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TB new treatments and new
methodological challenges
Dr Corinne Merle
Outline
 Current pipeline of new TB
drugs
 Methodological challenges
for designing TB trials (using
the OFLOTUB project as an
example)
 Challenges in TB regimen
development
TB drug development: to set the scene
1961
Ethambutol (E)
1952
Isoniazid (H)
1963
Rifampicin (R)
1943
Streptomycine (S)
1954
Pyrazinamide (Z)
1882
Description of the
agent of TB
1940
1950
1960
1970
1980
1990
1970s: short course
regimen: S/H/R or
S/H/Z -9 months
therapy
1st
1946:
drug: S
Montotherapy led
to S resistance
1952: 1st regimen:
S/PAS/H
18-24 months therapy
1980s: modern shortcourse regimen:
E (S) H R Z
6 months of therapy
2000
2010
TB drug development: to set the scene
1961
Ethambutol (E)
1952
Isoniazid (H)
Effective treatment: 95% of
treatment efficacy
But...
 6 months treatment regimen
 problem of treatment adherence
 Emergence of MDRTB
 8.8 millions new TB cases in 2010
1963
Rifampicin (R)
1943
Streptomycine (S)
1954
Pyrazinamide (Z)
1882
Description of the
agent of TB
1940
1950
1960
1970
1980
1990
1970s: short course
regimen: S/H/R or
S/H/Z -9 months
therapy
1st
1946:
drug: S
Montotherapy led
to S resistance
1952: 1st regimen:
S/PAS/H
18-24 months therapy
1980s: modern shortcourse regimen:
E (S) H R Z
6 months of therapy
2000
2010
Development pipeline for new TB drugs



Shortening TB treatment recognised as a major target for the improvement of
TB control
Since the late 90s: new agents discovered
Significant target diversity and potential for better combinations
Development pipeline for new TB drugs
Drugs at a Phase III stage
 Both gatifloxacin and moxifloxacin have
emerged as candidates from the 8methoxyfluoroquinolones drug class and
are proposed for shortened treatment
of pan-susceptible TB.
 Gatifloxacin was chosen based on its
bactericidal activity and its generic
status
 35 years after the East African/British Medical Research Council
trials, 3 new drugs currently assessed in large Phase III trials
 RIFAQUIN trial (Rifapentine)
 REMoxTB trial (Moxifloxacin)
 OFLOTUB trial (Gatifloxacin)
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Gatifloxacin Product Development Plan
 Pre-Clinical Toxicology studies
 Phase I Pharmacokinetic study (J Antimicrob Chemother.
2007 Dec;60(6):1398-401)
 Phase II SSCC study (Int J Tuberc Lung Dis. 2008 Feb;12(2):128-38. ).
More than 10
years in
development
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 Phase III pivotal trial with a nested PK/PD
also called OFLOTUB
Overview of OFLOTUB project: Phase III/PK
 Objective
To evaluate the efficacy and safety of 4-month gatifloxacin containing regimen
compared to the standard WHO-recommended 6-month regimen
 Study design
A randomized (1:1), open-label, non-inferiority, multi-centre controlled trial with
a nested Pharmacokinetic (PK/PD) study
 Patients
Newly diagnosed microbiologically confirmed TB sensitive adults patients in 5
countries in Africa
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Overview of OFLOTUB project: Phase III/PK
 Treatment

Test arm : 2 months GHRZ / 2 months GHR
Control arm: 2 months EHRZ / 4 months RH

Daily DOT during the 1st 2 months of treatment,


Weekly drug delivery during the continuation
phase
 Follow-up



2 years after completion of TB treatment
Patients seen at 1, 2, 4, 6, 9, 12, 15, 18 and 24 months after treatment
Clinical examination, 2 sputum samples collected for smear & culture
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Trial setting and OFLOTUB partners
London School of Hygiene and
Tropical Medicine (London)
Hôpital Raymond
Tropical Medical Institute
LUPIN Pharma
Poincaré (Paris)
(Antwerp)
(India)
St George’s Hospital Medical
School, (London)
WHO / TDR
Institute for Research &
Development (Marseille)
(Geneva)
Thamassat
University
(Bangkok)
PNLTB (Dakar, Senegal)
KEMRI (Nairobi, Kenya)
PNLTB (Conakry, Guinea)
PNLTB (Cotonou, Benin)
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MRC SA (Durban, South Africa)
Trial setting and OFLOTUB partners
London School of Hygiene and
Tropical Medicine (London)
Hôpital Raymond
Tropical Medical Institute
LUPIN Pharma
Poincaré (Paris)
(Antwerp)
(India)
St George’s Hospital Medical
School, (London)
WHO / TDR
Institute for Research &
Development (Marseille)
(Geneva)
Thamassat
University
(Bangkok)
PNLTB (Dakar, Senegal)
KEMRI (Nairobi, Kenya)
PNLTB (Conakry, Guinea)
PNLTB (Cotonou, Benin)
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MRC SA (Durban, South Africa)
Trial setting and OFLOTUB partners
London School of Hygiene and
Tropical Medicine (London)
Hôpital Raymond
Tropical Medical Institute
LUPIN Pharma
Poincaré (Paris)
(Antwerp)
(India)
St George’s Hospital Medical
School, (London)
WHO / TDR
Institute for Research &
Development (Marseille)
(Geneva)
Thamassat
University
(Bangkok)
PNLTB (Dakar, Senegal)
KEMRI (Nairobi, Kenya)
PNLTB (Conakry, Guinea)
PNLTB (Cotonou, Benin)
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MRC SA (Durban, South Africa)
Trial setting and OFLOTUB partners
London School of Hygiene and
Tropical Medicine (London)
Hôpital Raymond
Tropical Medical Institute
LUPIN Pharma
Poincaré (Paris)
(Antwerp)
(India)
St George’s Hospital Medical
School, (London)
WHO / TDR
Institute for Research &
Development (Marseille)
(Geneva)
Thamassat
University
(Bangkok)
PNLTB (Dakar, Senegal)
KEMRI (Nairobi, Kenya)
PNLTB (Conakry, Guinea)
PNLTB (Cotonou, Benin)
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MRC SA (Durban, South Africa)
Trial setting and OFLOTUB partners
London School of Hygiene and
Tropical Medicine (London)
Hôpital Raymond
Tropical Medical Institute
LUPIN Pharma
Poincaré (Paris)
(Antwerp)
(India)
St George’s Hospital Medical
School, (London)
WHO / TDR
Institute for Research &
Development (Marseille)
(Geneva)
Thamassat
University
(Bangkok)
PNLTB (Dakar, Senegal)
KEMRI (Nairobi, Kenya)
PNLTB (Conakry, Guinea)
PNLTB (Cotonou, Benin)
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MRC SA (Durban, South Africa)
Overview of OFLOTUB project: Phase III/PK
 Progress status
 1836 patients recruited
 316 in Benin, 452 in Guinea, 200 in Kenya,
358 in Senegal and 510 in South Africa
 Last patient completed treatment end of
April 2009
 Last patient last visit: April 2011 (i.e. 24
months of follow-up following the end of
treatment)
 Percentage of patients LTFU estimated to
be around 10 %
First results should be released in November 2012
Non-inferiority design
Rationale for Choice of Non-inferiority design
 Highly efficient current TB treatment (95% cure rate)
 Unlikely that a new regimen will demonstrate superiority
 Interest lies with showing whether a new regimen is not inferior
Non-inferiority design is an excellent choice for current TB
sensitive drug development (A. Nunn et al, Tuberculosis(2008))
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Non-inferiority design
Rationale for Choice of Non-inferiority design
 Highly efficient current TB treatment (95% cure rate)
 Unlikely that a new regimen will demonstrate superiority
 Interest lies with showing whether a new regimen is not inferior
NI design is an excellent choice for current TB sensitive drug
development (A. Nunn et al, Tuberculosis(2008))
Implication of NI design on trial population to be analysed
 Intention-To-Treat (ITT) Vs Per-Protocol (PP)
 ITT approach tends to minimise differences by including protocol deviations
 PP is biased because not including all randomised patients
In fact, both are equally important and require similar conclusions in
order to support final result (Piaggio G, Elbourne DR, et al. JAMA 2006;295(10):1152-60.)
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Choice & measurement of the endpoints
 In 1947, endpoint of BMRC Streptomycin trial: Survival or
Chest Xray
 Nowadays, bacteriological endpoints
 TB recurrence main outcome of interest
 But restricted to patients cured at the end of the treatment
A composite “unfavourable outcome” endpoint
including:
- treatment failure
- Death
- TB recurrences
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Choice & measurement of the endpoints
 Bacteriological diagnosis: Cultures
 Solid Vs liquid media
 False-positive cultures results from
 Misidentification of the strain
 Laboratory cross-contamination
 Clerical error reporting
 More than 3 % of false positive (Burman et al Clin Infect Dis 2000,
31(6):1390-1395)
Necessity to take 2 sputum samples per visit, per patient to minimise
unavailability or false positive culture results
Solid medium is the gold standard
Recurrence, relapse and re-infection
 Relapse : Reactivation of the original infection
 Re-infection: Infection with a new TB strain
 Effective treatment should prevent relapse but have no effect on reinfection
 Context of TB and HIV, proportion of re-infection can be high
 Non-inferiority design context
Necessity to differentiate relapse from re-infection
using molecular method (e.g. MIRU-VNTR)
Recurrence considered to allow comparison with
previous trials
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Length of patient follow-up

For a TB regimen to be acceptable:
•
Patient must convert to culture negative by
the end of treatment
•
most importantly, it must demonstrate
clearance of bacteria by keeping patients
relapse-free

How long is long enough?

When to start the clock…after the end of
treatment (equal follow-up between arms)? or
post randomization (unequal follow-up)?
 Conservative approach: 24 months after the end of the treatment
 In the light of BMRC trials: 1 year follow-up could be enough
(Nunn AJ et al. Int J Tuberc Lung Dis 2010, 14(2):241-242)
 Discussion on when to start the clock (even more important for shorter
treatment regimen trial)
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Blinded design versus Open-label design
Options
 i) non-blinded design: an arm with 4 months of test regimen vs an arm with 6
months of standard regimen
 ii) blinded design : 2-months placebo added to the test arm
Discussion
 Double blinding design favoured in many trial situations
 For a shorter regimen, one of the mechanisms for treatment efficacy might
be better adherence to treatment
 Aspect not captured in blinded design
 Pro and Cons
Requirements if Open-label design
Laboratory staff are blinded to the treatment regimen the patient is
receiving
Strict & objective endpoint definitions and a blinded endpoint committee
Sample size calculation
Sample size calculation for a constant 2.5% 1-sided level of significance and
variable values for primary outcome percentage, power and delta
Number per group for given delta and power
Delta=3%
Delta=5%
Delta=6%
‘Event’
percentage in
control group
80%
90%
80%
90%
80%
90%
5%
828
1110
298
399
207
277
10%
1570
2102
565
757
392
525
15%
2224
2977
801
1072
556
744
Sample size calculation
OFLOTUB
Major Efficacy Outcome
“Unfavourable”
events
% events in control arm
20%
1-sided significance level
2.5%
Power
80%
Non-inferiority margin δ
6%
# of patients overall
1,394 (2 arms)
Adjustment for non assessable patients
15%
Grand total
1,640
Importance of being powered for both ITT and PP analysis
TB Drug development challenges
 Objective is to get new TB treatment regimen not only new TB drug
 Novel 3-drug combinations that have potential to:
 Shorten treatment to 2 months or less
 Be co-administered with ARVs
24-30
 Be effective against MDR- and XDR-TB
Years
 Conventional approach would need 24-30
years to develop a combination that contains ≥
3 new drugs
ABCD
E
D
GFE
8-10
years
8-10
years
ABCE
 Adaptive multi-arm multistage (MAMS) trial
design, which has been successfully used in
cancer — is under discussion.
 Even if MAMS, TB drug trial are long and costly
ABFE
F 8-10 C
Years
AB
G
Gatifloxacin product development Length
Dec 2002, Grant
approval (P III)
August
2003,
Phase I
& PK
Jan - Mars 2005, initiation visits in the 5
recruitment sites for Phase III & PK/PD
July 2004,
Phase II SSCC
Phase III: April
2011, last patient FU
Phase I, Phase II, Phase III & PK/PD
Design of the phase III study
& set-up,
capacity building +++
Phase III Recruitment period
In total 10 to 11 years
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Follow-up period
Nov 2012, 1st
efficacy results
Phase III: last patient recruited:
31 Oct 2008
Gatifloxacin product development Length
Dec 2002, Grant
approval (P III)
August
2003,
Phase I
& PK
Jan - Mars 2005, initiation visits in the 5
recruitment sites for Phase III & PK/PD
July 2004,
Phase II SSCC
Phase III: April
2011, last patient FU
Phase I, Phase II, Phase III & PK/PD
Design of the phase III
study & set-up,
capacity building +++
2.5 years
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Phase III Recruitment period
Follow-up period
Nov 2012, 1st
efficacy results
Phase III: last patient recruited:
31 Oct 2008
Gatifloxacin product development Length
Dec 2002, Grant
approval (P III)
August
2003,
Phase I
& PK
Jan - Mars 2005, initiation visits in the 5
recruitment sites for Phase III & PK/PD
July 2004,
Phase II SSCC
Phase III: April
2011, last patient FU
Phase I, Phase II, Phase III & PK/PD
Design of the phase III study
& set-up,
capacity building +++
2.5 years
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Phase III Recruitment period
Follow-up period
Nov 2012, 1st
efficacy results
Phase III: last patient recruited:
31 Oct 2008
Gatifloxacin product development Length
Dec 2002, Grant
approval (P III)
August
2003,
Phase I
& PK
Jan - Mars 2005, initiation visits in the 5
recruitment sites for Phase III & PK/PD
July 2004,
Phase II SSCC
Phase III: April
2011, last patient FU
Phase I, Phase II, Phase III & PK/PD
Design of the phase III study
& set-up,
capacity building +++
Phase III Recruitment period
Follow-up period
3.5 years
Nov 2012, 1st
efficacy results
Phase III: last patient recruited:
31 Oct 2008
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Gatifloxacin product development Length
Dec 2002, Grant
approval (P III)
August
2003,
Phase I
& PK
Jan - Mars 2005, initiation visits in the 5
recruitment sites for Phase III & PK/PD
July 2004,
Phase II SSCC
Phase III: April
2011, last patient FU
Phase I, Phase II, Phase III & PK/PD
Design of the phase III study
& set-up,
capacity building +++
Phase III Recruitment period
Follow-up period
Nov 2012, 1st
efficacy results
2 years ?
Phase III: last patient recruited:
31 Oct 2008
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Gatifloxacin product development Length
Dec 2002, Grant
approval (P III)
August
2003,
Phase I
& PK
Jan - Mars 2005, initiation visits in the 5
recruitment sites for Phase III & PK/PD
July 2004,
Phase II SSCC
Phase I, Phase II, Phase III & PK/PD
Design of the phase III study
& set-up,
capacity building +++
Phase III: April
2011, last patient FU
Data management
Phase III Recruitment period
Follow-up period
Nov 2012, 1st
efficacy results
Phase III: last patient recruited:
31 Oct 2008
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To reduce the length of TB drug development
Set-up phase
Enhancing local capacity; training & retraining….. Huge capacity building investment,
important that it is being capitalised and
optimised
 Necessity to ensure continuity of the research
investments in these sites
 Necessity to adopt common guidelines for
designing TB treatment trials
Recruitment period
Patient follow-up & outcome of interest
 Reduced to 12 months post treatment
 Necessity to validate surrogate markers
Datamanagement
Conclusion




Shortening the duration of TB treatment is the major target
There are TB drug development challenges
There are methodological challenges when designing phase
III TB sensitive RCT
We are advocating for:





a non-inferiority design,
a non-blinded design,
a composite unfavourable endpoint,
a follow-up of 12 months post treatment completion,
added trial procedures specifically aiming at minimizing
unavailability of endpoints,
 and distinguishing between relapse and re-infection.
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Conclusion
1961
Ethambutol (E)
1952
Isoniazid (H)
?
1963
Rifampicin (R)
1943
Streptomycine (S)
1954
Pyrazinamide (Z)
1882
Description of the
agent of TB
1940
1950
1960
1970
1980
1990
1970s: short course
regimen: S/H/R or
S/H/Z -9 months
therapy
1st
1946:
drug: S
Montotherapy led
to S resistance
1952: 1st regimen:
S/PAS/H
18-24 months therapy
1980s: modern shortcourse regimen:
E (S) H R Z
6 months of therapy
2000
2010
Conclusion
TB Alliance is instrumental
(www.tballiance.org)
1961
Ethambutol (E)
1952
Isoniazid (H)
?
1963
Rifampicin (R)
1943
Streptomycine (S)
1954
Pyrazinamide (Z)
1882
Description of the
agent of TB
1940
1950
1960
1970
1980
1990
1970s: short course
regimen: S/H/R or
S/H/Z -9 months
therapy
1st
1946:
drug: S
Montotherapy led
to S resistance
1952: 1st regimen:
S/PAS/H
18-24 months therapy
1980s: modern shortcourse regimen:
E (S) H R Z
6 months of therapy
2000
2010
Conclusion
Ignoring the vulnerable

Children

TB/HIV co-infected
1961
Ethambutol (E)
patients
1952
Isoniazid (H)
?
1963
Rifampicin (R)
1943
Streptomycine (S)
1954
Pyrazinamide (Z)
1882
Description of the
agent of TB
1940
1950
1960
1970
1980
1990
1970s: short course
regimen: S/H/R or
S/H/Z -9 months
therapy
1st
1946:
drug: S
Montotherapy led
to S resistance
1952: 1st regimen:
S/PAS/H
18-24 months therapy
1980s: modern shortcourse regimen:
E (S) H R Z
6 months of therapy
2000
2010