Tuberculosis
Conditions
Keywords
Tuberculosis, Multi Drug-Resistant Tuberculosis, Drug-Sensitive Tuberculosis, PA-824, Bedaquiline, Moxifloxacin, Pyrazinamide, Quinolone, Pretomanid, NC-005
Brief summary
The purpose of this study is to determine the mycobactericidal activity of combinations of bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks of treatment.
Detailed description
The trial design is a phase 2, multi-center, open-label, partially randomized clinical trial in four parallel treatment groups. Subjects with drug-sensitive tuberculosis (DS-TB) will be randomized to receive either J(loading dose/three times a week)PaZ; or J(200mg)PaZ; or HRZE. Subjects with multi drug-resistant tuberculosis will receive J(200mg)MPaZ. The HRZE treatment arm is included as a control for the drug-sensitive treatments and as a control for the quantitative laboratory mycobacteriology testing. A total of approximately 240 male and female, newly diagnosed subjects with drug-sensitive or multi drug-resistant, smear positive pulmonary tuberculosis aged 18 to 75 years (inclusive) will be included in the study. A total of 180 subjects with drug-sensitive tuberculosis (60 per treatment arm) will be randomized. Up to 60 subjects with multi-drug resistant tuberculosis will be assigned. All subjects will have up to a maximum of 9 days screening, receive 8 weeks of treatment, and have follow-up visits at 2 and 12 weeks after study treatment completion or last dose of investigational medicinal product in the case of early withdrawal. Subjects who withdraw from the study after receiving \< 14 days of investigational medicinal product, will only attend a follow-up visit at 2 weeks after last dose of investigational medicinal product. Upon treatment completion, the subjects with drug-sensitive tuberculosis will be provided with sufficient doses of standard of care tuberculosis treatment, as appropriate, to cover the time period from attending their last visit at the study clinic until their scheduled visit at the TB clinic. All subjects with drug sensitive and multi-drug resistant tuberculosis will be referred to the local community tuberculosis clinics for standard anti-tuberculosis chemotherapy according to National Tuberculosis Guidelines.
Interventions
DRUGPA-824
oral
DRUGbedaquiline
oral
DRUGmoxifloxacin
oral
DRUGpyrazinamide
oral
DRUGisoniazid, rifampicin, pyrazinamide and ethambutol combination tablet
oral
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Provide written, informed consent prior to all trial-related procedures. Male or female, aged between 18 and 75 years inclusive. 2. Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive. 3. Tested at the trial appointed laboratory: M. Tb positive on molecular test (e.g. GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale. * For DS-TB treatment arms (defined as sensitive to rifampicin based on molecular sensitivity testing), Subjects should be: 1. either newly diagnosed or untreated for at least 3 years after cure from a previous episode (Subject can give a history of cure and previous treatment); AND 2. Previous TB treatment must be discontinued as per
Exclusion criteria
16. * For MDR-TB treatment arm (defined as resistant to rifampicin based on molecular sensitivity testing), Subjects should be: 1. sensitive to moxifloxacin by molecular sensitivity testing; AND 2. either newly diagnosed or could have previously been treated for DS-TB and/or MDR-TB (\< 7 days of treatment). Previous MDR-TB treatment must be discontinued as per
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System | Day 0 to Day 56 (8 weeks) | The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP\[0-56\]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days) | A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively. |
Countries
South Africa, Tanzania, Uganda
Participant flow
Recruitment details
This trial was conducted at 10 centers in 3 countries (South Africa, Tanzania, and Uganda) from 23 October 2014. Adult male and female participants with drug-sensitive (DS) or multi-drug resistant (MDR) smear-positive pulmonary tuberculosis (TB) were recruited into this open-label multi-center study.
Pre-assignment details
Participants were confirmed positive for M.tuberculosis on molecular test. DS-TB participants were to be sensitive to rifampicin and newly diagnosed with pulmonary TB (or untreated for at least 3 years). MDR-TB participants were to be resistant to rifampicin, sensitive to moxifloxacin and newly diagnosed with pulmonary TB (or treated for \<=7 days).
Participants by arm
| Arm | Count |
|---|---|
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26. | 59 |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26. | 60 |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26. | 61 |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26. | 60 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse event/Specific toxicity | 5 | 5 | 2 | 2 |
| Overall Study | Consent withdrawn | 1 | 0 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Failure to comply with protocol | 0 | 1 | 0 | 0 |
| Overall Study | Investigator/Sponsor decision | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Total |
|---|---|---|---|---|---|
| Age, Continuous | 35.1 years STANDARD_DEVIATION 13.03 | 33.9 years STANDARD_DEVIATION 10.45 | 33.3 years STANDARD_DEVIATION 8.6 | 34.0 years STANDARD_DEVIATION 12.68 | 34.1 years STANDARD_DEVIATION 11.26 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 46 Participants | 49 Participants | 49 Participants | 53 Participants | 197 Participants |
| Race (NIH/OMB) More than one race | 13 Participants | 11 Participants | 12 Participants | 5 Participants | 41 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 14 Participants | 12 Participants | 15 Participants | 17 Participants | 58 Participants |
| Sex: Female, Male Male | 45 Participants | 48 Participants | 46 Participants | 43 Participants | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 59 | 3 / 60 | 2 / 61 | 4 / 60 |
| other Total, other adverse events | 50 / 59 | 45 / 60 | 44 / 61 | 57 / 60 |
| serious Total, serious adverse events | 4 / 59 | 3 / 60 | 4 / 61 | 4 / 60 |
Outcome results
Primary
Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System
The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP\[0-56\]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).
Time frame: Day 0 to Day 56 (8 weeks)
Population: The modified intention-to-treat analysis population included all participants included in the safety analysis population for whom valid corresponding efficacy data were available. Pyrazinamide resistant participants were excluded from this analysis population (applicable to both participants with DS-TB and MDR-TB).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System | 4.878 percentage change in TTP/day | Standard Deviation 1.604 |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System | 5.182 percentage change in TTP/day | Standard Deviation 1.466 |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System | 4.046 percentage change in TTP/day | Standard Deviation 1.129 |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System | 5.194 percentage change in TTP/day | Standard Deviation 1.068 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively.
Time frame: First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days)
Population: The safety analysis population included all participants who were randomized (for the DS participant population) or assigned (for the MDR participant population) to study drug and received at least 1 administration of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to early withdrawal from study | 5 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of study drug | 6 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade IV TEAE | 8 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 4 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 1 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related TEAE | 38 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade III TEAE | 19 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related serious TEAE | 2 Participants |
| DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 50 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related serious TEAE | 0 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to early withdrawal from study | 5 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of study drug | 5 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related TEAE | 29 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 45 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 1 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade IV TEAE | 7 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade III TEAE | 17 Participants |
| DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 3 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related serious TEAE | 1 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 44 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related TEAE | 29 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 1 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 4 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of study drug | 2 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to early withdrawal from study | 2 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade III TEAE | 14 Participants |
| DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade IV TEAE | 2 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to early withdrawal from study | 2 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 4 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade IV TEAE | 1 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade III TEAE | 13 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related TEAE | 46 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of study drug | 2 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Drug-related serious TEAE | 2 Participants |
| MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 57 Participants |