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International Neonatal Immunotherapy Study (INIS)

Sir Richard Doll Controlled trials: the 1948 watershed BMJ 1998: 317: Sir Richard Doll Controlled trials: the 1948 watershed BMJ 1998: 317: “Early randomised trials (1940s) can properly be criticised on the grounds that they were often too small to have any chance of detecting moderate effects. “Small trials can be successful when the effect is large but this seldom occurs.“

“It was many years before randomisation was accepted as such a normal procedure.

“Only then (1980s) did it become possible to organise the groundbreaking international study of infarct survival (ISIS) trials for the treatment of myocardial infarction, which involved hundreds of centres and randomly allocated tens of thousands of patients, and thereby showed the value of moderate improvements in the treatment of common diseases.”

Impact of progressive, moderate benefits on deaths from myocardial infarction in 10 years ISIS-1 (n = 16,000) 13% Mortality in placebo group Mortality in best treatment arm ISIS-28% ISIS-47% more than threefold increase in sample size between ISIS-1 and ISIS-4

Number Needed to Treat for statins to avoid coronary heart disease or death For ~ every 50 hypertensive men aged 55 who take daily statins, one fewer will suffer a coronary event or death in the next 10 years.

Power calculations to detect large or moderate treatment effects with 90% power at 2p = 0.05 Adverse outcome in controls (C) Adverse outcome in treatment group (T) Absolute risk difference (C-T) Total sample needed (both groups) 30%20%10%824 20%15%5%2,502 25%21%4%4,748 30%26%4%5,392 15%13%2%~17,000

If premature newborns are to benefit from evidence as reliable as in cardiology, much larger numbers are needed –i.e. thousands, not hundreds

Thank you! With nearly 1900 babies recruited, INIS –is the largest MRC multi-centre neonatal trial –quadruples the number of patients in the meta- analysis of IVIG for neonatal sepsis –is a model for national and international collaboration in neonatal trials –participants are making an important academic and scientific contribution to neonatal medicine.