role(s) of eba studies – substitute for dose ranging jl johnson, md case western reserve univ
DESCRIPTION
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;121:939TRANSCRIPT
Role(s) of EBA Studies – Substitute for Dose Ranging
JL Johnson, MDCase Western Reserve Univ
Mitchison. Thorax 1950;5:144Mitchison. 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 0.422
logs• Day 2-14 mean decrease in cfu 0.129
logsJindani. ARRD 1980;121:939
Fall in CFU during Chemotherapy cfu 0-2 cfu 2-14
Nil -0.02 -0.02H 300 0.72 0.11R 10 per kg 0.19 0.10S 1g 0.09 0.13E 25 per kg 0.25 0.16Z 2g 0.04 0.11
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
DRUG EBA 0-2 EBA 2-5
INH 0.60 0.06OFL 0.39 0.17EMB 0.25RMP 0.20 0.30CIP 0.21STM 0.13RBT 0.08AMIK 0.05PZA 0.003
EBA in Different StudiesDrug Study EBA INH Jindani ’80 0.72
Chambers ’98 0.60Gosling ’03 0.77Dietze ’05 0.67
RMP Chan ’92 0.29RMP SA MRC 0.20RBT Chan ’92 0.05RBT SA MRC 0.08
CIPRO Kennedy ’93 0.20CIPRO SA MRC 0.21OFLO Chambers ’98 0.32MXF Gosling ’03 0.53
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 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
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)
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.
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.
Contemporary EBA Study Design1. Newly Dx, sputum smear + TB; 10-12
pts per arm2. No recent Rx w/ drugs w/ known anti-
TB activity3. Pts w/ severe TB (miliary, meningeal)
excluded4. Treatment w/ monotherapy for up to 7
days acceptable to IRBs, then all treated w/ std chemotherapy
Contemporary EBA Study Design5. Able to produce adequate amounts of
sputum6. Daily overnight sputum collections w/
2 pretreatment collections7. INH 300 comparator group useful8. PK sampling9. Pre- and post-Rx drug susceptibility
Types of Trials
EBA
60 patients
6-9 months
2 Mo culture conversion
350 patients 18 months
Formal clinical trial comparing relapse rates
1200 patients 5 years
Use in Dose Ranging
Example of possible use of EBA (0-2) to identify doses to be further
evaluated
-0.2-0.1
00.10.20.30.40.50.6
0 9 18.5 37.5 75 150 300 600
INH dose
EBA
(0 -
2)
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 295% CI for Mean
Drug nMean EBA SD
Lower Bound
Upper Bound
INHLevoGatiMoxi
10101010
0.670.450.350.33
0.170.350.270.39
0.550.200.150.05
0.800.710.540.62
EBA Day 2 to 795% CI for Mean
Drug nSlopeB2-7 SD
Lower Bound
Upper Bound
INHLevoGatiMoxi
910109
0.140.240.270.24
0.160.120.100.11
0.020.150.200.11
0.270.330.340.37
Use in Evaluating Combinations
EBA of Drug Combinations
00.10.20.30.40.50.60.70.80.9
1
H HR SHZ SHRZ
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 EBA1-7 8-14 >
HRZE HRZE HRZE
XH XH HRZEXR XR HRZEXZ XZ HRZEXE XS HRZE
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