/inis. INIS is funded by the Medical Research Council. INIS - hypothesis.

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International Neonatal Immunotherapy Study

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

  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 • Incidence 6.6 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 palsy5 • 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. 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) Cochrane systematic review– IVIG for treatment of infection

  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. Eligibility AND There is substantial uncertainty that IVIG is indicated

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

  32. *Specific IVIG • 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. Primary Outcome • Death or • Major disability at 2 years corrected age

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

  42. If you have any queries please contact :Clare Shakeshaft INIS Study Co-ordinator01865 289741inis@npeu.ox.ac.ukwww.npeu.ox.ac.uk/inis

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