Post on 18-Jan-2018
description
Phase IIb (8-week) studies
D A MitchisonD A MitchisonSt George’s, University of LondonSt George’s, University of London
Comparison of the bactericidal activities of the Fluoroquinolones: Gatifloxacin, Moxifloxacin and
Ofloxacin, substituted for Ethambutol in the 2-Month initial phase of standard treatment
Oflotub phase 2 surrogate marker study
South African Medical Research Council, Durban Dr R Rustomjee; Dr F Sirgel; Prof W Sturm; Dr B Fourie and staff
Prof D Mitchison; Dr C Lienhardt (Co-ordinator); Dr C Merle (Trial Monitor)
Supported by
European Commission
WHO TDR
Design Open label Phase II Randomised Controlled Trial
Aims Compare three fluoroquinolones substituted for
ethambutol in 2HRZE initial phases using serial sputum colony counting (SSCC)
Compare the use of different surrogate endpoints in Phase II studies
ScreeningNewly diagnosed smear +ve
412
Willing to collaborate226 Excluded
11
HRZEControl
54
HRZOOflo55
HRZGGati54
HRZMMoxi
548-weeks
RHcontinuation 4 months
Summary of recruitment
0 56
14 hour sputum collection
Sputum colony counts on selective 7H11 medium without decontamination at 10 time points during initial 8-week phase
Standard 7H11 culture + Liquid culture (MGIT)
2 7 14 21 28
Comparative bactericidal assessments
35 42 49
Standard 7H11 culture
Standard 7H11 culture + indirect
susceptibility tests
Analysis
Jonathan Levin (Durban): Proportions +ve at 2 months Survival analysis using SSCC Polynomial / spline mixed effects modelling of SSCC
Geraint Davies (Bangkok):
Non-linear mixed effects modelling of SSCC Denny Mitchison (London):
Summary regression estimates on SSCC
0 2 7 14 21 28 35 42 49 56
02
46
810
Days on therapy
Log 1
0CFU
/ m
l spu
tum
210
206
205
194
173127
105 60 3018
Summary of SSCC results
Limit of detection
Days on therapy 0 10 20 30 40 50
02
46
810
Log 1
0 CFU
/ml
Summary statistics & regression models
of colony counts Proportion positive at 2 months
Survival analysis & time to conversion
Relapse
Analytical approaches to Phase II surrogate endpoint studies
Limit of detection
0.000.10
0.200.300.400.50
0.600.700.80
0.901.00
HRZE HRZO HRZG HRZM
Prop
ortio
n po
sitiv
e
Proportion positive at two months
49.058.5
43.446.9
Chi-square test
2 (3)=2.63
p= 0.451
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Days on therapy
Pro
babi
lity
of s
putu
m c
onve
rsio
n
HRZEHRZOHRZGHRZM
Survival analysis
Log rank test
2 (3)=10.69
p= 0.0136
Hazard Ratio for culture conversion*
z-test
HRZO 0.83 -0.85 (p=0.393)
HRZG 1.25 1.07 (p=0.284)
HRZM 1.47 1.86 (p=0.063)
Survival analysis
* vs. HRZE
0 10 20 30 40 50
02
46
810
Days on therapy
Log 1
0CFU
/ m
l spu
tum
MonoexponentialBiexponential
Regression modelling of serial sputum colony counts
Limit of detection
ModelLog
likelihoodAkaike
Information Criterion
Likelihood Ratio Test
(p value)
Monoexponential -2141.314 4288.628 -
Biexponential -1967.841 3945.682 346.9456 (<0.0001)
Biexponential + Random effects
-1582.434 3182.867 754.500 (<0.0001)
Biexponential + Random effects +
Treatment
-1577.804 3179.608 9.259 (0.026)
Model fitting sequence
(early, 0-7 days)
Polynomial / Spline Mixed Effects
Summary regressions
b0-2 b0-7
Non-linear Mixed Effects
HRZM 0.220 0.615 0.340 0.742 HRZG 0.177 0.553 0.304 0.723 HRZO 0.099 0.421 0.254 0.481 HRZE 0.096 0.459 0.250 0.586 p-value **
** * **
** **
** **
β (late,
7-56 days)
b7-28
b7-56
HRZM 0.157 0.138 0.131 0.128 HRZG 0.153 0.138 0.134 0.120 HRZO 0.148 0.113 0.111 0.105 HRZE 0.139 0.125 0.113 0.105 p-value
* **
**
Regression estimates Signs of coefficients reversed)
* <0.05 M vs.E
**<0.01 M vs.E
* <0.05 M&G vs. E&O
**<0.01 M&G vs. E&O
0 10 20 30 40 50
01
23
45
67
Days on therapy
Log 1
0CFU
/ m
l spu
tum
HRZE = -0.586 HRZO = -0.481 HRZG = -0.723 HRZM = -0.742
HRZE = -0.104 HRZO = -0.093 HRZG = -0.123 HRZM = -0.121
Limit of detection
Estimated treatment effects
Forecasting duration of therapy by effect size
0 50 100-50-100
-17.8 9.2
-7.0 23.8
1.4 35.2
9.0 103.1
% Change in versus control
HRZO
HRZG
HRZM
(SHRZ)
-5.3
6.5
17.3
48.7
Approximate 95% confidence intervals derived from NLME
model
0 50 100 150 200
-20
-15
-10
-50
510
Days on therapyLo
g 10C
FU /
ml s
putu
m
HRZEHRZQ
Forecasting duration of therapy by extrapolation
138 days
~100 days ?
Biexponential model Triexponential model
0 50 100 150 200
-20
-15
-10
-50
510
Days on therapy
Log 1
0CFU
/ m
l spu
tum
HRZEHRZQ
Cost assessment (US$)
Patientsper arm Cost
Standard 120 120 x (8,000-250) = 930,000
SSCC 50 50 x 8,000= 400,000
Duration of study: 12 monthsNumber of sputum specimens: 2100
Technicians employed: 3
Conclusions 1
When substituted for Ethambutol, both Moxifloxacin and Gatifloxacin killed significantly faster in the early and late phases than control
Ofloxacin substitution had no significant effect The observed increases in late phase killing
with these regimens support a probable reduction in the duration of therapy of at least one and possibly two months
Conclusions 2
Several different methods of analysis detected a treatment effect but culture conversion at 8 weeks did not
It is important that methods discriminate between the early and late phases of killing and avoid overestimating “sterilizing activity”
Non-linear mixed effects modelling appears to be both an informative and sensitive approach
Conclusions 3
Modelling using SSCC data has significant advantages over methods based only on culture conversion
SSCC is also cheaper as it requires a smaller sample size
SSCC modelling should be the basis of future phase II studies aiming to evaluate new regimens suggested by mouse studies.