Clinical trial NCT00449644: TMC207-TiDP13-C208: Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Participants With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).
Official title: A Phase II, Placebo-controlled, Double-blind, Randomized Trial to Evaluate the Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Subjects With Newly Diagnosed Sputum Smear-positive Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: Tuberculosis
MDR TB
Lead sponsor: Janssen Infectious Diseases BVBA
Sponsor class: INDUSTRY
First posted: 2007-03-20
Enrollment: 208
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to demonstrate that the antibacterial activity of TMC207 is better than placebo when added to a standardized Background Regimen (BR) for treatment of multi-drug resistant TB. Also safety and tolerability will be evaluated.

Detailed description: The trial will be conducted in 2 consecutive stages, an exploratory (investigative) stage (Stage 1) and a proof of effectiveness stage (Stage 2). During Stage 1, a panel of 50 participants will be randomized (participants are assigned different treatments based on chance) to receive either TMC207 or placebo for 8 weeks on top of a BR. In Stage 2, another panel of 150 participants will be randomized to receive either TMC207 or placebo for 24 weeks on top of a BR. TMC207 will be dosed as 400 mg every day for the first 2 weeks, and as 200 mg 3 times/week for the following 6 or 22 weeks during Stages 1 and 2, respectively. When the participants in Stage 1 have completed 8 weeks double-blind (neither theparticipant nor the physician knows whether drug or placebo is being taken, or at what dosage) treatment with TMC207 or placebo (or have discontinued earlier), the primary Stage 1 analysis will be performed on all data of the first 8 weeks of treatment. Following this Stage 1 analysis, Stage 2 will be initiated and a panel of 150 new participants will be enrolled. After the double-blind treatment phase in both Stage 1 and Stage 2, participants will continue to receive MDR-TB treatment as per national treatment guidelines. They will be followed for safety, tolerability, pharmacokinetics, and microbiological efficacy for 96 weeks after receiving their last dose of TMC207 or placebo. The Data Safety Monitoring Board Committee will review these data on a regular basis. The DSMB/DSMC is a group of experts in tuberculosis and clinical trial conduct who have no commercial interests in the development of TMC207 and the company (Tibotec, BVBA) that is developing the new TB drug.

Eligibility criteria: Inclusion Criteria:

* Females of non-childbearing potential
* Patients with newly diagnosed sputum smear-positive pulmonary MDR-TB infection
* Patients must consent to HIV-testing
* Patients must be willing to discontinue all TB drugs to allow 7 days washout
* Patients having normal weight
* Patients are willing to be hospitalized per standard of care.

Exclusion Criteria:

* Previously having been treated for MDR-TB
* Having a significant cardiac arrhythmia that requires medication
* For HIV infected patients, having a CD4+ count \< 300 cells/µL
* Patients with complicated or severe extrapulmonary manifestations of TB or neurological manifestations of TB
* Patients who will require surgical procedure for management of their TB
* Evidence of chorioretinitis, optic neuritis, or uveitis at screening
* Having had a drug susceptibility test performed prior to screening and being not susceptible to at least 3 of the 5 classes of TB drugs used to treat MDR-TB
* Women who are pregnant and/or breastfeeding.

Primary outcomes:
measure: The Time to Sputum Culture Conversion at Week 8 (Stage 1)
timeFrame: Week 8, Stage 1
measure: The Time to Sputum Culture Conversion at Week 24 (Stage 2)
timeFrame: Week 24, Stage 2
Secondary outcomes:
measure: The Time to Sputum Culture Conversion at Week 24 (Stage 1)
timeFrame: Week 24, Stage 1
measure: The Time to Sputum Culture Conversion at Week 72 (Stage 2)
timeFrame: Week 72, Stage 2
measure: The Percentage of Participants With Sputum Culture Conversion (Stage 1)
timeFrame: Week 8, 24, and 104 (Stage 1)
measure: The Percentage of Participants With Sputum Culture Conversion (Stage 2)
timeFrame: Week 24, Week 72, and Week 120 (Stage 2)
Other outcomes:
Locations:
city: Rio De Janeiro
country: Brazil
city: Chennai
country: India
city: New Delhi
country: India
city: Stopinu Region
country: Latvia
city: Lima
country: Peru
city: Quezon City
country: Philippines
city: Moscow
country: Russian Federation
city: Bethelsdorp
country: South Africa
city: Cape Town
country: South Africa
city: Durban
country: South Africa
city: George
country: South Africa
city: Klerksdorp
country: South Africa
city: Sandringham
country: South Africa
city: Chiang Mai
country: Thailand
city: Nakhon
country: Thailand
city: Nonthaburi
country: Thailand
Study officials:
affiliation: Janssen Infectious Diseases BVBA
name: Janssen Infectious Diseases BVBA Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405. doi: 10.1056/NEJMoa0808427.
citation: Meyvisch P, Kambili C, Andries K, Lounis N, Theeuwes M, Dannemann B, Vandebosch A, Van der Elst W, Molenberghs G, Alonso A. Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial. PLoS One. 2018 Jul 19;13(7):e0200539. doi: 10.1371/journal.pone.0200539. eCollection 2018.
citation: Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeva I, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van Baelen B, van Heeswijk RP, Dannemann B; TMC207-C209 Study Group. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016 Feb;47(2):564-74. doi: 10.1183/13993003.00724-2015. Epub 2015 Dec 2.
citation: Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, Leimane V, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, De Paepe E, van Heeswijk RP, Dannemann B; TMC207-C208 Study Group. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014 Aug 21;371(8):723-32. doi: 10.1056/NEJMoa1313865.