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International Neonatal Immunotherapy Study

The International Neonatal Immunotherapy Study (INIS) investigates the hypothesis that administering non-specific polyclonal immunoglobulin reduces death and major disability in infants with serious sepsis receiving antibiotics. Currently in its fifth year, including 3,286 participants across 97 centers globally, this randomized controlled trial aims to enroll at least 3,500 babies. Background research indicates that neonatal sepsis significantly increases the risk of long-term neurological issues. With ongoing MRC funding, the trial seeks to provide clarity on the benefits of IV immunoglobulin in these vulnerable populations.

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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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