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

• ClinicalTrials.gov Identifier: NCT00449644
• Recruitment Status: Completed
• First Posted: March 20, 2007
• Results First Posted: June 25, 2013
• Last Update Posted: April 29, 2014
• Sponsor: Janssen Infectious Diseases BVBA
• Information provided by (Responsible Party): Janssen Infectious Diseases BVBA

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Tuberculosis	Drug: TMC207; Drug: Placebo; Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 208 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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 Start Date: June 2007
• Actual Primary Completion Date: March 2010
• Actual Study Completion Date: October 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: TMC207 Stage 1; 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; TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 or 22 weeks.; Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis); 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.
Placebo Comparator: Placebo Stage 1; 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; Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 or 22 weeks.; Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis); 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.
Experimental: TMC207 Stage 2; 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; TMC207 400mg (4 tablets) once daily for 14 days, 200mg (2 tablets) three times a week for 6 or 22 weeks.; Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis); 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.
Placebo Comparator: Placebo Stage 2; 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; Placebo 4 tablets once daily for 14 days, 2 tablets three times a week for 6 or 22 weeks.; Drug: Background regimen (BR) for MDR-TB (multi-drug resistant tuberculosis); 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.

Outcome Measures

Primary Outcome Measures :

1. The Time to Sputum Culture Conversion at Week 8 (Stage 1) [ Time Frame: 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.
2. The Time to Sputum Culture Conversion at Week 24 (Stage 2) [ Time Frame: 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.

Secondary Outcome Measures :

1. The Time to Sputum Culture Conversion at Week 24 (Stage 1) [ Time Frame: 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.
2. The Time to Sputum Culture Conversion at Week 72 (Stage 2) [ Time Frame: 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.
3. The Percentage of Participants With Sputum Culture Conversion (Stage 1) [ Time Frame: Week 8, 24, and 104 (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.
4. The Percentage of Participants With Sputum Culture Conversion (Stage 2) [ Time Frame: Week 24, Week 72, and Week 120 (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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Brazil

Rio De Janeiro, Brazil

India

Chennai, India

New Delhi, India

Latvia

Stopinu Region, Latvia

Peru

Lima, Peru

Philippines

Quezon City, Philippines

Russian Federation

Moscow, Russian Federation

South Africa

Bethelsdorp, South Africa

Cape Town, South Africa

Durban, South Africa

George, South Africa

Klerksdorp, South Africa

Sandringham, South Africa

Thailand

Chiang Mai, Thailand

Nakhon, Thailand

Nonthaburi, Thailand

Sponsors and Collaborators

Janssen Infectious Diseases BVBA

Investigators

• Study Director: Janssen Infectious Diseases BVBA Clinical Trial; Janssen Infectious Diseases BVBA

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: Janssen Infectious Diseases BVBA
• ClinicalTrials.gov Identifier: NCT00449644
• Obsolete Identifiers: NCT00614627, NCT00980265
• Other Study ID Numbers: CR011929; TMC207-TIDP13-C208 ( Other Identifier: Janssen Infectious Diseases BVBA ); 2007-004462-40 ( EudraCT Number )
• First Posted: March 20, 2007
• Results First Posted: June 25, 2013
• Last Update Posted: April 29, 2014
• Last Verified: April 2014

Keywords provided by Janssen Infectious Diseases BVBA:

Tuberculosis; MDR TB

Additional relevant MeSH terms:

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Bedaquiline; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents