Rifapentinecontaining treatment shortening regimens for pulmonary tuberculosis UZUCSF

Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis UZ-UCSF ARD April 08, 2016 W. Samaneka MBCh. B, MSc Clin Epi, Dip HIV Man

Background • TB continues to cause significant morbidity and mortality worldwide (Corbett et al. , 2003). • Multi-drug resistant (MDR) and extensively-drug resistant (XDR) TB cases are on the rise. • A major obstacle to the control of TB is poor adherence with lengthy (at minimum 6 months) and complicated treatment regimens • Shortening the duration of treatment for TB is a global research priority.

Background • Improved regimens that shorten treatment duration could reduce the incidence of TB by up to 27% by 2050 and reduce deaths by 25% (Abu-Raddad et al, 2009). • Use of directly observed (DOT) can improve patient adherence but is logistically difficult and expensive to implement (Mc. Donald et al. , 1982).

Recent TB Rx shortening trials • The Rapid Evaluation of Moxifloxacin in Tuberculosis (REMox. TB) (Gillespie et al 2014) • The Oflotub/Gatifloxacin for TB Project (Merle et al 2014) • The RIFAQUIN Trial (Jindani, 2014) • The shortened regimens were not noninferior

Design • This will be an international, multicenter, randomized, controlled , open label, 3 arm, phase 3 non-inferior trial.

Purpose • To determine whether one or two four-month regimens of tuberculosis treatment are as effective as a standard six-month regimen for treatment of pulmonary tuberculosis (TB).

Current DS TB regimen • 2 -month intensive phase with four drugs (rifampin, isoniazid, pyrazinamide, andethambutol) • followed by a 4 -month continuation phase with two drugs (isoniazid and rifampin (control)

Proposed short regimens • Regimen 1: single substitution of rifapentine (P) for rifampin: two months of H/P/E/Z , followed by two months of H/P. • Regimen 2: a double substitution of rifapentine for rifampin and moxifloxacin (M) for ethambutol: two months of H/P/M/Z followed by two months of H/P/M.

Primary Objectives • Evaluate efficacy of a high dose rifapentine-containing regimen to determine whether the single substitution of RPT for RIF makes it possible to reduce to 4 months (17 weeks) the duration of treatment – 2 PHZE/2 PH • Evaluate efficacy of a 4 month (17 weeks) regimen that substitutes a) high dose RPT for RIF and b) MOX for EMB to determine whether reduction to 4 months (17 weeks) duration is possible – 2 PHZM/2 PHM

Secondary Objectives • • Evaluate safety of the regimens Evaluate tolerability of the regimens Sparse PK: Conduct PK/PD study of the TB drugs EFV PK: Evaluate PK of efavirenz-based ARV treatment among patients with TB/HIV co-infection.

Study Population • M & F participants > 18 yr suspected to have PTB : AFB smear positive OR is Xpert positive • Safety labs: LFTs, Hb, Electrolytes • Target enrollment is 2, 500 participants (TBTC and ACTG Sites) • Harare site target 200 • Duration per participant is approximately 18 months 12

Participating Sites TBTC Study Sites 2010 -2020 ACTG Clinical Research Sites

Primary Endpoints • Efficacy: • TB disease-free survival at twelve months after study treatment assignment. • Safety: • Proportion of participants with grade 3 or higher adverse events during study drug treatment

Secondary Endpoints • TB disease-free survival at eighteen months after study treatment assignment • Proportion of participants who are culture negative at eight weeks • Time to stable sputum culture conversion • Discontinuation of assigned treatment for a reason other than microbiological ineligibility.

Study status • • • Open to accrual at TBTC sites Jan 2016 ACTG sites study not yet open Harare Site expected start date April 2016 City of Harare approvals in place Local clinics identified (DOT) Start up packages submitted JREC approval MRCZ- awaiting approval MCAZ -awaiting approval

Acknowledgements • • • NIAID, NIH CDC Sanofi UZ-UCSF Prof James Hakim ; CRS Leader Dr Chonzi Director , City Health Dept Dr Duri , City Of Harare TB Dr Bara (MDR TB Head) Matrons City of Harare Clinics ACTG site staff •

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