Pulmonary Tuberculosis
Conditions
Keywords
Early Bactericidal Activity, EBA, pulmonary tuberculosis, PA-824, Pretomanid, CL-007
Brief summary
The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of PA-824 at 200, 600, 1000 and 1200 mg per day in adult patients with newly diagnosed, uncomplicated, smear positive tuberculosis. A control group will receive standard TB treatment.
Interventions
DRUGPA-824
200 mg, 600 mg, 100 mg, 1200 mg qd
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* informed consent * M/F 18-64 yo * newly diagnosed pulmonary TB * sputum positive * adequate contraception
Exclusion criteria
* poor health * rifampicin resistance * treatment with other anti TB agents in last 3 mos. * extrapulmonary TB * COPD * neuropathy * ECG wih QRS prolongation ove 120 msec * CV disorder * diabetes requiring insulin * Metabolic disease * drug/alcohol abuse * pregnancy * use of substances that are strong inhibitors/inducers of CYP450 * use of ARV
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). | Day 0 and Day 14 |
Secondary
| Measure | Time frame |
|---|---|
| Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2). | Day 0 and Day 2 |
| Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14). | Day 2 and Day 14 |
| EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) | Day 0 and Day 14 |
| EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2) | Day 0 and Day 2 |
| EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified] | Day 2 and Day 14 |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PA-824 200 mg PA-824: 200 mg per day for 14 consecutive days | 15 |
| PA-824 600 mg PA-824: 600 mg per day for 14 consecutive days | 15 |
| PA-824 1000 mg PA-824: 1000 mg per day for 14 consecutive days | 16 |
| PA-824 1200 mg PA-824: 1200 mg per day for 14 consecutive days | 15 |
| Rifafour Rifafour e-275 on Days 1 to 14, dosed by weight | 8 |
| Total | 69 |
Baseline characteristics
| Characteristic | PA-824 200 mg | PA-824 600 mg | PA-824 1000 mg | PA-824 1200 mg | Rifafour | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 30.5 years STANDARD_DEVIATION 8.5 | 30.6 years STANDARD_DEVIATION 9.72 | 31.7 years STANDARD_DEVIATION 8.86 | 32.4 years STANDARD_DEVIATION 11.51 | 21.9 years STANDARD_DEVIATION 3.44 | 30.2 years STANDARD_DEVIATION 9.48 |
| Body Mass Index (BMI) | 20.19 kg/m^2 STANDARD_DEVIATION 4.031 | 20.09 kg/m^2 STANDARD_DEVIATION 3.899 | 19.09 kg/m^2 STANDARD_DEVIATION 2.562 | 19.41 kg/m^2 STANDARD_DEVIATION 3.058 | 17.53 kg/m^2 STANDARD_DEVIATION 1.785 | 19.43 kg/m^2 STANDARD_DEVIATION 3.294 |
| Race/Ethnicity, Customized Black | 10 Participants | 6 Participants | 8 Participants | 8 Participants | 3 Participants | 35 Participants |
| Race/Ethnicity, Customized Mixed Ethnic | 5 Participants | 9 Participants | 8 Participants | 7 Participants | 5 Participants | 34 Participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 7 Participants | 6 Participants | 4 Participants | 31 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 9 Participants | 9 Participants | 4 Participants | 38 Participants |
| Weight | 55.3 kg STANDARD_DEVIATION 8.58 | 55.9 kg STANDARD_DEVIATION 10.51 | 52.5 kg STANDARD_DEVIATION 9.82 | 53.5 kg STANDARD_DEVIATION 8.48 | 48.0 kg STANDARD_DEVIATION 8.7 | 53.6 kg STANDARD_DEVIATION 9.36 |
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 | 6 / 15 | 4 / 15 | 5 / 16 | 7 / 15 | 2 / 8 |
| serious Total, serious adverse events | 1 / 15 | 0 / 15 | 0 / 16 | 0 / 15 | 1 / 8 |
Outcome results
Primary
Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14).
Time frame: Day 0 and Day 14
Population: Some of the EBA values could not be calculated due to missing results. The number of participants given are the number of participants for whom the results were available for this time period and therefore for whom the relevant EBA could be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PA-824 200 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). | 0.106 log10 CFU/ml | Standard Deviation 0.049 |
| PA-824 600 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). | 0.107 log10 CFU/ml | Standard Deviation 0.053 |
| PA-824 1000 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). | 0.091 log10 CFU/ml | Standard Deviation 0.083 |
| PA-824 1200 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). | 0.088 log10 CFU/ml | Standard Deviation 0.084 |
| Rifafour | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). | 0.148 log10 CFU/ml | Standard Deviation 0.055 |
Secondary
Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2).
Time frame: Day 0 and Day 2
Population: Some of the EBA values could not be calculated due to missing results. The number of participants given are the number of participants for whom the results were available for this time period and therefore for whom the relevant EBA could be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PA-824 200 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2). | 0.109 log10 CFU/ml | Standard Deviation 0.487 |
| PA-824 600 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2). | 0.096 log10 CFU/ml | Standard Deviation 0.226 |
| PA-824 1000 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2). | 0.025 log10 CFU/ml | Standard Deviation 0.34 |
| PA-824 1200 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2). | -0.035 log10 CFU/ml | Standard Deviation 0.42 |
| Rifafour | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-2). | 0.403 log10 CFU/ml | Standard Deviation 0.29 |
Secondary
Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14).
Time frame: Day 2 and Day 14
Population: Some of the EBA values could not be calculated due to missing results. The number of participants given are the number of participants for whom the results were available for this time period and therefore for whom the relevant EBA could be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PA-824 200 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14). | 0.106 log10 CFU/ml | Standard Deviation 0.063 |
| PA-824 600 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14). | 0.113 log10 CFU/ml | Standard Deviation 0.079 |
| PA-824 1000 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14). | 0.095 log10 CFU/ml | Standard Deviation 0.062 |
| PA-824 1200 mg | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14). | 0.113 log10 CFU/ml | Standard Deviation 0.099 |
| Rifafour | Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 2-14). | 0.112 log10 CFU/ml | Standard Deviation 0.05 |
Secondary
EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14)
Time frame: Day 0 and Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PA-824 200 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) | 3.818 hours/day | Standard Deviation 2.327 |
| PA-824 600 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) | 4.776 hours/day | Standard Deviation 2.879 |
| PA-824 1000 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) | 4.865 hours/day | Standard Deviation 3.461 |
| PA-824 1200 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) | 4.440 hours/day | Standard Deviation 2.169 |
| Rifafour | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) | 9.741 hours/day | Standard Deviation 5.249 |
Secondary
EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2)
Time frame: Day 0 and Day 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PA-824 200 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2) | 1.115 hours/day | Standard Deviation 15.256 |
| PA-824 600 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2) | 5.788 hours/day | Standard Deviation 12.173 |
| PA-824 1000 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2) | 2.795 hours/day | Standard Deviation 9.23 |
| PA-824 1200 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2) | 1.400 hours/day | Standard Deviation 7.659 |
| Rifafour | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-2) | 24.125 hours/day | Standard Deviation 12.794 |
Secondary
EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified]
Time frame: Day 2 and Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PA-824 200 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified] | 3.833 hours/day | Standard Deviation 2.954 |
| PA-824 600 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified] | 5.09 hours/day | Standard Deviation 2.768 |
| PA-824 1000 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified] | 4.069 hours/day | Standard Deviation 1.916 |
| PA-824 1200 mg | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified] | 4.868 hours/day | Standard Deviation 3.224 |
| Rifafour | EBA Expressed as the Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 2-14) Show Description: [Not Specified] | 7.344 hours/day | Standard Deviation 4.66 |