TMC207-TiDP13-C208: Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Participants With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).

Study Overview
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Brief Summary
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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
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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.

Official Title
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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).

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: TMC207
* Drug: Placebo
* Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC207 Stage 1<br>TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 weeks in addition to Background Regimen (BR) for multi-drug resistant tuberculosis (MDR-TB). | Drug: TMC207<br>* TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 or 22 weeks.<br>Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)<br>* Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.<br>|
| Placebo Comparator: Placebo Stage 1<br>Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 weeks in addition to BR for MDR-TB. | Drug: Placebo<br>* Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 or 22 weeks.<br>Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)<br>* Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.<br>|
| Experimental: TMC207 Stage 2<br>TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 22 weeks in addition to BR for MDR-TB. | Drug: TMC207<br>* TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 or 22 weeks.<br>Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)<br>* Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.<br>|
| Placebo Comparator: Placebo Stage 2<br>Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 22 weeks in addition to BR for MDR-TB. | Drug: Placebo<br>* Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 or 22 weeks.<br>Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)<br>* Background Regimen (BR) of antibacterial drugs used in the treatment of TB according to national TB program and selected at the baseline visit as speciified in the protocol for up to 96 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time to Sputum Culture Conversion at Week 8 (Stage 1) | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. | Week 8, Stage 1 | 
| The Time to Sputum Culture Conversion at Week 24 (Stage 2) | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. | Week 24, Stage 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time to Sputum Culture Conversion at Week 24 (Stage 1) | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. | Week 24, Stage 1 | 
| The Time to Sputum Culture Conversion at Week 72 (Stage 2) | The table below shows the time to sputum culture conversion. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders and censored at their last assessment. | Week 72, Stage 2 | 
| The Percentage of Participants With Sputum Culture Conversion (Stage 1) | The table below shows the percentage of participants in Stage 1 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders. | Week 8, 24, and 104 (Stage 1) | 
| The Percentage of Participants With Sputum Culture Conversion (Stage 2) | The table below shows the percentage of participants in Stage 2 who were responders to treatment. Sputum culture conversion is defined as as having 2 consecutive negative cultures at least 25 days apart, not followed by a confirmed positive during the considered time period. Participants who discontinue or die during the considered time period are considered as non-responders. | Week 24, Week 72, and Week 120 (Stage 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, MDR TB