TBTC research update: are we ready for 3 month treatment? 2009 TBTC Recompetition. NTCA presentation outline

Transcription

1 TBTC research update: are we ready for 3 month treatment? Stefan Goldberg, MD Project officer, TBTC Studies 27, 28, 29 Tuberculosis Trials Consortium (TBTC) CDC Division of TB Elimination NTCA breakout B6, June 17, TBTC Recompetition Call for proposals based upon advice from 2007 external peer review Sustain US-based capacity Increase enrollment capacity through inclusion of international sites New TBTC site configuration September 2009 NTCA presentation outline Study 26, TLTBI Study 30, Linezolid for MDR TB Completed phase II moxifloxacin studies TBTC Studies 27 & 28 Rio and Durban studies Current phase II rifapentine study Study 29 Next TBTC study More Phase II data needed first? Possible treatment shortening regimens 1

2 Study 26 results are expected by June 2010 Could begin new era for LTBI treatment Study 26: 3mo INH/RPT 1X/week vs 9mo INH for LTBI Fully enrolled (8,222 participants to date) Since Feb 2008 enrolling HIV+ pats and children <12 ~400 RPT Pediatric PK studies 165 patients enrolled, under analysis Study 26A: 351 patients enrolled, closed, under analysis Hypersensitivity sub-study 190 patients enrolled, ongoing HIV coinfected LTBI Enrollments from ACTG US sites (approximately 8), Rio de Janeiro and Lima expected, 1 enrollment Pediatric LTBI Enrollments from IMPAACT HIV positive and negative children aged 2-12, all sites in Rio de Janeiro, site registration ongoing TBTC Study 30 Pilot study (64 patients) of MDR/XDR TB Randomized, double-blind, Placebo-controlled, Phase I/II clinical trial Linezolid Low dose 600 mg QD Limited duration 16 weeks Optimized background therapy (>4 effective drugs) Primary outcomes - safety and tolerability King George V Hospital, Durban, South Africa MDR treatment hospital (160 beds) Inpatient care for 4 months 70% HIV positive First enrollment May 4, 2009 Questions for moxifloxacin Treatment shortening potential? Use as second line drug? Presented here: 4 Phase II trials TBTC Studies 27 (EMB) and 28 (INH), international multicenter Rio de Janeiro, Brazil (EMB) Durban, South Africa (EMB) All used DOT for main study period during intensive phase (2-month) therapy; continuation phase therapy followed current treatment guidelines Previously, large 2-m advantages were associated with treatment shortening for rifampin (15%-20%) and pyrazinamide (13%) 2

3 Moxifloxacin in Phase II clinical trials Phase IIB trials: proof of concept efficacy and safety evaluation in TB patients Sample size based on surrogate markers of cure Moxifloxacin is highly active against M. tuberculosis in-vitro 8-week sputum culture conversion is a marker for potency of TB regimens Continuation therapy follows standard guidelines Activity of moxifloxacin in combination therapy in a mouse model of TB 10 Log CFU in entire lung logs 0.6 log reduction Untreated 2RHZ+4RH 2RHZM+4RHM 2RMZ+4RM Duration of treatment (mos.) Am J Respir Crit Care Med 2004; 164:421-6 TBTC Study 27 design Phase II placebo-controlled factorial design randomized Phase II clinical trial intensive phase treatment of smear (+) pulmonary TB HRZM (400 mg) compared with HRZE 5/7 frequency compared with 3/7 Endpoint: culture negativity at 2 months, combined solid and liquid media result 3

4 TBTC Study 27 main findings effect of moxifloxacin and dosing on 2-month sputum culture conversion Regimen Daily (5/7) Thriceweekly Sub-total HRZM 71% 72% 71% (99/139) HRZE 76% 66% 71% (98/138) Sub-total 74% (100/136) 69% (97/141) Am J Respir Crit Care Med 2006, 174:331 TBTC Study 27 time to conversion FDA/Moxi Study, Brazil, Schema TB / Sputum Smear + All subjects receive INH, RIF, PZA (5/7) Randomize Moxi dosage = 400 mg/d; EMB dosage = mg/kg/d Moxi + EMB-Plc x 8 weeks vs. EMB + Moxi-Plc x 8 weeks Assess for primary endpoint (8 week culture, LJ only) Lancet 2009; 373:1183 INH/RIF 3 x/week x 18 Weeks 4

5 Brazil mox study, proportion of patients with negative cultures by week Difference at week 8: 18.4% (95%CI ) MOX EMB % Culture Negative Week of Treatment OFLOTUB Phase II study design Phase 2 study in Durban, South Africa Microbiology Intensive: Serial sputum colony counts (SSCC) Standard: 2-month culture results on solid and liquid media Compared 4 daily (6/7) regimens 2HRZE vs E substitutions with ofloxacin (800 mg), gatifloxacin (400 mg), and moxifloxacin (400 mg) Endpoints: 2-month negativity, modeling of time to culture conversion, bi-exponential curve using non-linear mixedeffects regression modeling of SSCC data. Supported by European Developing Countries Clinical Trials Partnership, Tropical Disease Research program at WHO and Institute for Research and Development in Dakar, Senegal Int J Tuberc Lung Dis 2008, 12:128 Oflotub study two-month endpoint 5

6 Oflotub study bi-exponential curves fitted to SSCC (serial sputum colony counts) data TBTC Study 28 schema Sputum smear positive/ PTB suspect randomization INH MOX placebo RIF+PZA+EMB Daily for 8 weeks MOX (400 mg) INH placebo RIF+PZA+EMB Daily for 8 weeks assess for primary endpoints solid and liquid media ATS/CDC/IDSA-recommended continuation phase TBTC Study 28 main findings % of subjects having negative sputum cultures at end of study (intensive) phase Analysis INH Moxi P-value Protocol 55% 60% Correct (90/164) (99/164) 0.37 Group MITT 54% 61% Group (99/185) (119/196) 0.19 AJRCCM 2009, in press 6

7 TBTC Study 28, time to stable sputum culture conversion on liquid and solid media (very similar results for time to first negative) solid liquid Moxifloxacin answers Phase III trials underway for treatment shortening Using both solid and liquid media and evaluating them separately Safety and effectiveness look good for moxifloxacin use as a second line agent Widespread use of FQs poses a risk of emerging drug resistance Acknowledgements and cited studies First author Senior author Reference TBTC Study 27 TBTC Study 28 Rio Mox study D. Chaisson S. Dorman M. Conde W. Burman D. Chaisson D. Chaisson Am J Respir Crit Care Med 2006, 174:331 Am J Respir Crit Care Med 2006, in press Lancet 2009; 373:1183 OFLOTUB TBTC team lead, data team lead, branch chief, methodologist, Study 27, 28 PO R. Rustomjee M. E. Villarino L. Bozeman A. Vernon C. Heilig S. Goldberg D. Mitchisson Int J Tuberc Lung Dis 2008, 12:128 7

8 Activity of enhanced-dose rifapentine in the mouse model R 10 HZ (5/7) (M for H) P 10 HZ (5/7) (M for H) PLoS Medicine 2007: 4: e344 TBTC Study 29 Protocol Team Susan Dorman, P.I. Neil Schluger, Jason Stout (co-chairs) Ed Bates; Lorna Bozeman; Stefan Goldberg; John Johnson; Martino Laurenzi; Karen Megazzini; Grace Muzanye; Masa Narita; Payam Nahid; Susan Ray; Chad Heilig; Betial Teweldemedhin; Andrew Vernon; Marc Weiner TBTC Study 29 schema Sputum smear+ PTB suspect (n=480) randomization Rifapentine ~10 mg/kg INH+PZA+EMB 5/7 for 8 weeks Rifampin ~10 mg/kg INH+PZA+EMB 5/7 for 8 weeks assess for primary endpoints: Sputum culture conversion Regimen discontinuation ATS/CDC/IDSA-recommended continuation phase regimen 8

9 TBTC Study 29 Key inclusion criteria Non-pregnant adult with suspected TB with positive AFB smear Less than 6 days of TB treatment Informed consent Study regimens (open label) HRZE vs. HPZE, 5 days/week Primary endpoints 2-month culture status Completion of assigned study therapy TBTC Study 29 safety evaluations Web-based adverse event reports, In web-enrollment application Initial and update Daily review for urgent action, clarifications, MedDRA classification Biweekly study phase safety visits Symptoms and lab tests Weekly convening of data center safety group Review of biweekly visit data for AE reporting thresholds Review new and open events Missing forms reports Cumulative draft DSMB report TBTC Study 29 safety evaluations (cont d) DSMB reports Automated format SAS-programmed data extraction and organization Stratified treatment arm assignments AE listings and summaries Graphic display of every study phase value of key lab variables Frequent and regular submissions 4 weeks after 40 th enrollment After every 100 enrollments May 8 annual DSMB meeting in Atlanta 9

10 TBTC Study 29 milestones Protocol approved by CDC IRB May 2, st enrollment December 8, th enrollment February 20, st safety report submitted to DSMB March 20, wks after 40 th enrollment 100 th enrollment April 8, nd safety report to DSMB April 13, 2009 Atlanta DSMB meeting May 8, 2009 (3 rd safety report) Current enrollment June 8, (32%) 200 th enrollment July 2009 Last enrollment February 2010 Last 2-month culture result June 2010 TBTC Study 29 cumulative enrollments by week (through June 17, 2009) Number of enrollments Week of enrollment TBTC Study 29 cumulative enrollments by month (through June 17, 2009) N. America Spain S. Africa Uganda December January February March April May June 10

11 Rifapentine dose escalation studies before Phase III? Healthy volunteers Increasing daily RPT dose incrementally from 600 mg to 1200 mg Johns Hopkins based trial TB patients 50 patients each: 600, 900, 1200 mg 4-months rifapentine in 6-month regimens Primary endpoints of safety and tolerability Highest tolerated dose would advance to Phase III 11

12 Phase III regimens TBTC possibilities (P600 unless specified) 2HPZE/2HP 3HPZE 3HPZE P900 or HRZE R1200 3MPZE REMox 2MHRZ/2MHR 2EMRZ/2MR Rifaquin 2EMRZ/2P 2 M 2 2EMRZ/4P 1 M 1 OFLOTUB 2GHRZ/2GHR Savings in 2008 $ by Potential TB Treatment Regimen, Assuming Equal Efficacy and Adverse Events Estimated Cost of Drugs and DOT $5,000 $4,500 $4,000 $3,500 $3,000 $2,500 $2,000 $1,500 $1,000 $500 $0 0 $1,111 $1,883 $1,314 $2,228 $1,635 $4,613 $3,501 $2,730 $3,299 $2,384 $2,977 2HRZE/4HR 2HPZE/2HP (P 600) 3HPZE (P 600) 3HPZE (P 1200) 41% 48% 3HRZE (R 1200) 3MPZE (P 600) Savings Direct Costs * Suzanne Marks. Personal communication, June 2009 Next TBTC Studies Study 29 results? Last enrollment Feb 2010 Last 2-month culture result June 2010 Study 31 Phase II dose escalation? Phase II-III roll-over design? Phase III treatment shortening? Study 32 Phase III treatment shortening to follow Phase II dose escalation? 12