Tuberculosis Trials Consortium (TBTC) Update on New Drug Work for DS TB 2012

Transcription

1 Tuberculosis Trials Consortium (TBTC) Update on New Drug Work for DS TB 2012 Stop TB Work Group on New Drugs Annual Meeting, Kuala Lumpur, 2012 Clinical Development of TB Drugs Payam Nahid, MD, MPH Tuberculosis Trials Consortium San Francisco site PI and Vietnam site co-pi University of California, San Francisco National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

2 The TB Trials Consortium (TBTC) Sponsored by CDC s Division of TB Elimination (which serves at the U.S. national TB program), with Data & Coordinating Center in DTBE s Clinical Research Bran ch (CRB) Since 1995, TBTC has enrolled over 13,000 persons in TB trials

3 Classes of TBTC Studies, Type St udy Description Phase 3-4 DS TB Disease Phase 2-3 LTBI Phase 2-3 DS TB Disease Phase 2-3 MDR TB S22 S23 S24 S26 S33 S25 S27 S28 S29 S29X S31** S30 S32** Once weekly INH/RPT, contin. phase Intermittent RBT-based therapy in HIV-TB Intermittent therapy if INH resistant/intolerant Once-weekly 3-mo INH/RPT in LTBI by DOT 3HP for LTBI given as DOT vs self-administered Dose-ranging once weekly INH/RPT, contin. phase Moxi for EMB in intensive phase for disease Moxi for INH in intensive phase for disease Daily RPT for RIF in intensive phase for disease Dose ranging RPT in intensive phase for disease 3-4 mo RPT-based therapy for disease Pilot low-dose linezolid in MDR Dose optimization for levofloxacin in MDR *All include PK sub-studies except S24 ** Proposed

4 TBTC Study 26: Phase 4 and follow-up 1. Publications pending re pediatric results, findings in HIV-infected persons, adverse events, rifamycin hypersensitivity, adherence and retention 2. Phase 4 : a. Ongoing DTBE surveillance of severe adverse events in LTBI therapy b. Phase 4 implementation study in several cities (DTBE) c. TBESC LTBI study of >40,000 pts beginning d. TBTC Study 33 will assess 3HP by DOT vs self-administered e. ACTG 5279 is assessing an ultra-short 1-month HP regimen for HIV-LTBI

5 iadhere (TBTC Study 33) Goal: Compare adherence to the 3HP given by DOT versus SAT (standard and enhanced) Secondary: drug toxicity, development of TB, drug resistance, LTBI costs, and others Design: Open label multi-center (13 sites) international (USA, Spain, RSA, Brazil, Hong Kong) RCT Target population: adults with LTBI All 3H 900 P arms: 1. DOT (control) 2. SAT 3. esat (SAT + SMS) Comparison: non-inferiority (delta 15%) Sample Size: 1,000 (~333/arm) Visits: 3 (or 4) treatment visits (adherence, AEs) end of study (TB rates) Adherence: patient report, pill count, MEMS Current status First enrollment - Sept 18, pt. enrolled as of Nov 9, 2012 Projected completion - Dec, 2013 Future of LTBI Tx? + = 2xPriftin 150mg isoniazid PH 300/300 3 pills X 12 times by SAT

6 Four TBTC phase 2 studies to-date evaluating potential of moxifloxacin (M) and rifapentine (P) TBTC Study number: x first enrollment 2003 Jul 2006 Feb 2008 Dec 2011Nov last enrollment 2005 Mar 22 * 2007 Mar 13 * 2010 Nov 23 * 2011Oct 11 * total enrolled ** ** ** ** protocol correct for efficacy % % % primary outcome efficacy efficacy efficacy tolerability intervention M vs E *** M vs H *** P(10)vs R *** P10, P15 P20, or R10 *** frequency 3/7 vs 5/7 5/7 5/7 7/7 food empty stomach high fat meal * months to enroll ** enrollments / month *** components of standard 2-month intensive phase regimen, HRZE, followed by CDC/ATS continuation phase H, isoniazid; R, rifampin, Z, pyrazinamide; E, ethambutol; M, moxifloxacin; P, rifapentine; (mg/kg dose)

7 TBTC Studies 27 & 28 Both multi-site studies Moxi substituted for EMB (S27) & for INH (S28) Both failed to show a significant difference in 8-week sputum result Both found post-hoc differences at earlier time-points Proportion sputum culture negative, by Week of therapy Percent sputum cult negative P=0.05 P=0.05 Wk 2 Wk 4 Wk 6 Wk 8 3.5% MOXI P=0.57 INH TBTC Study 28 Solid Medium TBTC Study 27 Both Media Two separate single site studies in Durban and Rio found significant differences Now awaiting phase 3 results of Oflotub (?CROI 2013) and REMox (?early 2014)

8 TBTC St udy 29 Rifapentine Rifampin first enrollment 2008 Dec last enrollment 2010 Nov 23* total enrolled ** protocol correct for efficacy % primary outcome efficacy intervention P(10) vs R *** frequency 5/7 food empty stomach * months to enroll ** enrollments / month *** components of standard 2-month intensive phase regimen, HRZE, followed by CDC/ATS continuation phase H, isoniazid; R, rifampin, Z, pyrazinamide; E, ethambutol; M, moxifloxacin; P, rifapentine; (mg/kg dose) LJ MGIT

9 TBTC Study 29X [extension] Rifapentine dose escalation to evaluate safety of higher doses of rifapentine (not efficacy) Safety supported TBTC Study 29B up to 20 mg/kg (Dooley ATS 2011) TBTC Study 26: ~ 4000 LTBI patients, ~ 15 mg/kg (900 mg) 1x/ wk, 3 mont hs, (Sterling ATS 2011) 4 arm study, 80 patients in each arm, 7/7 days, DOT, with food Main objective is tolerability; efficacy is secondary endpoint Control=Rifampin, 10 mg/kg (open label) Rifapentine 10, 15, and 20 mg/kg (blinded) With placebo (dummy tabs) to conceal dosing Intensive and sparse PK sub-studies DSMB reviews after 80, 180, and 280 enrollments

10 TBTC Study 29x completion timeline Last patient in October 10, 2012 Last study phase visit December 19, 2012 Un-blinding for analysis Initial findings of primary analysis January, 2013 Tolerability Preliminary PK (efficacy pending) Last final study phase culture result February 13, 2013 Implication review May, 2013 Including Efficacy and other studies Proceed with phase 3? Last possible continuation phase visit July, 2013

11 Drug exposures RPT (linear scale) Mean concentration (mcg/ml) TBTC Study 29B: Single dose RPT PK 5 mg/kg RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg RPT Time from dose (h) 40 Median dose, by cohort: 5 mg/kg: 450 mg 10 mg/kg: 750 mg 15 mg/kg: 1200 mg 20 mg/kg: 1650 mg TBTC Study 29B: Multiple dose RPT PK Mean concentration (mcg/ml) mg/kg RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg RPT Dooley et al [Study 29B] Clinical Pharmacology and Therapeutics : Time from dose (h)

12 Rifapentine key questions Being addressed in ACTG Study A5311 [Chair Kelly Dooley] Given time-dependent clearance, when is steady state reached, and what are concentrations at that time? Design: 24 hour PK at dose day 1, 14, and 28 Is there really a lack of increase in drug concentrations as drug dose is increased from 15 to 20 mg/kg? What are some strategies for overcoming decreased absorption with increasing dose Divided dosing Design: 20 mg/kg/d, single dose vs 10 mg/kg twice daily Meal type (is an egg enough?) Design: low fat meal vs egg

13 Phase 3, rifapentine treatment shortening study-- determining whether to proceed Three questions for TBTC Study 29x Are higher doses safe and tolerable? Are higher drug exposures achieved with higher doses? Does time to first negative culture differ by treatment arm? Other rifapentine studies ACTG 5311 Dooley et al Rifaquin (dosing 1-2x per week) TBTC completing RioMAR study (phase 2 Moxi+RPT450), which began with NIAID/DMID funding Issues raised by Prof. Mitchison 1. Can RPT achieve sufficient increase in Cmax? 2. Is protein binding an intractable challenge?

14 Newest effort: Phase 2 Novel Regimens for DS TB Representatives of TBTC met with TB Alliance and industry colleagues on October 23, 2012 in Atlanta to discuss collaboration on a phase 2 trial of novel regimens in drug-sensitive TB Use of novel MAMS design considered Details under discussion TBTC effort being led by Jason Stout and Kelly Dooley

15 The End Thank you for your attention Atlanta-based TBTC team at CDC And thanks to - Neil Schluger - Bill Burman - Tim Sterling - Susan Dorman - Kelly Dooley - Jason Stout - Fred Gordin - Dick Chaisson - Bob Horsburgh - John Johnson - Stefan Goldberg - Andy Vernon - Elsa Villarino - Bill Mac Kenzie and the TBTC team

16 Key Acknowledgements Bayer provided moxifloxacin for Studies 27 and 28 Global Alliance for TB Drug Development supported clinical trial report writing for Study 28 sanofi-aventis provided rifapentine and rifampin for rifapentine studies, and supported sub-studies and report preparation Study 29B was supported by sanofi and the CDC Foundation, and was conducted at Johns Hopkins University Study 29 PK was also supported by the Veterans Administration Medical Center in San Antonio ACTG and NIAID are supporting A5311 (HD RPT PK in healthy volunteers); IMPAACT and ACTG enrolled into S26