Transcript Study 22 - TB Alliance

Global Alliance for TB Drug Development
Stakeholders Meeting - 17 October 2005
Tuberculosis Trials Consortium
(TBTC) Overview
Completed, Ongoing, and
Moxifloxacin Clinical Trials
Kenneth G. Castro, M.D.
Assistant Surgeon General, USPHS
Director, Division of Tuberculosis Elimination
National Center for HIV, STD and TB Prevention
Coordinating Center for Infectious Diseases
Acknowledgements
Dr. Elsa Villarino
Dr. Andrew Vernon
TBTC PIs & Study Coordinators
Data Management & Statistics Staff
DSMB Members
USPHS TB Clinical Trials Legacy
Studies Conducted 1947 ― 1988
Studies 11-17
1962-1969
Trials 1 and 2
1947-1949
Studies 1-10
1952-1959
Studies 18-20
1969-1970
Study 21
1981-1988
USPHS CLINICAL TRIALS
•SM and PAS
•Measured X-ray
improvement
•Basis for multidrug
therapy
•INH and PZA
•Measured bacteriologic
conversion
•Recommended duration of
therapy 24 mo.
•EMB and RIF
•Measured relapse rates
•Allowed the duration of
therapy to be shortened to 18
mos. (EMB) and to 15 mos.
(RIF)
•Supervised, intermittent,
ambulatory therapy
•Critical role of PZA in 6 mo.
therapy
•1986 ATS/CDC first
recommendation of short–
course therapy
•INH and RIF most potent anti-TB
regimen
•Optimal dose for RIF
•1971 FDA approval of RIF
•Shortened duration of therapy to
9 mos.
•1973 TB Research Section moved
from NIH to CDC
TB Trials Consortium (TBTC)
• Constituted in 1995 for multicenter trial (Study 22)
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– Funded by CDC
– Integrated as a consortium in 1998
28 clinical sites worldwide
Links academia to local TB control programs
Formal by-laws and policies
Data & Coordinating Center at CDC
Data Safety Monitoring Board
TBTC Mission: “… to conduct programmatically
relevant clinical, laboratory, and epidemiologic
research concerning the diagnosis, clinical
management, and prevention of tuberculosis
infection and disease.”
Programmatically Relevant ― How to
Improve Treatment of TB Infection/ Disease?
• Less frequent dosing - highly effective once•
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and twice-weekly therapy
Improve outcomes in patients at high risk for
treatment failure or relapse
Improve identification of patients with LTBI
and risk of disease progression
Effective therapy in < 6 months
(<9 months for LTBI)
Safer and better-tolerated therapies
TBTC Studies Conducted 1995 ― Present
Study 22
1995-1998
Study 23
1999-2002
TBTC CLINICAL TRIALS
•RBT replaces RIF in patients with HIV
and HAART
•Failure/relapse rate and tolerability
•Paradoxical reactions
•RIF monoresistance
•Drug-drug interactions
23A: All TB drugs in S23 patients
23B: Nelfinavir and RBT (nested)
23C: Efavirenz and RBT (nested)
•22PK all drugs in relapse vs. non-relapse
patients, NAT2 genotyping
•Cavitation and 2 month culture conversion
as risk factors for relapse
•RIF resistance in HIV (+) patients
•2003 ATS/CDC recommends
extended duration for H.R. pats
and use of RPT in L.R. patients
Study 25
1999-2000
Study 24
1999-
Study 26
2001-
Study 27
2003-2005
Study 27PK
2004Study 28
CDC IRB
02/2005
ONGOING TBTC CLINICAL TRIALS
•RPT dose
escalation (600 mg
vs. 900 mg vs. 1200
mg)
•PK evaluation
•Risk factors for
relapse
•What is the best
management of
patients with INH
resistance or
intolerance?
•Evaluation of MOXI in
a Phase II trial
•Can MOXI decrease
infectious period and
potentially shorten
duration of therapy?
•Can a Phase III RTC of
LTBI be
accomplished?
•What is the efficacy
and tolerability of a 12
dose INH/RPT weekly
regimen to prevent
active TB?
•What would be the effect
of substituting MOXI for
INH in the induction
phase?
•Does RIF decrease the
concentrations of MOXI?
•Is the PK of MOXI different in
TB patients?
28 clinical sites
worldwide
CDC Administrative,
Statistical, and Data
Management Center
TBTC Budget FY2005
• Adjusted annual budget
~ US$9.2 million
• Anticipated “level funds” and rescission in
FY2006…
Cost per Patient by Study Site, TBTC FY 04*
$14,000
median
$12,000
Cost per patient
$10,000
$8,000
$6,000
$4,000
$2,000
$0
13 14 15 16 17 20 21 22 23 24 25 26 27 28 29 30 31 32 40 53 54 58 59 61 62 63 66 70
Site
*Enrollments in Studies 24, 26, 27, and NAA.
Site 32 – cost is approximated.
TBTC Study 27:
Placebo-controlled, Factorial Study –
Randomization to Study Drug and Rx Frequency
Global Alliance Role in IRB Approval
Study Drug
Treatment Frequency
Moxifloxacin
HRZM Daily
HRZM
Intermittent
Ethambutol
HRZE Daily
HRZE
Intermittent
Study 27 Patients (n=288) with 2-month Culture
Conversion Endpoint, by Enrolling Site
136
20
18
16
14
12
10
8
6
4
2
0
17
Overall: 85%
Overall Rate: 85%
12 12
11
10
7
10
7
8
4
2
1
2
1
2
2
1
0
1
2
1
12 13 14 15 16 17 20 21 22 23 24 25 26 27 28 30 32 53 59 62 63 66 70
Evaluable
Not Evaluable
*Ineligible patients (n=13) excluded
*Data for Site 32 is provisional
M. tuberculosis Log Colony-Forming Units
(CFU) in Lungs of Mice, by Treatment
10
Am J Respir Crit Care Med 2004; 164:421-6
Log CFU in entire lung
9
8
7
Untreated
2RHZ+4RH
2RHZM+4RHM
2RMZ+4RM
6
5
4
3
2
2.5 logs
1
0
0
1
2
3
4
Duration of treatment (mos.)
5
6
TBTC Study 28
• Phase II clinical trial
• Compare safety and bactericidal activity of
MOXI substitution for INH (MRZE vs. HRZE)
• Measure sputum-culture conversion at 2 mos
• Improved 2-mos sputum-culture conversion
with MRZE treatment would justify Phase III
clinical trials of Moxifloxacin in regimens
shorter than 6 months
TBTC Study 28 Treatment Arms
Sputum smear+ PTB suspect
randomization
INH
MOX placebo
RIF+PZA+EMB
Daily for 8 weeks
MOX
INH placebo
RIF+PZA+EMB
Daily for 8 weeks
assess for primary endpoints
ATS/CDC/IDSA-recommended continuation phase regimen
TBTC Study 28 Primary Endpoints
• Number and proportion patients with
negative sputum culture at 2 months of
therapy
• Number and proportion patients who
discontinue assigned study therapy for
any reason during the first 2 months
2005 TBTC Update
• Completed, ongoing, prospective drug trials
– Rifapentine in continuation phase (Study 22)
– Rifapentine for LTBI (Study 26)
– Moxifloxacin (Study 27, 28, 29…)
– PA824
– R207910
Summary Observations
10 years in operation, TBTC has
 Experienced sites, investigators, coordinators
 Administrative structure - QA process, protocol
development, regulatory process
 State-of-the-art scientific agenda
 Treatment, diagnostic, PK, and preventive
treatment trials that enroll ~235 patients/month
 Study sites in high-burden countries
 Budget restrictions & future challenges