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Effect of Mass Distribution of Azithromycin for Trachoma Control on Overall Mortality in Ethiopian Children: A Randomize

This study evaluates the effect of mass distribution of azithromycin on overall mortality in Ethiopian children. The trial examines the efficacy of different treatment frequencies and the impact on trachoma infection rates. The results indicate a significant reduction in mortality with mass azithromycin treatment.

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Effect of Mass Distribution of Azithromycin for Trachoma Control on Overall Mortality in Ethiopian Children: A Randomize

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  1. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial Travis C. Porco FI Proctor Foundation UCSF 18 April 2018

  2. Mass treatment for an ophthalmological infection • Mass administration of azithromycin is the cornerstone of trachoma elimination • The infection: Chlamydia trachomatis

  3. TANA Trial • TANA trial: Trachoma Amelioration in Northern Abyssinia • Lietman Group NIH/NEI U10 conducted in Ethiopia

  4. Where? Where?

  5. Trial

  6. TANA Specific Aims • Annual vs Biannual treatment to reduce trachoma infection at village level (PCR) • Demonstrate efficacy of quarterly treatment of children (at village level); herd effect • Determine efficacy of intensive latrine construction in trachoma prevention • Determine whether or not azithromycin use changes mortality in children • Compare trends in macrolide resistant pneumococcus

  7. What is a community? Sentinel state team State teams A A A A A A Subkebele

  8. Enumerative census • The trial began with an enumerative census of all subkebeles (before randomization). • For all subkebele in the first two specific aims, we conducted a second enumerative census one year later, which formed the basis for the mortality study of Specific Aim 4.

  9. Trial

  10. Available mortality data One-year mortality data available for three treatment groups-- Annual Biannual (twice yearly) Children-quarterly AND for the Delayed group who were not treated

  11. Outcome • Compare mortality in the treated arms vs the control arm, in children aged 1-9

  12. Statistical considerations • Cluster-randomized--we can not treat the individuals in a community as independent. • We randomized at the subkebele level and therefore analyze at the subkebele level. • Poisson or negative binomial regression, or similar methods • Prespecified hypothesis test

  13. Trial

  14. TANA • May 2006 to March 2007 • 66,404 people in 48 subkebele • Annual: 50 state teams; 4,437 children • Biannual: 61 ST; 4,462 children • Children Qt: 49 ST; 4,150 children • Delay: 57 ST; 5,166 children

  15. Table 1 Age Fem Alt Dist Acc JAMA 302(9):962-968, 2009

  16. Table 2

  17. Death rates

  18. Hypothesis test • Null hypothesis: mortality rates same in treatment and control groups • Method: negative binomial regression • P=0.01 • Relative rate 0.50 • Several slightly different ways to do this; details omitted

  19. Effect • 50%? • Is this too good to be true?

  20. Questionnaire • We asked experts what they thought • Quantified uncertainty • Estimate median value • Upper and lower credible interval

  21. Expert opinion

  22. Why was TANA not definitive? • Effect size larger than expected • Small trial—only 82 deaths • No placebo control • Timing of deaths not ascertained • Dose response not seen (but not powered) • Real value—justify larger trial • Questionnaire—power for 15%

  23. MORDOR Trial • Placebo controlled • Double masked • Malawi, Niger, Tanzania • Major funding: BMGF. Placebo donated by Pfizer.

  24. MORDOR • 1512 communities • 190,238 children at baseline

  25. MORDOR • Azithromycin or placebo, every six months, to ages 1-59 months • Enumerative census • Present on one census, absent on the next due to death

  26. MORDOR • “Large Simple” design • Trade bias for noise, and average away the noise

  27. MORDOR • Census began December 2014. • Four waves conducted. • Database locked 15 Oct 2017.

  28. MORDOR • Did we fail to find evidence of a treatment effect of mass azithromycin? • Or did we find evidence of a treatment effect? • Final results under embargo until 25 April 2018.

  29. Acknowledgments • Study participants, DSMC, TANA Team • Major funding from US NIH National Eye Institute

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