Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (TMC207-CL001)

• Sponsor: Global Alliance for TB Drug Development (Other)
• Overall Status: Completed
• CT.gov ID: NCT01215110
• Collaborator: (none)
• Enrollment: 68
• Location: 1
• Arms: 5
• Duration (Months): 5
• Patients Per Site Per Month: 13.5

Study Details

Study Description

Brief Summary

The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of TMC207 at multiple doses as determined by the rate of change of log10 colony forming units (CFU) per ml sputum over the time period Day 7-14 in participants with smear positive pulmonary tuberculosis (TB). A control group will receive standard treatment.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Tuberculosis	Drug: TMC207; Drug: Rifafour e-275 mg	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II Dose Ranging Trial to Evaluate the Extended Early Bactericidal Activity, Safety, Tolerability, and Pharmacokinetics of TMC207 in Adult Patients With Newly Diagnosed, Uncomplicated, Smear-Positive, Pulmonary Tuberculosis.
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TMC207 700/500/400 TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Drug: TMC207
Experimental: TMC207 500/400/300 TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	Drug: TMC207
Experimental: TMC207 400/300/200 TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	Drug: TMC207
Experimental: TMC207 200/100 TMC207- 200 mg Day 1 and 100 mg Days 2-14	Drug: TMC207
Active Comparator: Rifafour e-275 mg Rifafour e-275 mg	Drug: Rifafour e-275 mg

Outcome Measures

Primary Outcome Measures

1. Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-14). [Fourteen consecutive days of treatment]

   The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.

Secondary Outcome Measures

1. Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 7-14). [Days 7-14 of fourteen consecutive days of treatment]

   The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Since Day 7 is later than the node day, the rate of change for this outcome is equal to the slope at Day 14. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.

2. Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 2-14). [Days 2-14 of fourteen consecutive days of treatment]

   The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.

3. Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-2). [Two consecutive days of treatment]

   The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Since this range (Days0-2) is before the node day, the rate of change for this outcome is equal to the slope at Day 0. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.

4. Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14) [Fourteen consecutive days of treatment]

   The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.

5. Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2) [Two consecutive days of treatment]

   The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.

6. Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14) [Days 2-14 of fourteen consecutive days of treatment]

   The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.

7. Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14) [Days 7-14 of fourteen consecutive days of treatment]

   The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.

8. Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 [Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, 24, and 30 hour post-dose)]

9. Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 [Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, 24, and 30 hour post-dose)]

10. Summary of Statistical Analysis of TMC207 Area Under the Concentration-time Curve Over the Dose Interval of 0 to 24 h (AUC(0-24)) on Day 1 and Day 14 [Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provide written, informed consent prior to all trial-related procedures including HIV testing.

• Male or female, aged between 18 and 65 years inclusive.

• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

• Newly diagnosed, previously untreated, uncomplicated, sputum smear-positive, pulmonary TB.

• A chest X-ray picture which in the opinion of the Investigator is compatible with TB.

• Sputum positive on direct microscopy for acid-fast bacilli …(at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD)/World Health Organization (WHO) scale).

• Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).

• Females may participate if they are of non-childbearing potential, if they are using effective birth control methods and are willing to continue practicing birth control methods throughout treatment or if they are non-heterosexually active or willing to practice sexual abstinence throughout the treatment period or have a vasectomized partner (confirmed sterile). Therefore to be eligible for this study women of childbearing potential should either:1) use a double barrier method to prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device in combination with a barrier contraceptive. They must also be willing to continue these contraception until 6 months after last study drug or 6 months after discontinuation from study medication in case of premature discontinuation. (Note: Hormone-based contraception may not be reliable when taking TMC207; therefore, hormone-based contraceptives cannot be used by female patients to prevent pregnancy).

• Male patients must be willing to use a condom with spermicide when having heterosexual intercourse throughout treatment and until 1 month after last study drug administration or 1 month after discontinuation from study medication in case of premature discontinuation.

Exclusion Criteria:

1. Evidence of clinically significant metabolic, gastrointestinal neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).

2. Known or suspected hypersensitivity to study medications (including any rifamycin antibiotics)

3. Rifampicin-resistant and/or isoniazid-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.

4. Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the investigator.

5. Current or past history of alcohol and/or drug use that, in the investigator's opinion, would compromise the participant's safety or compliance to the study protocol procedures.

6. HIV infected patients:

7. having a cluster of differentiation 4 (CD4)+ count <300 cells/µL;

8. or having received antiretroviral therapy medication within the last 90 days:

9. or having received oral or intravenous antifungal medication within the last 90 days;

10. or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).

11. Significant cardiac arrhythmia requiring medication

12. Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.

13. Patients with the following QT/corrected QT(QTc) interval characteristics at screening:

14. Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QT corrected for heart rate using Fridericia's method (QTcF) interval >450 ms at screening;

15. History of additional risk factors for Torsade de Pointes, e.g., heart failure, hypokalemia, family history of Long QT Syndrome;

16. Use of concomitant medications that prolong the QT/QTc interval listed as disallowed medication in Section 2.10.2;

17. Pathological Q waves (defined as >40ms or depth >0.4-0.5mV);

18. Evidence of ventricular pre-excitation;

19. ECG evidence of complete or incomplete left bundle branch block or right bundle branch block;

20. Evidence of second or third degree heart block;

21. Intraventricular conduction delay with QRS duration >120ms;

22. Bradycardia as defined by sinus rate <50bpm

23. Women who are pregnant or breastfeeding

24. History and/or presence (or evidence) of neuropathy or epilepsy.

25. Diabetics using insulin

26. Poor general condition where any delay in treatment cannot be tolerated per discretion of Investigator.

27. Previously received treatment with TMC207 as part of a clinical trial.

28. Treatment received with any drug active against Mycobacterium tuberculosis within 3 months prior to Visit 1.

29. Any disease or conditions in which any of the medicinal products listed in the section pertaining to prohibited medications is used.

30. Patients with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):

31. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);

32. lipase grade 3 or greater (>2.0 x ULN);

33. hemoglobin grade 4 (<6.5 g/dL) except after discussion with the Medical Monitor;

34. aspartate aminotransferase (AST) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor;

35. alanine aminotransferase (ALT) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor;

36. alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor;

37. total bilirubin grade 3 or greater (>2.00 x ULN, or >1.50 x ULN when accompanied by any increase in other liver function test) to be excluded, grade 2 (>1.50 x ULN, or >1.25 x ULN when accompanied by any increase in other liver function test) must be discussed with the Medical Monitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Karl Bremer Hospital	Belville	Cape Town	South Africa	7531

Sponsors and Collaborators

• Global Alliance for TB Drug Development

Investigators

• Principal Investigator: Andreas Diacon, TASK APPLIED SCIENCE, Karl Bremer Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Global Alliance for TB Drug Development
• ClinicalTrials.gov Identifier: NCT01215110
• Other Study ID Numbers: TMC207-CL001
• First Posted: Oct 6, 2010
• Last Update Posted: Apr 26, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Global Alliance for TB Drug Development: Bedaquiline; Sirturo; Early Bactericidal Activity; EBA; Pulmonary Tuberculosis; TMC207
• Additional relevant MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Bedaquiline

Study Results

Participant Flow

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1; and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14.	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14	TMC207- 700 mg Day 1; 500 mg Day 2; and 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Period Title: Overall Study
STARTED	15	15	15	15	8
COMPLETED	15	15	13	14	8
NOT COMPLETED	0	0	2	1	0

Baseline Characteristics

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg	Total
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets	Total of all reporting groups
Overall Participants	15	15	15	15	8	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.5 (9.4)	34.7 (18.1)	31.4 (7.4)	31.8 (10.9)	26.1 (4.9)	27 (11.45)
Sex: Female, Male (Count of Participants)
Female	6 40%	4 26.7%	7 46.7%	5 33.3%	2 25%	24 35.3%
Male	9 60%	11 73.3%	8 53.3%	10 66.7%	6 75%	44 64.7%
Race/Ethnicity, Customized (participants) [Number]
Black	6 40%	5 33.3%	9 60%	7 46.7%	6 75%	33 48.5%
Mixed Ethnic	9 60%	10 66.7%	6 40%	8 53.3%	2 25%	35 51.5%
Height (meters (m)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters (m)]	1.638 (0.082)	1.677 (0.094)	1.674 (0.082)	1.660 (0.057)	1.660 (0.087)	1.662 (0.080)
Weight at Day 1 (kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms (kg)]	53.0 (7.74)	52.5 (7.55)	52.7 (8.20)	50.6 (5.96)	49.1 (6.69)	51.8 (7.23)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	19.80 (2.988)	18.63 (1.955)	18.80 (2.754)	18.36 (2.174)	17.83 (2.018)	18.77 (2.459)
HIV Status (participants) [Number]
Positive	1 6.7%	1 6.7%	1 6.7%	2 13.3%	1 12.5%	6 8.8%
Negative	14 93.3%	14 93.3%	14 93.3%	13 86.7%	7 87.5%	62 91.2%
Baseline log10 colony forming units (CFU) of M. Tuberculosis per ml sputum (log(10) CFU/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log(10) CFU/ml]	6.302 (0.697)	6.001 (0.903)	6.071 (1.087)	6.625 (0.756)	5.995 (1.018)	6.199 (0.892)
Baseline time to sputum culture positivity (TTP) in liquid culture media (hours) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [hours]	104.8 (23.5)	111.1 (30.6)	115.7 (40.8)	88.5 (10.8)	106.7 (28.8)	105.3 (26.9)

Outcome Measures

1. Primary Outcome

Title	Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-14).
Description	The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.
Time Frame	Fourteen consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	14	15	13	14	8
Mean (Standard Deviation) [log10CFU/ml/day]	0.040 (0.068)	0.056 (0.051)	0.077 (0.064)	0.104 (0.077)	0.112 (0.077)

2. Secondary Outcome

Title	Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 7-14).
Description	The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Since Day 7 is later than the node day, the rate of change for this outcome is equal to the slope at Day 14. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.
Time Frame	Days 7-14 of fourteen consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	14	15	13	14	8
Mean (Standard Deviation) [log10CFU/ml/day]	0.053 (0.088)	0.086 (0.048)	0.098 (0.084)	0.107 (0.082)	0.046 (0.101)

3. Secondary Outcome

Title	Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 2-14).
Description	The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.
Time Frame	Days 2-14 of fourteen consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	14	15	13	14	8
Mean (Standard Deviation) [log10CFU/ml/day]	0.047 (0.074)	0.071 (0.047)	0.088 (0.071)	0.106 (0.078)	0.046 (0.101)

4. Secondary Outcome

Title	Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-2).
Description	The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Since this range (Days0-2) is before the node day, the rate of change for this outcome is equal to the slope at Day 0. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.
Time Frame	Two consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	14	15	13	14	8
Mean (Standard Deviation) [log10CFU/ml/day]	0.004 (0.168)	-0.033 (0.128)	0.015 (0.149)	0.093 (0.136)	0.413 (0.291)

5. Secondary Outcome

Title	Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14)
Description	The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.
Time Frame	Fourteen consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	13	13	13	12	8
Mean (Standard Deviation) [hours/day]	4.0 (5.1)	4.2 (3.1)	4.9 (5.1)	5.4 (3.4)	14.3 (11.4)

6. Secondary Outcome

Title	Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2)
Description	The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.
Time Frame	Two consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	13	13	13	12	8
Mean (Standard Deviation) [hours/day]	1.5 (2.3)	3.7 (4.3)	4.1 (4.7)	6.2 (3.3)	27.3 (13.8)

7. Secondary Outcome

Title	Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14)
Description	The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.
Time Frame	Days 2-14 of fourteen consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	13	13	13	12	8
Mean (Standard Deviation) [hours/day]	4.4 (5.9)	4.3 (3.1)	5.1 (5.3)	5.3 (3.5)	11.5 (13.9)

8. Secondary Outcome

Title	Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14)
Description	The TTP was measured in the Mycobacterial Growth Indicator Tube (MGIT) (Bactec MGIT960) automated liquid culture system from overnight sputum. TTP rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group.
Time Frame	Days 7-14 of fourteen consecutive days of treatment

Outcome Measure Data

Analysis Population Description

Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400	Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.	TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14	Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
Measure Participants	13	13	13	12	8
Mean (Standard Deviation) [hours/day]	6.9 (11.2)	4.8 (4.4)	5.9 (7.2)	4.4 (5.0)	11.5 (13.9)

9. Secondary Outcome

Title	Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14
Time Frame	Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, 24, and 30 hour post-dose)

Outcome Measure Data

Analysis Population Description

On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400
Arm/Group Description	TMC207- 200 mg Day 1; and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14.	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14	TMC207- 700 mg Day 1; 500 mg Day 2; and 400 mg Days 3-14
Measure Participants	15	15	15	15
C(max) Day 1	1846.13 (613.55)	2700.73 (858.54)	3128.00 (1239.26)	5386.67 (3069.95)
C(max) Day 14	1553.27 (691.36)	2884.67 (789.44)	3902.31 (771.77)	5178.57 (2663.75)

10. Secondary Outcome

Title	Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14
Time Frame	Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, 24, and 30 hour post-dose)

Outcome Measure Data

Analysis Population Description

On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400
Arm/Group Description	TMC207- 200 mg Day 1; and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14.	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14	TMC207- 700 mg Day 1; 500 mg Day 2; and 400 mg Days 3-14
Measure Participants	15	15	15	15
T(max) Day 1	5.33 (1.80)	5.20 (1.90)	5.53 (0.83)	5.67 (1.05)
T(max) Day 14	5.13 (1.19)	4.60 (1.06)	5.15 (1.46)	5.29 (1.59)

11. Secondary Outcome

Title	Summary of Statistical Analysis of TMC207 Area Under the Concentration-time Curve Over the Dose Interval of 0 to 24 h (AUC(0-24)) on Day 1 and Day 14
Time Frame	Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose)

Outcome Measure Data

Analysis Population Description

On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants

Arm/Group Title	TMC207 100	TMC207 200	TMC207 300	TMC207 400
Arm/Group Description	TMC207- 200 mg Day 1; and 100 mg Days 2-14	TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14.	TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14	TMC207- 700 mg Day 1; 500 mg Day 2; and 400 mg Days 3-14
Measure Participants	15	15	15	15
AUC(0-24) Day 1	18995.57 (6947.92)	26619.51 (8453.09)	31357.35 (10596.74)	53179.27 (20699.64)
AUC(0-24) Day 14	18689.03 (4450.56)	33314.07 (5780.02)	50547.15 (11914.16)	69069.64 (27062.36)

Adverse Events

Time Frame	49 days
Adverse Event Reporting Description	Adverse events were collected by the Investigator from the time a participant signed the Informed Consent Form until the end of follow-up visit (Day 49). Data reported are treatment-emergent adverse events.
Arm/Group Title	TMC207 100		TMC207 200		TMC207 300		TMC207 400		Rifafour e-275 mg
Arm/Group Description	TMC207- 200 mg Day 1 and 100 mg Days 2-14		TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14		TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.		TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14		Daily Doses: 30 to 37 kg, 2 tablets; 38 to 54 kg, 3 tablets; 55 to 70 kg, 4 tablets; 71 kg and over, 5 tablets
All Cause Mortality
	TMC207 100		TMC207 200		TMC207 300		TMC207 400		Rifafour e-275 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	TMC207 100		TMC207 200		TMC207 300		TMC207 400		Rifafour e-275 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		1/15 (6.7%)		0/8 (0%)
Hepatobiliary disorders
Hepatitis	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	0/8 (0%)	0
Other (Not Including Serious) Adverse Events
	TMC207 100		TMC207 200		TMC207 300		TMC207 400		Rifafour e-275 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/15 (26.7%)		4/15 (26.7%)		5/15 (33.3%)		5/15 (33.3%)		2/8 (25%)
Gastrointestinal disorders
Vomiting	0/15 (0%)		0/15 (0%)		0/15 (0%)		1/15 (6.7%)		2/8 (25%)
Nausea	0/15 (0%)		0/15 (0%)		0/15 (0%)		1/15 (6.7%)		0/8 (0%)
Toothache	0/15 (0%)		1/15 (6.7%)		0/15 (0%)		0/15 (0%)		0/8 (0%)
General disorders
Chest discomfort	0/15 (0%)		0/15 (0%)		1/15 (6.7%)		0/15 (0%)		0/8 (0%)
Non-cardiac chest pain	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		1/8 (12.5%)
Infections and infestations
Body tinea	0/15 (0%)		1/15 (6.7%)		0/15 (0%)		0/15 (0%)		0/8 (0%)
Investigations
Aspartate aminotransferase increased	1/15 (6.7%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/8 (0%)
Hepatic enzyme increased	0/15 (0%)		1/15 (6.7%)		0/15 (0%)		0/15 (0%)		0/8 (0%)
Weight decreased	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/15 (0%)		1/15 (6.7%)		1/15 (6.7%)		0/15 (0%)		0/8 (0%)
Arthralgia	1/15 (6.7%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/8 (0%)
Joint swelling	0/15 (0%)		0/15 (0%)		1/15 (6.7%)		0/15 (0%)		0/8 (0%)
Nervous system disorders
Headache	2/15 (13.3%)		0/15 (0%)		1/15 (6.7%)		1/15 (6.7%)		0/8 (0%)
Dizziness	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Pruritus	0/15 (0%)		0/15 (0%)		2/15 (13.3%)		1/15 (6.7%)		0/8 (0%)
Acne	0/15 (0%)		0/15 (0%)		1/15 (6.7%)		0/15 (0%)		0/8 (0%)
Rash	0/15 (0%)		0/15 (0%)		0/15 (0%)		1/15 (6.7%)		0/8 (0%)
Rash macular	1/15 (6.7%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/8 (0%)
Skin exfoliation	0/15 (0%)		0/15 (0%)		1/15 (6.7%)		0/15 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator or any Sub-Investigator shall submit any oral or written publication or abstract concerning this study to the Sponsor not less than thirty (30) days prior to submission to any journal, other publication or meeting, for review and removal of confidential information.