The purpose of this study is to provide safety and efficacy data for TMC207 and to demonstrate that TMC207 added to a background regimen (BR) is superior to treatment with the BR plus placebo.
This is a randomized (individuals will be assigned by chance to study treatments), double-blind (individual and investigator will not know the identity of study treatments), placebo (substance containing no active medication)-controlled, 2-arm study in patients with sputum smear-positive pulmonary infection with multi-drug resistant tuberculosis (MDR-TB) defined as tuberculosis (TB) due to infection with a strain of Mycobacterium tuberculosis (M. tuberculosis) that is resistant to both isoniazid and rifampin, or pre-extensively drug resistant (pre-XDR-TB) defined as TB due to infection with an MDR strain of M. tuberculosis that is resistant either to at least one of the injectable second-line drugs \[amikacin, kanamycin, or capreomycin\] or to any fluoroquinolone, but not both). Approximately 600 patients with sputum smear-positive pulmonary infection with MDR-TB or pre-XDR TB will receive a background regimen (BR) of MDR-TB therapy and will be randomly assigned in a 1:1 ratio to one of 2 treatment arms (Arms A \[TMC207 + BR\] and B \[placebo + BR\]). All patients will receive TMC207 or placebo in combination with a BR of MDR-TB therapy. TMC207 (or matching placebo) will be taken as oral tablets at a once daily dose of 400 mg for the first 2 weeks and 200 mg 3 times/week for the remaining period of TMC207 (or matching placebo) administration. The study will consist of a screening phase of a maximum of 3 weeks, a 36-week double-blind treatment phase, followed by a 48-week follow-up phase up to Week 84, also referred to as the treatment-free follow-up. After the treatment-free follow-up phase, there will be a safety follow-up phase of 48 weeks up to Week 132. Patients from Arms A or B who fail treatment according to prespecified criteria will be given the option to receive 24 weeks of TMC207 plus an individualized salvage regimen taken for a duration consistent with national TB guidelines. Efficacy and pharmacokinetic evaluations will be performed at time points as detailed in the protocol. Safety will be monitored throughout the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Type=exact number, unit=mg, number=400 mg for the first 2 weeks and 200 mg 3 times per week for the remainder of the treatment period, form=tablet, route=oral administration.
Form=tablet, route=oral administration, taken once daily for 2 weeks then 3 times per week for the remainder of the treatment period.
Type=exact number, unit=mg, number=200 mg 3 times per week, form=tablet, route=oral administration.
Unnamed facility
Number of patients with favorable treatment outcome at Week 60
Time frame: Week 60
Number of patients with confirmed culture conversion at Week 84
Time frame: Week 84
Number of patients with confirmed culture conversion at Week 60 or at time of trial discontinuation
Time frame: Up to Week 132
The number of patients with development of pre-extensively drug-resistant tuberculosis and extensively drug-resistant tuberculosis
Time frame: Up to Week 132
Time to sputum culture conversion
Time frame: Up to Week 132
Number of patients with negative culture and smear for tuberculosis
Time frame: Up to Week 132
Time to positive signal in Mycobacteria Growth Indicator Tube (MGIT960)
Time frame: Up to Week 132
Number of patients with confirmed culture conversion by lung cavity status
Time frame: Up to Week 132
Number of patients with confirmed culture conversion by geographic region
Time frame: Up to Week 132
Number of patients with confirmed culture conversion by human immunodeficiency virus status
Time frame: Up to Week 132
Number of patients with confirmed culture conversion by baseline resistance to anti-tuberculosis therapy
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Type=exact number, unit=mg, number=400 mg once daily for 2 wks and 200mg three times per week for 22 weeks, form=tablet, route=oral administration.
Porto Alegre, Brazil
Unnamed facility
Rio de Janeiro, Brazil
Unnamed facility
São Paulo, Brazil
Unnamed facility
Phnom Penh, Cambodia
Unnamed facility
Beijing, China
Unnamed facility
Changsha, China
Unnamed facility
Chongqing, China
Unnamed facility
Fuzhou, China
Unnamed facility
Jinan, China
Unnamed facility
Nanjing, China
...and 34 more locations
Time frame: Up to Week 132
Number of patients with Tuberculosis Symptom Profile symptoms at Week 36 and at the end of the treatment-free follow up
Time frame: Up to Week 132
Number of tuberculosis-related deaths per investigator assessment
Time frame: Up to Week 132
Number of patients with weight gain (greater than 5 percent) at Week 36 and at the end of the treatment-free follow up
Time frame: Up to Week 132
Number of patients with improvements in laboratory assessments at Week 36 and at the end of the treatment-free follow up
Time frame: Up to Week 132
Number of patients with improvements in chest radiograph assessments at Week 36 and at the end of the treatment-free follow up
Time frame: Up to Week 132
Number of patients that received salvage regimen with favorable treatment outcome 24 weeks after the end of the individualized salvage regimen
Time frame: Up to Week 132
Mean plasma concentrations of TMC207
Time frame: Up to Week 36
Mean plasma concentrations of N-monodesmethyl metabolite of TMC207
Time frame: Up to Week 36
Number of patients affected by an adverse event
Time frame: Up to Week 132
Number of patients with confirmed culture conversion at Week 36
Time frame: Up to Week 132
Number of patients who required lung surgeries (resection or pneumonectomy) during the study
Time frame: Week 84
Number of patients with confirmed culture conversion by baseline albumin grade
Time frame: Up to Week 132
Number of patients with confirmed culture conversion by baseline TMC207 minimal inhibitory concentration
Minimal inhibitory concentration is defined as lowest concentration of an antimicrobial agent that will inhibit the visible growth of an organism.
Time frame: Up to Week 132
Number of patients with confirmed culture conversion at Week 132
Time frame: Week 132
Number of patients who required lung surgeries (resection or pneumonectomy) during the study
Time frame: Week 132
Number of patients who experienced death
Time frame: Up to Week 132
Number of patients will be qualified as cure based on the WHO outcome definition and the number of treatment failures, deaths, transfer out/defaults, and treatment completed
Cure is defined as an multidrug-resistant tuberculosis (MDR-TB) patient who has completed the study procedures according to the protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of the study. If only one positive culture is reported during that time, a patient may still be considered cured, provided that this positive culture is followed by a minimum of 3 consecutive negative cultures taken at least 30 days apart. Treatment failure is defined as a patient who completed the study procedures and was not cured as per the "Cure" definition based on the WHO classification during the study procedures. Defaults is defined as patients who discontinued study procedures for any reason. Treatment completed is defined as an MDR-TB patient who has completed the study procedures but does not meet the definition for cure or treatment failure due to lack of bacteriologic results.
Time frame: Up to Week 132