Clinical trial NCT01600963: A Study to Evaluate the Efficacy and Safety of TMC207 in Patients With Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis
Official title: A Phase III Placebo-controlled, Double-blind, Randomized Trial to Evaluate the Efficacy and Safety of TMC207 in Subjects With Sputum Smear-positive Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Multi-drug Resistant Tuberculosis
Keywords: Multi-drug resistant tuberculosis
Pre-extensively drug resistant tuberculosis
TMC207
Background regimen
Lead sponsor: Janssen Infectious Diseases BVBA
Sponsor class: INDUSTRY
First posted: 2012-05-17
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

- Diagnosed with sputum smear-positive pulmonary Mycobacterium multi-drug resistant tuberculosis; including pre-extensively drug resistant TB, and positive for acid fast bacilli on direct smear examination of expectorated or induced sputum specimen (\>=1+ smear positive within the preceding 3 weeks) at screening and also on Day -1

Exclusion Criteria:

* Has known infection with extensively drug resistant tuberculosis isolate
* Has a clinically significant active medical condition such as, but not limited to, hepatic, pancreatic, renal, cardiovascular, gastrointestinal, hematologic, neurologic, locomotor, immunologic, ophthalmologic (e.g., corneal opacification or ulcers, uveitis, chorioretinitis), metabolic (except stable diabetes based on the investigator's judgement), endocrine, oncological disease, muscular disease (e.g., myositis, rhabdomyolysis), or psychiatric, dermatological illness, or any other illness that the investigator considers should exclude the patient or that could interfere with the interpretation of the study results. Eligibility of patients with poorly controlled diabetes as indicated by hemoglobin A1c higher than the normal range at screening should be based on the investigators judgment

Primary outcomes:
measure: Number of patients with favorable treatment outcome at Week 60
timeFrame: Week 60
Secondary outcomes:
measure: Number of patients with confirmed culture conversion at Week 84
timeFrame: Week 84
measure: Number of patients with confirmed culture conversion at Week 60 or at time of trial discontinuation
timeFrame: Up to Week 132
measure: The number of patients with development of pre-extensively drug-resistant tuberculosis and extensively drug-resistant tuberculosis
timeFrame: Up to Week 132
measure: Time to sputum culture conversion
timeFrame: Up to Week 132
measure: Number of patients with negative culture and smear for tuberculosis
timeFrame: Up to Week 132
measure: Time to positive signal in Mycobacteria Growth Indicator Tube (MGIT960)
timeFrame: Up to Week 132
measure: Number of patients with confirmed culture conversion by lung cavity status
timeFrame: Up to Week 132
measure: Number of patients with confirmed culture conversion by geographic region
timeFrame: Up to Week 132
measure: Number of patients with confirmed culture conversion by human immunodeficiency virus status
timeFrame: Up to Week 132
measure: Number of patients with confirmed culture conversion by baseline resistance to anti-tuberculosis therapy
timeFrame: Up to Week 132
measure: Number of patients with Tuberculosis Symptom Profile symptoms at Week 36 and at the end of the treatment-free follow up
timeFrame: Up to Week 132
measure: Number of tuberculosis-related deaths per investigator assessment
timeFrame: Up to Week 132
measure: Number of patients with weight gain (greater than 5 percent) at Week 36 and at the end of the treatment-free follow up
timeFrame: Up to Week 132
measure: Number of patients with improvements in laboratory assessments at Week 36 and at the end of the treatment-free follow up
timeFrame: Up to Week 132
measure: Number of patients with improvements in chest radiograph assessments at Week 36 and at the end of the treatment-free follow up
timeFrame: Up to Week 132
measure: Number of patients that received salvage regimen with favorable treatment outcome 24 weeks after the end of the individualized salvage regimen
timeFrame: Up to Week 132
measure: Mean plasma concentrations of TMC207
timeFrame: Up to Week 36
measure: Mean plasma concentrations of N-monodesmethyl metabolite of TMC207
timeFrame: Up to Week 36
measure: Number of patients affected by an adverse event
timeFrame: Up to Week 132
measure: Number of patients with confirmed culture conversion at Week 36
timeFrame: Up to Week 132
measure: Number of patients who required lung surgeries (resection or pneumonectomy) during the study
timeFrame: Week 84
measure: Number of patients with confirmed culture conversion by baseline albumin grade
timeFrame: Up to Week 132
measure: Number of patients with confirmed culture conversion by baseline TMC207 minimal inhibitory concentration
timeFrame: Up to Week 132
measure: Number of patients with confirmed culture conversion at Week 132
timeFrame: Week 132
measure: Number of patients who required lung surgeries (resection or pneumonectomy) during the study
timeFrame: Week 132
measure: Number of patients who experienced death
timeFrame: Up to Week 132
measure: 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
timeFrame: Up to Week 132
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
city: Rio De Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Phnom Penh
country: Cambodia
city: Beijing
country: China
city: Changsha
country: China
city: Chongqing
country: China
city: Fuzhou
country: China
city: Jinan
country: China
city: Nanjing
country: China
city: Shanghai
country: China
city: Kohtla-Järve
country: Estonia
city: Talinn
country: Estonia
city: Addis Ababa
country: Ethiopia
city: Gondar
country: Ethiopia
city: Tbilisi
country: Georgia
city: Busan
country: Korea, Republic of
city: Daegu
country: Korea, Republic of
city: Gwangju
country: Korea, Republic of
city: Gyeongsangnam-Do
country: Korea, Republic of
city: Incheon
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Stopinu Region
country: Latvia
city: Monterrey
country: Mexico
city: Lima
country: Peru
city: Quezon City
country: Philippines
city: Arkhangelsk
country: Russian Federation
city: Ekaterinburg
country: Russian Federation
city: Moscow
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Orel
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Paarl
country: South Africa
city: Sandringham
country: South Africa
city: Ysterplaat
country: South Africa
city: Changhua County
country: Taiwan
city: New Taipei City
country: Taiwan
city: Taichung
country: Taiwan
city: Tainan
country: Taiwan
city: Nonthaburi
country: Thailand
city: Kecioren
country: Turkey
city: Donetsk
country: Ukraine
city: Kiev
country: Ukraine
city: Ternopil
country: Ukraine
Study officials:
affiliation: Janssen Infectious Diseases BVBA
name: Janssen Infectious Diseases BVBA Clinical Trial
role: STUDY_DIRECTOR
References: