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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TMC207 700/500/400 | Experimental | TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 |
|
| TMC207 500/400/300 | Experimental | TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14. |
|
| TMC207 400/300/200 | Experimental | TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14 |
|
| TMC207 200/100 | Experimental | TMC207- 200 mg Day 1 and 100 mg Days 2-14 |
|
| Rifafour e-275 mg | Active Comparator | Rifafour e-275 mg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TMC207 | Drug |
| ||
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Fourteen consecutive days of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
Evidence of clinically significant metabolic, gastrointestinal neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
Known or suspected hypersensitivity to study medications (including any rifamycin antibiotics)
Rifampicin-resistant and/or isoniazid-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.
Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the investigator.
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.
HIV infected patients:
Significant cardiac arrhythmia requiring medication
Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.
Patients with the following QT/corrected QT(QTc) interval characteristics at screening:
Women who are pregnant or breastfeeding
History and/or presence (or evidence) of neuropathy or epilepsy.
Diabetics using insulin
Poor general condition where any delay in treatment cannot be tolerated per discretion of Investigator.
Previously received treatment with TMC207 as part of a clinical trial.
Treatment received with any drug active against Mycobacterium tuberculosis within 3 months prior to Visit 1.
Any disease or conditions in which any of the medicinal products listed in the section pertaining to prohibited medications is used.
Patients with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):
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| Name | Affiliation | Role |
|---|---|---|
| Andreas Diacon | TASK APPLIED SCIENCE, Karl Bremer Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Karl Bremer Hospital | Belville | Cape Town | 7531 | South Africa |
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| ID | Title | Description |
|---|---|---|
| FG000 | TMC207 100 | TMC207- 200 mg Day 1; and 100 mg Days 2-14 |
| FG001 | TMC207 200 | TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14. |
| FG002 | TMC207 300 | TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14 |
| FG003 | TMC207 400 | TMC207- 700 mg Day 1; 500 mg Day 2; and 400 mg Days 3-14 |
| FG004 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | TMC207 100 | TMC207- 200 mg Day 1 and 100 mg Days 2-14 |
| BG001 | TMC207 200 | TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations. | Posted | Mean | Standard Deviation | log10CFU/ml/day | Fourteen consecutive days of treatment |
|
49 days
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | TMC207 100 | TMC207- 200 mg Day 1 and 100 mg Days 2-14 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hepatitis | Hepatobiliary disorders | MedDRA (13.0) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Aspartate aminotransferase increased | Investigations | MedDRA (13.0) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Daniel E. Everitt, MD, Vice President and Senior Medical Officer | Global Alliance for TB Drug Development | 212-227-7540 | Dan.Everitt@tballiance.org |
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| ID | Term |
|---|---|
| D014397 | Tuberculosis, Pulmonary |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
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| ID | Term |
|---|---|
| C493870 | bedaquiline |
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| Rifafour e-275 mg |
| Drug |
|
| Days 7-14 of fourteen consecutive days of treatment |
| 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. | Days 2-14 of fourteen consecutive days of treatment |
| 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. | Two consecutive days of treatment |
| 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. | Fourteen consecutive days of treatment |
| 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. | Two consecutive days of treatment |
| 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. | Days 2-14 of fourteen consecutive days of treatment |
| 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. | Days 7-14 of fourteen consecutive days of treatment |
| 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) |
| BG002 | TMC207 300 | TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14. |
| BG003 | TMC207 400 | TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 |
| BG004 | 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 |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Height | Mean | Standard Deviation | meters (m) |
|
| Weight at Day 1 | Mean | Standard Deviation | kilograms (kg) |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m^2 |
|
| HIV Status | Number | participants |
|
| Baseline log10 colony forming units (CFU) of M. Tuberculosis per ml sputum | Mean | Standard Deviation | log(10) CFU/ml |
|
| Baseline time to sputum culture positivity (TTP) in liquid culture media | Mean | Standard Deviation | hours |
|
| OG001 | TMC207 200 | TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14 |
| OG002 | TMC207 300 | TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14. |
| OG003 | TMC207 400 | TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 |
| OG004 | 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 |
|
|
| 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. | Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations. | Posted | Mean | Standard Deviation | log10CFU/ml/day | Days 7-14 of fourteen consecutive days of treatment |
|
|
|
| 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. | Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations. | Posted | Mean | Standard Deviation | log10CFU/ml/day | Days 2-14 of fourteen consecutive days of treatment |
|
|
|
| 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. | Because of insufficient data for bilinear regression, four patients were omitted from EBA(CFU) calculations. | Posted | Mean | Standard Deviation | log10CFU/ml/day | Two consecutive days of treatment |
|
|
|
| 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. | Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations. | Posted | Mean | Standard Deviation | hours/day | Fourteen consecutive days of treatment |
|
|
|
| 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. | Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations. | Posted | Mean | Standard Deviation | hours/day | Two consecutive days of treatment |
|
|
|
| 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. | Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations. | Posted | Mean | Standard Deviation | hours/day | Days 2-14 of fourteen consecutive days of treatment |
|
|
|
| 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. | Because of insufficient data for bilinear regression, nine participants were omitted from TTP calculations. | Posted | Mean | Standard Deviation | hours/day | Days 7-14 of fourteen consecutive days of treatment |
|
|
|
| Secondary | Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 | On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants | Posted | Mean | Standard Deviation | ng/mL | 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) |
|
|
|
| Secondary | Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 | On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants | Posted | Mean | Standard Deviation | hour | 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) |
|
|
|
| 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 | On Day 14, N=13 for TMC207 300 group and N=14 for TMC207 400 group due to early withdrawal of three participants | Posted | Mean | Standard Deviation | ng*h/mL | 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) |
|
|
|
| 0 |
| 15 |
| 4 |
| 15 |
| EG001 | TMC207 200 | TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14 | 0 | 15 | 4 | 15 |
| EG002 | TMC207 300 | TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14. | 0 | 15 | 5 | 15 |
| EG003 | TMC207 400 | TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 | 1 | 15 | 5 | 15 |
| EG004 | 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 | 0 | 8 | 2 | 8 |
| Hepatic enzyme increased | Investigations | MedDRA (13.0) |
|
| Weight decreased | Investigations | MedDRA (13.0) |
|
| Chest discomfort | General disorders | MedDRA (13.0) |
|
| Non-cardiac chest pain | General disorders | MedDRA (13.0) |
|
| Body tinea | Infections and infestations | MedDRA (13.0) |
|
| Headache | Nervous system disorders | MedDRA (13.0) |
|
| Dizziness | Nervous system disorders | MedDRA (13.0) |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (13.0) |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA (13.0) |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (13.0) |
|
| Rash macular | Skin and subcutaneous tissue disorders | MedDRA (13.0) |
|
| Skin exfoliation | Skin and subcutaneous tissue disorders | MedDRA (13.0) |
|
| Vomiting | Gastrointestinal disorders | MedDRA (13.0) |
|
| Nausea | Gastrointestinal disorders | MedDRA (13.0) |
|
| Toothache | Gastrointestinal disorders | MedDRA (13.0) |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (13.0) |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (13.0) |
|
| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA (13.0) |
|
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.
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012141 | Respiratory Tract Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| C(max) Day 14 |
|
| T(max) Day 14 |
|
| AUC(0-24) Day 14 |
|