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

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

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 logs Day 2-14 mean decrease in cfu logs Jindani. ARRD 1980;121:939

Fall in CFU during Chemotherapy  cfu 0-2  cfu 2-14 Nil-0.02 H R 10 per kg S 1g E 25 per kg Z 2g

Nairobi EBA Study First 2 days of therapy - significant differences identified between drugs Days 2-14 differences between drugs was smaller & less frequently statistically significant ARRD 1980; 121: 939; AJRCCM 2003; 167: 1348

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)

Response to TB Treatment

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

EBA for Current Drugs S. African MRC EBA Studies DRUGEBA 0-2EBA 2-5 INH OFL EMB0.25 RMP CIP0.21 STM0.13 RBT0.08 AMIK0.05 PZA0.003

EBA in Different Studies DrugStudyEBA INHJindani ’ Chambers ’ Gosling ’ Dietze ’ RMPChan ’ RMPSA MRC0.20 RBTChan ’ RBTSA MRC0.08 CIPROKennedy ’ CIPROSA MRC0.21 OFLOChambers ’ MXFGosling ’030.53

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

Source of Variability in EBA Studies In 8 studies from S Africa, overall variability was 0.03 log 10 cfu/ml/day –due to laboratory processing –due to pt characteristics & sputum collection EBA is reproducible; greatest source of variation is interpatient variation due to disease characteristics & sputum sampling

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

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

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

Contemporary EBA Study Design 1.Newly Dx, sputum smear + TB; pts per arm 2.No recent Rx w/ drugs w/ known anti-TB activity 3.Pts w/ severe TB (miliary, meningeal) excluded 4.Treatment w/ monotherapy for up to 7 days acceptable to IRBs, then all treated w/ std chemotherapy

Contemporary EBA Study Design 5.Able to produce adequate amounts of sputum 6.Daily overnight sputum collections w/ 2 pretreatment collections 7.INH 300 comparator group useful 8.PK sampling 9.Pre- and post-Rx drug susceptibility

Types of Trials

Use in Dose Ranging

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

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

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

Use in Comparing Different Drugs in a Class

EBA Day 0 to 2 95% CI for Mean Drugn Mean EBA SD Lower Bound Upper Bound INH Levo Gati Moxi

EBA Day 2 to 7 95% CI for Mean Drugn Slope B2-7SD Lower Bound Upper Bound INH Levo Gati Moxi

Use in Evaluating Combinations

Fall in CFU during Chemotherapy  cfu 0-2  cfu 2-14 H SH EH RH HZ Am Rev Respir Dis 1980;121:939

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

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

Two Drug Combination EBA > HRZE XH HRZE XR HRZE XZ HRZE XEXSHRZE

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

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

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