Efficacy and Safety of 'Fixed Dose' versus 'Loose' Drug Regimens for Treatment of Pulmonary Tuberculosis in Two High TB-Burden African Countries: A Randomized Controlled Trial.
BACKGROUND
There are limited data on the performance of the use of fixed-dose combination (FDC) TB drugs when used under programmatic settings in high TB-endemic countries. We evaluated the efficacy and safety of FDC versus loose formulation (LF) TB treatment regimens for treatment of pulmonary TB (PTB) in the context of actual medical practice in prevailing conditions within programmatic settings in five sites in two high TB-burden African countries.


METHODS
A two-arm, single-blind, randomized clinical trial comparing FDCs with separate LFs involving 1000 adults newly diagnosed with culture positive PTB was conducted at five sites in two African countries between 2007 and 2011. Participants were randomized to receive daily treatment with anti-TB drugs given as either FDC or separate LFs for 24 weeks (intensive phase- 8 weeks of isoniazid, rifampicin, ethambutol and pyrazinamide; continuation phase- 16 weeks of rifampicin and isoniazid). Primary outcome measures were microbiological cure and safety at the end of six months' treatment; pre-specified non-inferiority margin for difference in cure rate was 4%. The primary efficacy analysis was based on the modified intent to treat (mITT) cohort comprising all randomized patients with a positive baseline culture result for TB and who received at least one dose of study treatment. Patients missing end of treatment culture results were considered failures. Further analyses were done in which mITT patients without an end of treatment (EOT) culture were excluded in a complete case analysis (mITTcc) and a per protocol cohort analysis defined as mITTcc patients who received at least 95% of their intended doses and had an EOT culture result.


RESULTS
In the mITT analysis, the cure rate in the FDC group was 86.7% (398/459) and in the LF group 85.2% (396/465) (difference 1.5-% (90% confidence interval (CI) (-2.2%- 5.3%)). Per Protocol analysis showed similar results: FDC 98.9% (359/363) versus LF 96.9% (345/356), (difference 2.0% (90% CI: 0.1%- 3.8%)). The two arms showed no significant differences in terms of safety, early culture conversion and patient adherence to treatment.


CONCLUSIONS
The comparison of the two drug regimens satisfied the pre-specified non-inferiority criterion. Our results support the WHO recommendations for the use of FDC in the context of actual medical practice within health services in high TB-endemic countries.


BACKGROUND
ISRCTN Registry 95204603.
Armauer Hansen Research Institute (AHRI), ALERT Compound, Addis Ababa, Ethiopia.
Abraham
A
Aseffa
German Leprosy and Tuberculosis Relief Association, Hill View, Enugu, Nigeria.
Joseph N
JN
Chukwu
Special Programme for Research and Training in Tropical Diseases (WHO/TDR), Avenue Appia, Geneva, Switzerland.
Mahnaz
M
Vahedi
University of Nigeria Enugu Campus, Enugu, Nigeria.
Emmanuel N
EN
Aguwa
Armauer Hansen Research Institute (AHRI), ALERT Compound, Addis Ababa, Ethiopia.
Ahmed
A
Bedru
Armauer Hansen Research Institute (AHRI), ALERT Compound, Addis Ababa, Ethiopia.
Tesfamariam
T
Mebrahtu
Division of Clinical Sciences, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria.
Oliver C
OC
Ezechi
Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Getnet
G
Yimer
Armauer Hansen Research Institute (AHRI), ALERT Compound, Addis Ababa, Ethiopia.
Lawrence K
LK
Yamuah
Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia.
Girmay
G
Medhin
Biostatistics Unit, Medical Research Council, Durban, South Africa.
Cathy
http://orcid.org/0000-0002-3506-4915
C
Connolly
Biostatistics Consultant, Arlington, Virginia, United States of America.
Wasima
http://orcid.org/0000-0001-7671-7305
W
Rida
Department of Internal Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
Getachew
G
Aderaye
Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom.
Alimuddin I
AI
Zumla
World Health Organization, Inter-country Support Team for East and Southern Africa, Harare, Zimbabwe.
Philip C
PC
Onyebujoh
D000328:Adult; D000349:Africa; D000368:Aged; D000995:Antitubercular Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide / Q000008:administration & dosage; D012293:Rifampin / Q000008:administration & dosage; D013183:Sputum / Q000187:drug effects / Q000382:microbiology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin