Tuberculosis, Pulmonary, Tuberculosis, Multidrug-Resistant, Tuberculosis, MDR, Tuberculosis, Drug-Resistant Tuberculosis
Conditions
Keywords
tuberculosis, drug-resistant tuberculosis, TB, DR-TB, pretomanid, PA-824, bedaquiline, TMC207, moxifloxacin, pyrazinamide, HRZE, TB Alliance, NC-008, drug-sensitive tuberculosis, DS-TB
Brief summary
To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: Drug Sensitive TB (DS-TB) patients given BPaMZ for 17 Weeks ( or 4 months) vs. Standard HRZE/HR treatment given for 26 weeks (or 6 months) and Drug Resistant TB (DR-TB) patients given BPaMZ for 26 Weeks (or 6 months)
Detailed description
Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants. All participants in the below arms will have follow-up for a period of 104 weeks (24 months) from the start of therapy. Participants with Drug Sensitive TB (DS-TB): Participants with DS-TB will be randomized to one of two treatment arms. These participants will receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets daily for 26 weeks (6 months). participants will be stratified for co-infection with human immunodeficiency virus (HIV) and cavitation. Participants with Drug Resistant TB (DR-TB): Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months).
Interventions
DRUGPretomanid
200 mg tablets
DRUGBedaquiline
100 mg tablets
DRUGMoxifloxacin
400 mg tablets
DRUGPyrazinamide
500 mg tablets
DRUGHRZE
isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 275 mg combination tablets
DRUGHR
isoniazid 75 mg plus rifampicin 150 mg combination tablets
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease \[IUATLD\]/WHO scale (Appendix 1) on smear microscopy) at the trial laboratory. * Participants with one of the following pulmonary TB conditions: DS-TB treatment arm participants should be: * sensitive to rifampicin and isoniazid by rapid sputum based test AND * either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB. DR-TB treatment arm participants should be Resistant to rifampicin and/or isoniazid. * Of non-childbearing potential or willing to practice effective methods of birth control * Body weight (in light clothing and no shoes) ≥ 30 kg. * Completed informed consent form
Exclusion criteria
* Karnofsky score \<60% * Any risk factor for QT prolongation * Any planned contraindicated medicines * Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests). Any of the following lab toxicities/abnormalities: * CD4+ count \< 100 cells/µL (HIV infected participants) * platelets \<75,000/mm³ * creatinine \>1.5 times upper limit of normal (ULN) * eGFR ≤ 60 mL/min * haemoglobin \<8.0 g/dL * serum potassium less than the lower limit of normal for the laboratory. * GGT: greater than 3 x ULN * AST: ≥3.0 x ULN to be excluded; * ALT: ≥3.0 x ULN to be excluded * ALP: ≥3.0 x ULN to be excluded * Total bilirubin: \>1.5 x ULN to be excluded; * Direct bilirubin: greater than 1x ULN to be excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Culture Negative Status by 8 Weeks | Days 0-56 (8 weeks) | Culture negative status is achieved when a participant produces at least two negative culture results at different visits (at least 7 days apart) without an intervening positive culture result for M.tb. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | 52 weeks after start of therapy | Unfavorable status: 1. Participants not classified as having achieved or maintained culture negative status when last seen 2. Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture 3. Participants who had a positive culture not followed by at least two negative cultures when last seen 4. Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide 5. Participants definitely or possibly dying from TB related cause during the follow-up phase 6. Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy 7. Participants lost to follow up or withdrawn from the study before end of treatment |
| Time to Culture Negative Status | During treatment (17 or 26 weeks) | Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with a tuberculosis can no longer produce tuberculosis cell cultures, that point is considered culture negativity |
Countries
Brazil, Georgia, Malaysia, Philippines, Russia, South Africa, Tanzania, Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Drug Sensitive-TB 4BPaMZ Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months)
Pretomanid: 200 mg tablets
Bedaquiline: 100 mg tablets
Moxifloxacin: 400 mg tablets
Pyrazinamide: 500 mg tablets | 150 |
| Drug Sensitive-TB 2HRZE/4HR isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9 to 26
HRZE: isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 275 mg combination tablets
HR: isoniazid 75 mg plus rifampicin 150 mg combination tablets
Participant Dosage based on weight | 153 |
| Drug Resistant-TB 6BPaMZ Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)
Pretomanid: 200 mg tablets
Bedaquiline: 100 mg tablets
Moxifloxacin: 400 mg tablets
Pyrazinamide: 500 mg tablets | 152 |
| Total | 455 |
Baseline characteristics
| Characteristic | Total | Drug Resistant-TB 6BPaMZ | Drug Sensitive-TB 2HRZE/4HR | Drug Sensitive-TB 4BPaMZ |
|---|---|---|---|---|
| Age, Continuous | 36.7 years | 37.6 years | 36.3 years | 36.4 years |
| Alcohol Use Current | 180 Participants | 48 Participants | 69 Participants | 63 Participants |
| Alcohol Use Former | 141 Participants | 49 Participants | 42 Participants | 50 Participants |
| Alcohol Use Never | 134 Participants | 55 Participants | 42 Participants | 37 Participants |
| BMI | 19.9 Kg/m^2 | 20.1 Kg/m^2 | 19.5 Kg/m^2 | 20.0 Kg/m^2 |
| Chest x-ray at Screening Abnormal | 440 Participants | 144 Participants | 151 Participants | 145 Participants |
| Chest x-ray at Screening Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Chest x-ray at Screening Normal | 14 Participants | 7 Participants | 2 Participants | 5 Participants |
| Chest X-Ray Cavities at Screening Bilateral | 134 Participants | 50 Participants | 40 Participants | 44 Participants |
| Chest X-Ray Cavities at Screening Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Chest X-Ray Cavities at Screening None | 99 Participants | 31 Participants | 37 Participants | 31 Participants |
| Chest X-Ray Cavities at Screening Unilateral | 221 Participants | 70 Participants | 76 Participants | 75 Participants |
| Height | 168.3 cm | 167.8 cm | 168.9 cm | 168.1 cm |
| HIV Status Negative | 368 Participants | 117 Participants | 126 Participants | 125 Participants |
| HIV Status Positive | 87 Participants | 35 Participants | 27 Participants | 25 Participants |
| Previous Tuberculosis (TB) diagnoses Drug Sensitive (DS-TB) | 336 participants | 33 participants | 153 participants | 150 participants |
| Previous Tuberculosis (TB) diagnoses Extensively Resistant (XDR-TB) | 2 participants | 2 participants | 0 participants | 0 participants |
| Previous Tuberculosis (TB) diagnoses Mono-resistant TB | 45 participants | 45 participants | 0 participants | 0 participants |
| Previous Tuberculosis (TB) diagnoses Multi-drug Resistant (MDR-TB) | 99 participants | 99 participants | 0 participants | 0 participants |
| Previous Tuberculosis (TB) diagnoses Pre-extensively Resistant (Pre-XDR TB) | 1 participants | 1 participants | 0 participants | 0 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 13 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 309 Participants | 82 Participants | 119 Participants | 108 Participants |
| Race (NIH/OMB) More than one race | 37 Participants | 26 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 85 Participants | 31 Participants | 25 Participants | 29 Participants |
| Region of Enrollment Brazil | 35 Participants | 28 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Georgia | 52 Participants | 9 Participants | 20 Participants | 23 Participants |
| Region of Enrollment Malaysia | 7 Participants | 4 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Philippines | 17 Participants | 9 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Russia | 24 Participants | 15 Participants | 5 Participants | 4 Participants |
| Region of Enrollment South Africa | 196 Participants | 72 Participants | 68 Participants | 56 Participants |
| Region of Enrollment Tanzania | 107 Participants | 7 Participants | 48 Participants | 52 Participants |
| Region of Enrollment Uganda | 17 Participants | 8 Participants | 6 Participants | 3 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) 1+ | 85 Participants | 37 Participants | 28 Participants | 20 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) 2+ | 149 Participants | 47 Participants | 53 Participants | 49 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) 3+ | 220 Participants | 67 Participants | 72 Participants | 81 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) No AFB seen | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) Scanty Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 131 Participants | 58 Participants | 35 Participants | 38 Participants |
| Sex: Female, Male Male | 324 Participants | 94 Participants | 118 Participants | 112 Participants |
| Smoking Current | 162 Participants | 39 Participants | 64 Participants | 59 Participants |
| Smoking Former | 113 Participants | 41 Participants | 40 Participants | 32 Participants |
| Smoking Never | 180 Participants | 72 Participants | 49 Participants | 59 Participants |
| Time to positive at baseline | 6.2 days | 7.4 days | 5.8 days | 5.4 days |
| Weight | 56.3 kg | 56.6 kg | 55.6 kg | 56.5 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 150 | 2 / 153 | 4 / 149 |
| other Total, other adverse events | 139 / 150 | 144 / 153 | 142 / 149 |
| serious Total, serious adverse events | 17 / 150 | 7 / 153 | 16 / 149 |
Outcome results
Primary
Number of Participants With Culture Negative Status by 8 Weeks
Culture negative status is achieved when a participant produces at least two negative culture results at different visits (at least 7 days apart) without an intervening positive culture result for M.tb.
Time frame: Days 0-56 (8 weeks)
Population: Limited to Drug Sensitive TB groups. Participants were considered unassessable and therefore excluded from the Modified Intent to Treat (MITT) population if they were late exclusion or if they did not have culture confirmation of M.tb at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Drug Sensitive-TB 2HRZE/4HR | Number of Participants With Culture Negative Status by 8 Weeks | 70 Participants |
| Drug Sensitive-TB 4BPaMZ | Number of Participants With Culture Negative Status by 8 Weeks | 122 Participants |
p-value: <0.00195% CI: [2.17, 3.96]Log Rank
Secondary
Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months)
Unfavorable status: 1. Participants not classified as having achieved or maintained culture negative status when last seen 2. Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture 3. Participants who had a positive culture not followed by at least two negative cultures when last seen 4. Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide 5. Participants definitely or possibly dying from TB related cause during the follow-up phase 6. Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy 7. Participants lost to follow up or withdrawn from the study before end of treatment
Time frame: 52 weeks after start of therapy
Population: TB Specific Modified Intent to Treat (TB-MITT) population participants were unassessable and excluded if they were a late exclusion, became pregnant and stopped treatment, had suspected or confirmed COVID-19 and stopped treatment, died during treatment from violent or accidental cause, died during follow-up with no evidence of TB, reinfected with a different strain of TB, had contaminated or missing sputum samples at the endpoint visit (and able to produce sputum).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Drug Sensitive-TB 2HRZE/4HR | Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | Favorable | 120 Participants |
| Drug Sensitive-TB 2HRZE/4HR | Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | Unfavorable | 24 Participants |
| Drug Sensitive-TB 4BPaMZ | Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | Favorable | 134 Participants |
| Drug Sensitive-TB 4BPaMZ | Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | Unfavorable | 10 Participants |
| Drug Resistant-TB 6BPaMZ | Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | Favorable | 111 Participants |
| Drug Resistant-TB 6BPaMZ | Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months) | Unfavorable | 22 Participants |
Secondary
Time to Culture Negative Status
Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with a tuberculosis can no longer produce tuberculosis cell cultures, that point is considered culture negativity
Time frame: During treatment (17 or 26 weeks)
Population: Participants were unassessable and excluded from the Modified Intent to Treat (MITT) population if they were a late exclusions.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Drug Sensitive-TB 2HRZE/4HR | Time to Culture Negative Status | 6 weeks |
| Drug Sensitive-TB 4BPaMZ | Time to Culture Negative Status | 11 weeks |
| Drug Resistant-TB 6BPaMZ | Time to Culture Negative Status | 5 weeks |