David's New Book

Tuesday, November 2, 2010

Ear Infection - Antibiotics Work!




The data are in!  The NIH funded placebo-controlled trial of augmentin vs. placebo in children ages 6 months to two years with well documented otitis media (AOM) shows that antibiotics work at some cost of increased adverse events.  In this study, careful tympanography (assessing the swelling, redness and lack of movement of the tympanic membrane) was carried out to document that patients had acute otitis media usually caused by bacterial pathogens and not the confusing, and usually non-bacterially caused serous otitis.  A drawback of the study was that ear punctures were not performed – but even as it was, it took three years to complete enrollment.

The study enrolled 291 patients of whom 284 completed therapy. The only serious adverse events in the trial included one case of mastoiditis and one of pneumonia in the placebo arm. There was an increased incidence of diarrhea, diaper rash and thrush in the antibiotic treated group. Although the overall protocol-defined time to resolution of symptoms did not differ between groups, the antibiotic group did have a significantly faster rate of durable resolution of symptoms (symptoms resolved over two questioning periods = 24 hours) than the placebo group.  23% of placebo treated patients were clinical failures compared to 3% of antibiotic treated subjects at the on therapy visit (within 72 hours).   16% of antibiotic-treated patients and 51% of placebo patients were failures at end of therapy (7 days).  These data establish a treatment effect of 11% during the first 72 hours and 35% during the 7 days of therapy. The latter number should establish a reasonable NI margin for non-inferiority trials in otitis media with an endpoint of 7 days. Although not powered for this result, it is possible if not likely that antibiotics would prevent complications such as mastoiditis and pneumonia in patients with AOM. Since this study is contemporary, there is little justification for the usual discounting in defining the NI margin for a non-inferiority trial as usually practiced by the FDA. A 10% margin seems justified and reasonable.

Hopefully, this should be the last placebo-controlled trial needed for acute otitis media in young children.  The data show that when this diagnosis is established carefully, even in the absence of clear microbiological culture confirmation (which would have required puncture of the ear drum for culture), antibiotic therapy is superior to placebo.  It also confirms what most parents already knew – that symptoms resolve more quickly and completely when antibiotics are given than when they are withheld.  One plausible and likely explanation for the failure of previous trials to show a difference between antibiotic therapy and placebo in acute otitis media is the lack of a clear and consistent diagnosis using tympanography.

The current FDA and EMEA guidances require that placebo controlled trials be used to study the efficacy of antibiotics in acute otitis media.  The data provided by this NIH-sponsored trial belie the basis for the regulatory guidance by demonstrating a clear antibiotic effect.  Where do we go from here?  Is there a sponsor out there who would like to rediscuss phase 3 trial design with the FDA or EMEA?  Sanofi-Aventis?
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