Role(s) of EBA Studies – Substitute for Dose Ranging

1. Role(s) of EBA Studies – Substitute for Dose Ranging JL Johnson, MD Case Western Reserve Univ

2. Quantitative Culture in Response to TB Treatment Mitchison. Thorax 1950;5:144

3. Nairobi EBA Study • 27 regimens of single drugs or combinations • Sputum cfu on day -2, -1, 2, 4, 6, 8, 10, 12, 14 days • Day 0-2 mean decrease in cfu 0.422 logs • Day 2-14 mean decrease in cfu 0.129 logs Jindani. ARRD 1980;121:939

4. Fall in CFU during Chemotherapy

5. Bacillary Killing During Early Treatment • Phase 1 (Day 0-2) Rapid, exponential killing of rapidly dividing organisms. Rate determined by action of drug on log phase bacilli • Phase 2 (Day 2 and beyond) – killing of slowly dividing bacilli; sterilizing action of drugs; rate determined by bacterial metabolism & rapidity of action of drug(s)

6. Response to TB Treatment

7. EBA • EBA = EBA 0-2 – penetration into lesions & bactericidal action against rapidly dividing bacilli • Extended EBA = EBA 2-7 – rough estimate of possible sterilizing activity

8. EBA for Current Drugs S. African MRC EBA Studies DRUG EBA 0-2 EBA 2-5 INH 0.60 0.06 OFL 0.39 0.17 EMB 0.25 RMP 0.20 0.30 CIP 0.21 STM 0.13 RBT 0.08 AMIK 0.05 PZA 0.003

9. EBA in Different Studies Drug Study EBA INH Jindani ’80 0.72 Chambers ’98 0.60 Gosling ’03 0.77 Dietze ’05 0.67 RMP Chan ’92 0.29 RMP SA MRC 0.20 RBT Chan ’92 0.05 RBT SA MRC 0.08 CIPRO Kennedy ’93 0.20 CIPRO SA MRC 0.21 OFLO Chambers ’98 0.32 MXF Gosling ’03 0.53

10. Sources of Variation between Patientsin the Same EBA Study • EBA unrelated to age, sex, weight, HIV status • EBA correlated w/ radiographic severity of disease, cavitary disease in 2 studies

11. Source of Variability in EBA Studies • In 8 studies from S Africa, overall variability was 0.03 log10 cfu/ml/day • due to laboratory processing 0.0011 • due to pt characteristics & sputum collection 0.0212 • EBA is reproducible; greatest source of variation is interpatient variation due to disease characteristics & sputum sampling

12. Risk of Acquired Drug Resistancein EBA Studies • Not examined carefully in all studies, but appears to be low • Only 1 pt in studies to date (over 880 patients)

13. Need for Untreated Nil Group • Weighted mean EBA 0-2 for nil in 9 studies was 0.00036 • Can test drug arms vs. zero. Should measure pretreatment cfu for 2 days for pts Sirgel. J Antimicrob Chemother 2001;47:177.

14. Need for INH Comparator Group • Mean EBA 0-2 for INH 300 was 0.575 (95% CI 0.515-0.636) • INH 300 arm useful as positive comparator & to assess whether assay is working Sirgel. J Antimicrob Chemother 2001;47:177.

15. Contemporary EBA Study Design • Newly Dx, sputum smear + TB; 10-12 pts per arm • No recent Rx w/ drugs w/ known anti-TB activity • Pts w/ severe TB (miliary, meningeal) excluded • Treatment w/ monotherapy for up to 7 days acceptable to IRBs, then all treated w/ std chemotherapy

16. Contemporary EBA Study Design • Able to produce adequate amounts of sputum • Daily overnight sputum collections w/ 2 pretreatment collections • INH 300 comparator group useful • PK sampling • Pre- and post-Rx drug susceptibility

17. Types of Trials

18. Use in Dose Ranging

19. Example of possible use of EBA (0-2) to identify doses to be further evaluated Donald. AJRCCM 1997;156:895

20. EBA 0-2 of INH, Rifampicin and Streptomycin Sirgel. AJRCCM 2005;172:128.

21. EBA - RMP & Rifapentine Sirgel. AJRCCM 2005;172:128

22. Use in Comparing Different Drugsin a Class

23. EBA Day 0 to 2

24. EBA Day 2 to 7

25. Use in Evaluating Combinations

26. EBA of Drug Combinations Am Rev Respir Dis 1980;121:939

27. What Might Be Learned from Combination EBA Studies? • Drug-drug interactions • Synergy vs antagonism vs indifference • Increased toxicity

28. Two Drug Combination EBA

29. EBA Method - Advantages • Reproducible; small # of pts required • Can detect significant differences between drugs during the initial days of administration • Drugs can be compared with one another • Different doses can be evaluated to define dose for phase 2b & 3 trials • PK can be compared to bactericidal activity • Short term toxicity in humans with TB can be evaluated

30. EBA - Disadvantages • May not tell us much about sterilization by a drug or regimen as later measurements. • Not useful for some drugs. Rifampin & PZA have little & no EBA but are best current sterilizing drugs. • Less valuable for comparing regimens particularly in combination w/ INH • Little experience w/ EBA of drugs that accumulate or are given infrequently

31. EBA Study of New Drug • Evaluate highest tolerable dose based on initial toxicology data • If EBA 0-2 less than 0.2, further EBA studies unlikely to be helpful • If EBA 0-2 significant, conduct dose ranging studies to define therapeutic margin • Do PK sampling of all subjects