1. 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 Global Alliance for TB Drug Development Stakeholders Meeting - 17 October 2005

2. Acknowledgements Dr. Elsa Villarino Dr. Andrew Vernon TBTC PIs & Study Coordinators Data Management & Statistics Staff DSMB Members

3. Trials 1 and 2 1947-1949 Studies 1-10 1952-1959 Studies 11-17 1962-1969 Studies 18-20 1969-1970 Study 21 1981-1988 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 Legacy Studies Conducted 1947 ― 1988

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

5. 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

6. Study 22 1995-1998 Study 23 1999-2002 Study 25 1999-2000 Study 24 1999- Study 26 2001- Study 27 2003-2005 Study 27PK 2004- Study 28 CDC 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

7. 28 clinical sites worldwide CDC Administrative, Statistical, and Data Management Center

8. TBTC Budget FY2005 Adjusted annual budget ~ US$9.2 million Anticipated “level funds” and rescission in FY2006…

9. Cost per Patient by Study Site, TBTC FY 04* *Enrollments in Studies 24, 26, 27, and NAA. Site 32 – cost is approximated. median

10. Study DrugTreatment Frequency MoxifloxacinHRZM DailyHRZM Intermittent EthambutolHRZE DailyHRZE Intermittent TBTC Study 27: Placebo-controlled, Factorial Study – Randomization to Study Drug and Rx Frequency Global Alliance Role in IRB Approval

11. 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%

12. 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

13. 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

14. TBTC Study 28 Treatment Arms INH MOX placebo RIF+PZA+EMB Daily for 8 weeks MOX INH placebo RIF+PZA+EMB Daily for 8 weeks Sputum smear+ PTB suspect assess for primary endpoints randomization ATS/CDC/IDSA-recommended continuation phase regimen

15. 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

16. 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

17. 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