E FFICACY AND S AFETY OF A 4-D RUG F IXED -D OSE C OMBINATION R EGIMEN C OMPARED W ITH S EPARATE D RUGS FOR T REATMENT OF P ULMONARY T UBERCULOSIS T HE S TUDY C R ANDOMIZED C ONTROLLED T RIAL Christian Lienhardt, MD, MSc, PhD / Sharlette V. Cook, MSc / Marcos Burgos, MD Victoria Yorke-Edwards, MSc / Leen Rigouts, MD / Gladys Anyo, MD / Sang-Jae Kim, MD Amina Jindani, MD / Don A. Enarson, MD / Andrew J. Nunn, MSc for the Study C Trial Group JAMA, April 13, 2011—Vol 305, No. 14 호흡기내과 R2 박재훈

INTRODUCTION Fixed-dose combinations(FDCs) prevent the emergence of drug resistance reduce the risk of incorrect dosage, simplify drug procurement 2-/3-drug FDCs are well tolerated and no difference in acquired drug resistance 3-drug FDC had an similar efficacy of a separate- drugs regimen and some advantages of acceptability to patients (randomized trial conducted in Hong Kong) To evaluate the efficacy and safety of an FDC in the initial intensive phase of treatment of patients with newly diagnosed smear-positive pulmonary tuberculosis

METHODS – DESIGN AND PROCEDURES The Study C trial(2003~2008) parallel-group, open-label, noninferiority, randomized controlled trial 11 clinical trial sites in 9 countries in Africa, Asia, Latin America The test (FDC) regimen initial intensive phase of 8 weeks of daily rifampicin, isoniazid, pyrazinamide, ethambutol in FDC tablets followed by 18 weeks of rifampicin and isoniazid FDC tablets 3 times weekly The control (separate-drugs) regimen same drugs in separate formulations administered daily in the initial intensive phase, followed by 18 weeks of rifampicin and isoniazid FDC tablets 3 times weekly

8 wks 18 wks

METHODS – ELIGIBILITY CRITERIA Patients newly diagnosed pulmonary Tb 18 years older, 2 sputum specimens AFB(+) no previous anti-Tb hemotherapy less than 4 weeks of chemotherapy for the current disease episode Patients were not eligible unlikely to survive the initial weeks of treatment tuberculous meningitis, extrapulmonary disease, DM, chronic liver/kidney disease, blood disorders, peripheral neuritis, pregnant, breast feeding psychiatric illness, alcoholism negative culture result at entry, rifampicin resistance before treatment

METHODS Follow-up 2, 3, 5, 6 months during treatment 8, 10, 12, 15, 18, 24, 30 months in the f/u phase Sample size Noninferiority trial - the FDC regimen was not inferior to the separate-drugs regimen To achieve 90% power to demonstrate noninferiority as defined required 412 patients in each treatment group 749 patients were required in each treatment group to ensure adequate numbers of participants for the per-protocol analysis

METHODS – STATISTICAL ANALYSIS Modified intention-totreat (ITT) population randomized patients who received study medication on at least 1 occasion excluding no culture-confirmed Tb, rifampicin- or multidrugresistant disease, patients who died by non-Tb cause, reinfection after cure, those unassessable at 18 months Per-protocol population all patients included in the ITT excluding those who did not receive the regimen as prescribed 9 weeks of Tx in intensive phase 60 doses(2 weeks) in the continuation phase * protocol requirement : 18 weeks of 3-times-weekly treatment, 54 doses modified Tx. for reasons other than bacteriological failure or relapse (including patients changing treatment for adverse drug reactions, following return after default, or attributable to concomitant HIV infection)

METHODS – EFFICACY ANALYSIS “unfavorable” outcome (1) bacteriological failure or relapse by 18 months > 20 colonies or 2 cultures of > 10 colonies’ growth no reinfection (2) Changing treatment after month 5 because of AFB(+) or a clinical or radiographic deterioration in the absence of bacteriological confirmation (3) death due to active Tb “favorable” outcome

METHODS – EFFICACY ANALYSIS Classifying patients who changed treatment Modified ITT model 1 changing or refusal of continuing treatment for whatever reason (eg, bacteriological failure/relapse, adverse event, default, drug resistance) Modified ITT model 2 (recommended post hoc) changing of treatment for reasons other than therapeutic outcomes

RESULTS

COMMENT 4-drug FDC regimen may be noninferior to a regimen of separately administered drugs in term (1) the use of a combined failure/relapse end point (2) the need to exclude individuals with proven reinfection (3) follow-up period of at least 18 months post randomizations of efficacy

COMMENT Noninferiority per-protocol analysis : satisfaction Modified ITT 1 analysis : unsatisfaction Modified ITT 2 analysis : satisfaction Adverse events Few, similar frequency FDC group  removal

COMMENT Limitation rifampicin and isoniazid FDC tablets during the continuation phase in both groups  decreased the possibility of observing a difference in efficacy between the 2 groups Advantage of FDCs Fewer pills (3-4 vs 9-16) No difference of drug resistance emergence

COMMENT Support the WHO recommendations for use of FDCs because of the potential advantages associated with administration For efficient tuberculosis control worldwide quality-assured FDCs are made available