Download DMID 01-553 FQ EBA Study Results

Role(s) of EBA Studies
– Substitute for Dose Ranging
JL Johnson, MD
Case Western Reserve Univ
Quantitative Culture in Response to TB Treatment
Mitchison. Thorax 1950;5:144
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
Fall in CFU during Chemotherapy
 cfu 0-2
 cfu 2-14
Nil
-0.02
-0.02
H 300
0.72
0.11
R 10 per kg
0.19
0.10
S 1g
0.09
0.13
E 25 per kg
0.25
0.16
Z 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
OFL
EMB
RMP
CIP
STM
RBT
AMIK
PZA
0.60
0.39
0.25
0.20
0.21
0.13
0.08
0.05
0.003
0.06
0.17
0.30
EBA in Different Studies
Drug
INH
Study
Jindani ’80
Chambers ’98
Gosling ’03
Dietze ’05
EBA
0.72
0.60
0.77
0.67
RMP
RMP
RBT
RBT
Chan ’92
SA MRC
Chan ’92
SA MRC
0.29
0.20
0.05
0.08
CIPRO
CIPRO
OFLO
MXF
Kennedy ’93
SA MRC
Chambers ’98
Gosling ’03
0.20
0.21
0.32
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 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 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 Design
1. Newly Dx, sputum smear + TB; 10-12 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
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
EBA (0 - 2)
Example of possible use of EBA (0-2) to
identify doses to be further evaluated
0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.2
0
9
18.5
37.5
75
150
300
INH dose
Donald. AJRCCM 1997;156:895
600
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
Drug
INH
Levo
Gati
Moxi
n
Mean
EBA
10
10
10
10
0.67
0.45
0.35
0.33
SD
Lower
Bound
Upper
Bound
0.17
0.35
0.27
0.39
0.55
0.20
0.15
0.05
0.80
0.71
0.54
0.62
EBA Day 2 to 7
95% CI for Mean
Drug
INH
Levo
Gati
Moxi
n
Slope
B2-7
9
10
10
9
0.14
0.24
0.27
0.24
SD
Lower
Bound
Upper
Bound
0.16
0.12
0.10
0.11
0.02
0.15
0.20
0.11
0.27
0.33
0.34
0.37
Use in Evaluating Combinations
EBA of Drug Combinations
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
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 EBA
1-7
8-14 >
HRZE
HRZE
XH
XR
XH
XR
HRZE
HRZE
XZ
XZ
HRZE
XE
XS
HRZE
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