Pulmonary Tuberculosis
Conditions
Keywords
Bedaquiline, Sirturo, Early Bactericidal Activity, EBA, Pulmonary Tuberculosis, TMC207
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.
Interventions
DRUGTMC207
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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: 1. having a cluster of differentiation 4 (CD4)+ count \<300 cells/µL; 2. or having received antiretroviral therapy medication within the last 90 days: 3. or having received oral or intravenous antifungal medication within the last 90 days; 4. or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB). 7. Significant cardiac arrhythmia requiring medication 8. Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start. 9. Patients with the following QT/corrected QT(QTc) interval characteristics at screening: 1. 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; 2. History of additional risk factors for Torsade de Pointes, e.g., heart failure, hypokalemia, family history of Long QT Syndrome; 3. Use of concomitant medications that prolong the QT/QTc interval listed as disallowed medication in Section 2.10.2; 4. Pathological Q waves (defined as \>40ms or depth \>0.4-0.5mV); 5. Evidence of ventricular pre-excitation; 6. ECG evidence of complete or incomplete left bundle branch block or right bundle branch block; 7. Evidence of second or third degree heart block; 8. Intraventricular conduction delay with QRS duration \>120ms; 9. Bradycardia as defined by sinus rate \<50bpm 10. Women who are pregnant or breastfeeding 11. History and/or presence (or evidence) of neuropathy or epilepsy. 12. Diabetics using insulin 13. Poor general condition where any delay in treatment cannot be tolerated per discretion of Investigator. 14. Previously received treatment with TMC207 as part of a clinical trial. 15. Treatment received with any drug active against Mycobacterium tuberculosis within 3 months prior to Visit 1. 16. Any disease or conditions in which any of the medicinal products listed in the section pertaining to prohibited medications is used. 17. Patients with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007): 1. creatinine grade 2 or greater (\>1.5 times upper limit of normal \[ULN\]); 2. lipase grade 3 or greater (\>2.0 x ULN); 3. hemoglobin grade 4 (\<6.5 g/dL) except after discussion with the Medical Monitor; 4. aspartate aminotransferase (AST) grade 4 (\>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor; 5. alanine aminotransferase (ALT) grade 4 (\>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor; 6. alkaline phosphatase (ALP) grade 4 (\>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor; 7. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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) | — |
| 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) | — |
| 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) | — |
| 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. |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TMC207 100 TMC207- 200 mg Day 1 and 100 mg Days 2-14 | 15 |
| TMC207 200 TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14 | 15 |
| TMC207 300 TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14. | 15 |
| TMC207 400 TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 | 15 |
| Rifafour e-275 mg 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 | 8 |
| Total | 68 |
Baseline characteristics
| Characteristic | TMC207 100 | TMC207 200 | TMC207 300 | TMC207 400 | Rifafour e-275 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 29.5 years STANDARD_DEVIATION 9.4 | 34.7 years STANDARD_DEVIATION 18.1 | 31.4 years STANDARD_DEVIATION 7.4 | 31.8 years STANDARD_DEVIATION 10.9 | 26.1 years STANDARD_DEVIATION 4.9 | 27 years STANDARD_DEVIATION 11.45 |
| Baseline log10 colony forming units (CFU) of M. Tuberculosis per ml sputum | 6.302 log(10) CFU/ml STANDARD_DEVIATION 0.697 | 6.001 log(10) CFU/ml STANDARD_DEVIATION 0.903 | 6.071 log(10) CFU/ml STANDARD_DEVIATION 1.087 | 6.625 log(10) CFU/ml STANDARD_DEVIATION 0.756 | 5.995 log(10) CFU/ml STANDARD_DEVIATION 1.018 | 6.199 log(10) CFU/ml STANDARD_DEVIATION 0.892 |
| Baseline time to sputum culture positivity (TTP) in liquid culture media | 104.8 hours STANDARD_DEVIATION 23.5 | 111.1 hours STANDARD_DEVIATION 30.6 | 115.7 hours STANDARD_DEVIATION 40.8 | 88.5 hours STANDARD_DEVIATION 10.8 | 106.7 hours STANDARD_DEVIATION 28.8 | 105.3 hours STANDARD_DEVIATION 26.9 |
| Body Mass Index (BMI) | 19.80 kg/m^2 STANDARD_DEVIATION 2.988 | 18.63 kg/m^2 STANDARD_DEVIATION 1.955 | 18.80 kg/m^2 STANDARD_DEVIATION 2.754 | 18.36 kg/m^2 STANDARD_DEVIATION 2.174 | 17.83 kg/m^2 STANDARD_DEVIATION 2.018 | 18.77 kg/m^2 STANDARD_DEVIATION 2.459 |
| Height | 1.638 meters (m) STANDARD_DEVIATION 0.082 | 1.677 meters (m) STANDARD_DEVIATION 0.094 | 1.674 meters (m) STANDARD_DEVIATION 0.082 | 1.660 meters (m) STANDARD_DEVIATION 0.057 | 1.660 meters (m) STANDARD_DEVIATION 0.087 | 1.662 meters (m) STANDARD_DEVIATION 0.08 |
| HIV Status Negative | 14 participants | 14 participants | 14 participants | 13 participants | 7 participants | 62 participants |
| HIV Status Positive | 1 participants | 1 participants | 1 participants | 2 participants | 1 participants | 6 participants |
| Race/Ethnicity, Customized Black | 6 participants | 5 participants | 9 participants | 7 participants | 6 participants | 33 participants |
| Race/Ethnicity, Customized Mixed Ethnic | 9 participants | 10 participants | 6 participants | 8 participants | 2 participants | 35 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 7 Participants | 5 Participants | 2 Participants | 24 Participants |
| Sex: Female, Male Male | 9 Participants | 11 Participants | 8 Participants | 10 Participants | 6 Participants | 44 Participants |
| Weight at Day 1 | 53.0 kilograms (kg) STANDARD_DEVIATION 7.74 | 52.5 kilograms (kg) STANDARD_DEVIATION 7.55 | 52.7 kilograms (kg) STANDARD_DEVIATION 8.2 | 50.6 kilograms (kg) STANDARD_DEVIATION 5.96 | 49.1 kilograms (kg) STANDARD_DEVIATION 6.69 | 51.8 kilograms (kg) STANDARD_DEVIATION 7.23 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 15 | 4 / 15 | 5 / 15 | 5 / 15 | 2 / 8 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 1 / 15 | 0 / 8 |
Outcome results
Primary
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).
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
Population: Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | 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). | 0.040 log10CFU/ml/day | Standard Deviation 0.068 |
| TMC207 200 | 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). | 0.056 log10CFU/ml/day | Standard Deviation 0.051 |
| TMC207 300 | 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). | 0.077 log10CFU/ml/day | Standard Deviation 0.064 |
| TMC207 400 | 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). | 0.104 log10CFU/ml/day | Standard Deviation 0.077 |
| Rifafour e-275 mg | 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). | 0.112 log10CFU/ml/day | Standard Deviation 0.077 |
Secondary
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).
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
Population: Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | 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). | 0.004 log10CFU/ml/day | Standard Deviation 0.168 |
| TMC207 200 | 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). | -0.033 log10CFU/ml/day | Standard Deviation 0.128 |
| TMC207 300 | 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). | 0.015 log10CFU/ml/day | Standard Deviation 0.149 |
| TMC207 400 | 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). | 0.093 log10CFU/ml/day | Standard Deviation 0.136 |
| Rifafour e-275 mg | 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). | 0.413 log10CFU/ml/day | Standard Deviation 0.291 |
Secondary
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).
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
Population: Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | 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). | 0.047 log10CFU/ml/day | Standard Deviation 0.074 |
| TMC207 200 | 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). | 0.071 log10CFU/ml/day | Standard Deviation 0.047 |
| TMC207 300 | 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). | 0.088 log10CFU/ml/day | Standard Deviation 0.071 |
| TMC207 400 | 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). | 0.106 log10CFU/ml/day | Standard Deviation 0.078 |
| Rifafour e-275 mg | 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). | 0.046 log10CFU/ml/day | Standard Deviation 0.101 |
Secondary
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).
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
Population: Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | 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). | 0.053 log10CFU/ml/day | Standard Deviation 0.088 |
| TMC207 200 | 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). | 0.086 log10CFU/ml/day | Standard Deviation 0.048 |
| TMC207 300 | 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). | 0.098 log10CFU/ml/day | Standard Deviation 0.084 |
| TMC207 400 | 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). | 0.107 log10CFU/ml/day | Standard Deviation 0.082 |
| Rifafour e-275 mg | 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). | 0.046 log10CFU/ml/day | Standard Deviation 0.101 |
Secondary
Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14)
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
Population: Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14) | 4.0 hours/day | Standard Deviation 5.1 |
| TMC207 200 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14) | 4.2 hours/day | Standard Deviation 3.1 |
| TMC207 300 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14) | 4.9 hours/day | Standard Deviation 5.1 |
| TMC207 400 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14) | 5.4 hours/day | Standard Deviation 3.4 |
| Rifafour e-275 mg | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14) | 14.3 hours/day | Standard Deviation 11.4 |
Secondary
Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2)
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
Population: Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2) | 1.5 hours/day | Standard Deviation 2.3 |
| TMC207 200 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2) | 3.7 hours/day | Standard Deviation 4.3 |
| TMC207 300 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2) | 4.1 hours/day | Standard Deviation 4.7 |
| TMC207 400 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2) | 6.2 hours/day | Standard Deviation 3.3 |
| Rifafour e-275 mg | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2) | 27.3 hours/day | Standard Deviation 13.8 |
Secondary
Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14)
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
Population: Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14) | 4.4 hours/day | Standard Deviation 5.9 |
| TMC207 200 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14) | 4.3 hours/day | Standard Deviation 3.1 |
| TMC207 300 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14) | 5.1 hours/day | Standard Deviation 5.3 |
| TMC207 400 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14) | 5.3 hours/day | Standard Deviation 3.5 |
| Rifafour e-275 mg | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14) | 11.5 hours/day | Standard Deviation 13.9 |
Secondary
Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14)
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
Population: Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TMC207 100 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14) | 6.9 hours/day | Standard Deviation 11.2 |
| TMC207 200 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14) | 4.8 hours/day | Standard Deviation 4.4 |
| TMC207 300 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14) | 5.9 hours/day | Standard Deviation 7.2 |
| TMC207 400 | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14) | 4.4 hours/day | Standard Deviation 5 |
| Rifafour e-275 mg | Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14) | 11.5 hours/day | Standard Deviation 13.9 |
Secondary
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)
Population: On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TMC207 100 | 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 | AUC(0-24) Day 1 | 18995.57 ng*h/mL | Standard Deviation 6947.92 |
| TMC207 100 | 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 | AUC(0-24) Day 14 | 18689.03 ng*h/mL | Standard Deviation 4450.56 |
| TMC207 200 | 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 | AUC(0-24) Day 14 | 33314.07 ng*h/mL | Standard Deviation 5780.02 |
| TMC207 200 | 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 | AUC(0-24) Day 1 | 26619.51 ng*h/mL | Standard Deviation 8453.09 |
| TMC207 300 | 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 | AUC(0-24) Day 1 | 31357.35 ng*h/mL | Standard Deviation 10596.74 |
| TMC207 300 | 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 | AUC(0-24) Day 14 | 50547.15 ng*h/mL | Standard Deviation 11914.16 |
| TMC207 400 | 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 | AUC(0-24) Day 1 | 53179.27 ng*h/mL | Standard Deviation 20699.64 |
| TMC207 400 | 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 | AUC(0-24) Day 14 | 69069.64 ng*h/mL | Standard Deviation 27062.36 |
Secondary
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)
Population: On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TMC207 100 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 1 | 1846.13 ng/mL | Standard Deviation 613.55 |
| TMC207 100 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 14 | 1553.27 ng/mL | Standard Deviation 691.36 |
| TMC207 200 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 14 | 2884.67 ng/mL | Standard Deviation 789.44 |
| TMC207 200 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 1 | 2700.73 ng/mL | Standard Deviation 858.54 |
| TMC207 300 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 1 | 3128.00 ng/mL | Standard Deviation 1239.26 |
| TMC207 300 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 14 | 3902.31 ng/mL | Standard Deviation 771.77 |
| TMC207 400 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 1 | 5386.67 ng/mL | Standard Deviation 3069.95 |
| TMC207 400 | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | C(max) Day 14 | 5178.57 ng/mL | Standard Deviation 2663.75 |
Secondary
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)
Population: On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TMC207 100 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 1 | 5.33 hour | Standard Deviation 1.8 |
| TMC207 100 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 14 | 5.13 hour | Standard Deviation 1.19 |
| TMC207 200 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 14 | 4.60 hour | Standard Deviation 1.06 |
| TMC207 200 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 1 | 5.20 hour | Standard Deviation 1.9 |
| TMC207 300 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 1 | 5.53 hour | Standard Deviation 0.83 |
| TMC207 300 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 14 | 5.15 hour | Standard Deviation 1.46 |
| TMC207 400 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 1 | 5.67 hour | Standard Deviation 1.05 |
| TMC207 400 | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | T(max) Day 14 | 5.29 hour | Standard Deviation 1.59 |