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

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