Tuberculosis Trials Consortium (TBTC) Overview

Completed, Ongoing, and Moxifloxacin Clinical Trials

Kenneth G. Castro, M.D.Assistant Surgeon General, USPHS

Director, Division of Tuberculosis EliminationNational Center for HIV, STD and TB Prevention

Coordinating Center for Infectious Diseases

Global Alliance for TB Drug DevelopmentStakeholders Meeting - 17 October 2005

Acknowledgements

Dr. Elsa Villarino

Dr. Andrew Vernon

TBTC PIs & Study Coordinators

Data Management & Statistics Staff

DSMB Members

Trials 1 and 2 1947-1949

Studies 1-10 1952-1959

Studies 11-17 1962-1969

Studies 18-20 1969-1970

Study 211981-1988

•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

USPHS CLINICAL TRIALS

USPHS TB Clinical Trials LegacyStudies Conducted 1947 ― 1988

TB Trials Consortium (TBTC) • Constituted in 1995 for multicenter trial (Study 22)

– 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:TBTC Mission: “… to conduct programmatically “… to conduct programmatically relevant clinical, laboratory, and epidemiologic relevant clinical, laboratory, and epidemiologic research concerning the diagnosis, clinical research concerning the diagnosis, clinical management, and prevention of tuberculosis management, and prevention of tuberculosis infection and disease.”infection and disease.”

Programmatically Relevant ― How to Improve Treatment of TB Infection/ Disease?

• Less frequent dosing - highly effective once- 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

Study 22 1995-1998

Study 231999-2002

Study 251999-2000

Study 241999-

Study 262001-

Study 272003-2005

Study 27PK2004-

Study 28CDC IRB 02/2005

•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

•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)

•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?

•Does RIF decrease the concentrations of MOXI?•Is the PK of MOXI different in TB patients?

•What would be the effect of substituting MOXI for INH in the induction phase?

•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?

TBTC CLINICAL TRIALS ONGOING TBTC CLINICAL TRIALS

TBTC Studies Conducted 1995 ― Present

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*

*Enrollments in Studies 24, 26, 27, and NAA. Site 32 – cost is approximated.

$0

$2,000

$4,000

$6,000

$8,000

$10,000

$12,000

$14,000

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

Co

st p

er p

atie

nt

median

Study Drug Treatment Frequency

Moxifloxacin HRZM Daily HRZM Intermittent

Ethambutol HRZE Daily HRZE Intermittent

TBTC Study 27: Placebo-controlled, Factorial Study –

Randomization to Study Drug and Rx FrequencyGlobal Alliance Role in IRB Approval

2

10

1

7

2

4

11

78

12

10

10

17

1

12 12

21

136

2

024

68

101214

161820

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

Study 27 Patients (n=288) with 2-month Culture Conversion Endpoint, by Enrolling Site

*Ineligible patients (n=13) excluded*Data for Site 32 is provisional

Overall: 85%Overall Rate: 85%

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6

Duration of treatment (mos.)

Log

CF

U in

ent

ire lu

ng

Untreated

2RHZ+4RH

2RHZM+4RHM

2RMZ+4RM

M. tuberculosis Log Colony-Forming Units (CFU) in Lungs of Mice, by Treatment

2.5 logs

Am J Respir Crit Care Med 2004; 164:421-6

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

INHMOX placeboRIF+PZA+EMBDaily for 8 weeks

MOXINH placeboRIF+PZA+EMBDaily for 8 weeks

Sputum smear+ PTB suspect

assess for primary endpoints

randomization

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 Observations10 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