Pulmonary Tuberculosis
Conditions
Keywords
Tuberculosis, MDR-TB, XDR-TB, Multi-drug resistant, Extensively drug resistant, Bedaquiline, PA-824, Linezolid, TB, Pretomanid, TMC-207, NiX-TB
Brief summary
The purpose of this study is to evaluate the efficacy, safety, tolerability and pharmacokinetics of bedaquiline plus PA-824 plus linezolid after 6 months of treatment (option for 9 months for participants who remain culture positive at month 4) in participants with either pulmonary extensively drug resistant tuberculosis (XDR-TB), treatment intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).
Detailed description
Up to 200 male and female participants aged 14 and over with confirmed sputum positive for M.tb. in culture pulmonary XDR-TB, or with pulmonary MDR-TB with a documented intolerability or non-response to the best treatment available for 6 months or more will be enrolled. All participants will have up to a maximum of 9 days for screening, receive 6 months of treatment, and have followup visits performed 1 and 2 months after treatment completion and every 3 months after study treatment completion for 24 months. If a participant is culture positive or revert to being culture positive between Month 4 and Month 6 visits and their clinical condition suggests they may have ongoing TB infection, they may have treatment extended to 9 months (with 24 months of Follow Up) or be withdrawn from the study. Participants who withdraw after \<14 days of IMP should attend an Early Withdrawal visit. Participants who withdraw after \>15 days of IMP should return for an Early Withdrawal visit and follow-up visits at 3, 6 and 24 months after their last dose of IMP to check for survival, SAEs and resolution of TB symptoms.
Interventions
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria 1. Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian). 2. Body weight of ≥35 kg (in light clothing and no shoes). 3. Male or female, aged 14 years or above. 4. Subjects with one of the following pulmonary TB conditions (WHO definitions prior to 2021): a. Extensively Drug Resistant Tuberculosis (XDR-TB) with i. documented culture positive (for M.tb.) results within 3 months prior to screening or M.tb. confirmed in sputum based on molecular test within 3 months prior to or at screening; ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening; b. Multi-Drug Resistant Tuberculosis (MDR-TB) documented by culture positive results (for M.tb.) within 3 months prior to or at screening with documented non-response to treatment with the best available regimen for 6 months or more prior to enrolment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen; c. MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to or at screening who are unable to continue second line drug regimen due to a documented intolerance to: i. PAS, ethionamide, aminoglycosides or fluoroquinolones; ii. Current treatment not listed above that renders subject eligible for the study in the Investigator's opinion. 6\. Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary TB in the opinion of the Investigator. Key
Exclusion criteria
1. Karnofsky score \< 50 within 30 days prior to entry. 2. Body Mass index (BMI) \< 17 kg/m² 3. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances. 4. HIV infected Subjects having a CD4+ count ≤ 50 cells/μL 5. Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational study that includes treatment with medicinal agents. Subjects who are participating in observational studies or who are in a follow up period of a trial that included drug therapy may be considered for inclusion. 6. Significant cardiac arrhythmia requiring medication. 7. Subjects with the following at Screening: 1. QTcF interval on ECG \>500 msec. 2. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); 3. Clinically significant ventricular arrhythmias; 4. Subjects with other cardiac abnormalities that may place them at risk of arrhythmias must be discussed with the sponsor medical monitor before enrolment. Such abnormalities include: Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome); Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; Evidence of second or third degree heart block; Intraventricular conduction delay with QRS duration more than 120 msec. 8. Females who have a positive pregnancy test at Screening or already known to be pregnant, breastfeeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment. 9. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, subjects with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator. 10. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment. 11. Subjects with the following toxicities at Screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007): a. serum potassium less than the lower limit of normal for the laboratory; b. Hemoglobin level grade 2 or greater (\< 8.0 g/dL); c. Platelets grade 2 or greater(\<75,000/mm3); d. Absolute neutrophil count (ANC) \< 1000/ mm3; e. Aspartate aminotransferase (AST) \> 3 x ULN g. Total bilirubin \> or = to 2xULN h. Direct bilirubin \> ULN i. Serum creatinine level greater than 2 times upper limit of normal j. Albumin \<32 g/L
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. | 6 Months post End of Treatment | Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative. Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline. Clinical failure: A change from protocol-specified tuberculosis (TB) treatment due to treatment failure, retreatment for TB during follow up, or TB-related death. Note: Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart. Participants who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Sputum Culture Conversion to Negative Status Through the Treatment Period | Day 1 through End of Treatment, approximately 6 to 9 months of treatment | Median time (in weeks) to culture negative status (first of 2 negative cultures without an intervening positive culture), MITT analysis. |
| Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4, 6, 8, 12, 16, 26, 39 | Proportion of participants with sputum culture conversion to negative status for those positive at baseline at 4, 6, 8, 12, 16, and End of Treatment (26 or 39 weeks) |
| Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. | 24 Months post End of Treatment | Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative. Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline. Clinical failure: A change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death. Note: Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart. Participants who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit. |
| Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Day 1 to 14 days post-End of Treatment | Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. TEAEs of special interest: Identified by prespecified SMQ codes as confirmed by TB Alliance. Section 7.3 of the protocol specified the Monitoring and Safety for Specific Toxicities and are presented here as TEAEs of special interest. These specific toxicities of interest were based on nonclinical toxicology findings of concern for any of the 3 trial drugs, or from identified toxicities based on the IBs for pretomanid and bedaquiline, on the product label for linezolid and literature reports of linezolid long-term toxicity. |
| Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Day 1 to 14 days post-End of Treatment | Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. #: Indicates TEAEs of special interest. TEAEs of special interest: Identified by pre-specified SMQ codes as confirmed by TB Alliance. Adverse events in System Organ Class NERVOUS SYSTEM DISORDERS are presented into the table. Preferred term PERIPHERAL NEUROPATHY was a grouping of terms PERIPHERAL SENSORY NEUROPATHY, NEUROPATHY PERIPHERAL, PARAESTHESIA, HYPOAESTHESIA, PERIPHERAL MOTOR NEUROPATHY, BURNING SENSATION, HYPOREFLEXIA and PERIPHERAL SENSORIMOTOR NEUROPATHY. |
| Number of Treatment Emergent Adverse Events (TEAEs) | Day 1 to 14 days post-End of Treatment | Treatment-emergent adverse events (TEAEs): adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. Grade I, II, III, IV TEAEs: DMID grade is indicated as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life-threatening). TEAEs of special interest based on Section 7.3 of the protocol. Liver-related adverse events: any adverse event with a High Level Group Term of HEPATIC AND BILIARY NEOPLASMS BENIGN, HEPATIC AND HEPATOBILIARY DISORDERS, HEPATOBILIARY DISORDERS CONGENITAL, HEPATOBILIARY NEOPLASMS MALIGNANT AND UNSPECIFIED, HEPATOBILIARY INVESTIGATIONS or HEPATOBILIARY THERAPEUTIC PROCEDURES. |
Countries
South Africa
Participant flow
Pre-assignment details
Screening Phase: 143 participants were screened to determine eligibility to participate in the study using inclusion and exclusion criteria within 9 days of scheduled day 1 treatment dosing. 34 participants did not meet treatment criteria and were excluded from further study participation. 109 participants were enrolled in the study and began the treatment phase of the study.
Participants by arm
| Arm | Count |
|---|---|
| Bedaquiline + PA-824 + Linezolid bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 1200mg once daily .
Bedaquiline: 100mg tablets
PA-824: 200mg tablets
Linezolid: Scored 600mg tablets | 109 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 6 Month Follow Up Period | Death | 1 |
| 6 Month Follow Up Period | Physician Decision | 1 |
| 7 to 24 Month Follow Up Period | Lost to Follow-up | 1 |
| 7 to 24 Month Follow Up Period | Physician Decision | 1 |
| Treatment Period | Death | 6 |
| Treatment Period | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Bedaquiline + PA-824 + Linezolid |
|---|---|
| Age, Continuous | 35.6 years STANDARD_DEVIATION 10.12 |
| BMI (kg/m^2) | 20.60 kg/m^2 STANDARD_DEVIATION 5.046 |
| CD4 Count (cells/uL) | 394.0 cells/uL STANDARD_DEVIATION 212 |
| Height (cm) | 165.78 cm STANDARD_DEVIATION 10.408 |
| Karnofsky Score (%) 0 (Dead) | 0 Participants |
| Karnofsky Score (%) 10 | 0 Participants |
| Karnofsky Score (%) 100 (Normal, no complaints) | 9 Participants |
| Karnofsky Score (%) 20 | 0 Participants |
| Karnofsky Score (%) 30 | 0 Participants |
| Karnofsky Score (%) 40 | 0 Participants |
| Karnofsky Score (%) 50 | 0 Participants |
| Karnofsky Score (%) 60 | 2 Participants |
| Karnofsky Score (%) 70 | 19 Participants |
| Karnofsky Score (%) 80 | 29 Participants |
| Karnofsky Score (%) 90 | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 83 Participants |
| Race (NIH/OMB) More than one race | 25 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 57 Participants |
| Weight (kg) | 56.95 kg STANDARD_DEVIATION 15.034 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 44 | 3 / 65 | 8 / 109 |
| other Total, other adverse events | 44 / 44 | 65 / 65 | 109 / 109 |
| serious Total, serious adverse events | 13 / 44 | 6 / 65 | 19 / 109 |
Outcome results
Primary
Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment.
Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative. Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline. Clinical failure: A change from protocol-specified tuberculosis (TB) treatment due to treatment failure, retreatment for TB during follow up, or TB-related death. Note: Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart. Participants who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit.
Time frame: 6 Months post End of Treatment
Population: Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Total | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. | Favourable (treatment success) | 98 Participants |
| Total | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. | Unfavourable (treatment failure) | 9 Participants |
| XDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. | Favourable (treatment success) | 63 Participants |
| XDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. | Unfavourable (treatment failure) | 7 Participants |
| TI/NR MDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. | Favourable (treatment success) | 35 Participants |
| TI/NR MDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. | Unfavourable (treatment failure) | 2 Participants |
Secondary
Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped
Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. #: Indicates TEAEs of special interest. TEAEs of special interest: Identified by pre-specified SMQ codes as confirmed by TB Alliance. Adverse events in System Organ Class NERVOUS SYSTEM DISORDERS are presented into the table. Preferred term PERIPHERAL NEUROPATHY was a grouping of terms PERIPHERAL SENSORY NEUROPATHY, NEUROPATHY PERIPHERAL, PARAESTHESIA, HYPOAESTHESIA, PERIPHERAL MOTOR NEUROPATHY, BURNING SENSATION, HYPOREFLEXIA and PERIPHERAL SENSORIMOTOR NEUROPATHY.
Time frame: Day 1 to 14 days post-End of Treatment
Population: The Safety analysis population is defined as all participants who received at least 1 administration of trial treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness | 3 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Sinus Headache | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Tension Headache | 0 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Chronic Inflammatory Demyelinating Polyradiculoneurpoathy | 0 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dysgeusia | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Seizure | 0 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Nervous System Disorders | 94 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Optic Neuritis | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Migraine | 0 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Generalized Tonic-Clonic Seizure | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dystonia | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Syncope | 0 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Headache | 16 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Peripheral Neuropathy | 68 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness Postural | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Taste Disorder | 1 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Tension Headache | 1 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Taste Disorder | 0 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Syncope | 2 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Nervous System Disorders | 83 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness | 2 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dysgeusia | 3 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Chronic Inflammatory Demyelinating Polyradiculoneurpoathy | 1 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness Postural | 0 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dystonia | 0 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Generalized Tonic-Clonic Seizure | 0 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Migraine | 1 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Peripheral Neuropathy | 56 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Optic Neuritis | 0 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Seizure | 1 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Headache | 16 events |
| XDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Sinus Headache | 0 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Migraine | 1 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Syncope | 2 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Seizure | 1 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Peripheral Neuropathy | 51 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Tension Headache | 0 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Nervous System Disorders | 75 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Optic Neuritis | 0 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dysgeusia | 1 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Headache | 15 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Generalized Tonic-Clonic Seizure | 1 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness Postural | 1 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Taste Disorder | 1 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Chronic Inflammatory Demyelinating Polyradiculoneurpoathy | 0 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Sinus Headache | 0 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness | 1 events |
| TI/NR MDR-TB | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dystonia | 0 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Syncope | 0 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness Postural | 0 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Tension Headache | 1 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dystonia | 1 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Generalized Tonic-Clonic Seizure | 0 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Peripheral Neuropathy | 73 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Sinus Headache | 1 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Migraine | 0 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Headache | 17 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Seizure | 0 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dysgeusia | 3 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Nervous System Disorders | 102 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness | 4 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Optic Neuritis | 1 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Chronic Inflammatory Demyelinating Polyradiculoneurpoathy | 1 events |
| 1200 mg QD Linezolid | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Taste Disorder | 0 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Migraine | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Nervous System Disorders | 177 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Peripheral Neuropathy | 124 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Headache | 32 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness | 5 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dysgeusia | 4 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Chronic Inflammatory Demyelinating Polyradiculoneurpoathy | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dizziness Postural | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Dystonia | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Generalized Tonic-Clonic Seizure | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Optic Neuritis | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Tension Headache | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Seizure | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Sinus Headache | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | Taste Disorder | 1 events |
| Total | Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped | #Syncope | 2 events |
Secondary
Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest
Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. TEAEs of special interest: Identified by prespecified SMQ codes as confirmed by TB Alliance. Section 7.3 of the protocol specified the Monitoring and Safety for Specific Toxicities and are presented here as TEAEs of special interest. These specific toxicities of interest were based on nonclinical toxicology findings of concern for any of the 3 trial drugs, or from identified toxicities based on the IBs for pretomanid and bedaquiline, on the product label for linezolid and literature reports of linezolid long-term toxicity.
Time frame: Day 1 to 14 days post-End of Treatment
Population: The Safety analysis population is defined as all participants who received at least 1 administration of trial treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmia Terms (Incl. Bradyarrhythmias and Tachyarrhythmias) | 3 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Failure, Fibrosis and Cirrhosis and Other Liver Damage-Related Conditions | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Supraventricular Tachyarrhythmias | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Disorders | 16 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias | 22 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Peripheral Neurpoathy | 44 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Tachyarrhythmias (Incl. Supraventricular and Ventricular Tachyarrhythmias) | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Comprehensive Search | 16 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Lactic Acidosis | 5 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Convulsions | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Bradyarrhythmias (Incl. Conduction Defects and Disorders of Sinus Node Function) | 2 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Liver-Related Investigations, Signs, and Symptoms | 15 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Thrombocytopenia | 3 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Optic Nerve Disorders | 9 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Disorders of Sinus Node Function | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Erythropenia | 16 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cholestasis and Jaundice of Hepatic Origin | 2 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmias | 5 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Rhabdomyolysis/Myopathy | 8 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Arrhythmia-Related Investigations, Signs, and Symptoms | 3 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Acute Pancreatitis | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Severe Events Only | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias Affecting More Than One Type of Blood Cell | 4 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Leukopenia | 2 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Conduction Defects | 2 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Conduction Defects | 4 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Failure, Fibrosis and Cirrhosis and Other Liver Damage-Related Conditions | 1 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Bradyarrhythmias (Incl. Conduction Defects and Disorders of Sinus Node Function) | 4 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Optic Nerve Disorders | 5 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Lactic Acidosis | 3 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmia Terms (Incl. Bradyarrhythmias and Tachyarrhythmias) | 4 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmias | 7 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Leukopenia | 10 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Rhabdomyolysis/Myopathy | 3 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Thrombocytopenia | 3 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias | 30 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Arrhythmia-Related Investigations, Signs, and Symptoms | 3 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias Affecting More Than One Type of Blood Cell | 1 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Peripheral Neurpoathy | 44 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Supraventricular Tachyarrhythmias | 0 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Disorders | 26 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Comprehensive Search | 26 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Disorders of Sinus Node Function | 0 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Liver-Related Investigations, Signs, and Symptoms | 25 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Acute Pancreatitis | 2 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cholestasis and Jaundice of Hepatic Origin | 3 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Erythropenia | 24 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Tachyarrhythmias (Incl. Supraventricular and Ventricular Tachyarrhythmias) | 0 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Severe Events Only | 1 Participants |
| XDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Convulsions | 1 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Disorders | 19 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Peripheral Neurpoathy | 33 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias | 25 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Erythropenia | 20 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Leukopenia | 5 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Thrombocytopenia | 4 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias Affecting More Than One Type of Blood Cell | 4 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Comprehensive Search | 19 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Liver-Related Investigations, Signs, and Symptoms | 17 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cholestasis and Jaundice of Hepatic Origin | 4 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Severe Events Only | 2 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Failure, Fibrosis and Cirrhosis and Other Liver Damage-Related Conditions | 2 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Optic Nerve Disorders | 4 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmias | 2 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmia Terms (Incl. Bradyarrhythmias and Tachyarrhythmias) | 0 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Bradyarrhythmias (Incl. Conduction Defects and Disorders of Sinus Node Function) | 0 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Conduction Defects | 0 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Disorders of Sinus Node Function | 0 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Rhabdomyolysis/Myopathy | 3 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Tachyarrhythmias (Incl. Supraventricular and Ventricular Tachyarrhythmias) | 0 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Supraventricular Tachyarrhythmias | 0 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Arrhythmia-Related Investigations, Signs, and Symptoms | 2 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Lactic Acidosis | 2 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Acute Pancreatitis | 3 Participants |
| TI/NR MDR-TB | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Convulsions | 2 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias Affecting More Than One Type of Blood Cell | 1 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias | 27 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Supraventricular Tachyarrhythmias | 1 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Peripheral Neurpoathy | 55 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Severe Events Only | 0 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Disorders | 23 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Comprehensive Search | 23 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Thrombocytopenia | 2 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Convulsions | 0 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Rhabdomyolysis/Myopathy | 8 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Liver-Related Investigations, Signs, and Symptoms | 23 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Leukopenia | 7 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Disorders of Sinus Node Function | 1 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Conduction Defects | 6 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cholestasis and Jaundice of Hepatic Origin | 1 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmias | 10 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Arrhythmia-Related Investigations, Signs, and Symptoms | 4 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Tachyarrhythmias (Incl. Supraventricular and Ventricular Tachyarrhythmias) | 1 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmia Terms (Incl. Bradyarrhythmias and Tachyarrhythmias) | 7 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Acute Pancreatitis | 0 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Optic Nerve Disorders | 10 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Failure, Fibrosis and Cirrhosis and Other Liver Damage-Related Conditions | 0 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Erythropenia | 20 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Bradyarrhythmias (Incl. Conduction Defects and Disorders of Sinus Node Function) | 6 Participants |
| 1200 mg QD Linezolid | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Lactic Acidosis | 6 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Bradyarrhythmias (Incl. Conduction Defects and Disorders of Sinus Node Function) | 6 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias | 52 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Conduction Defects | 6 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cholestasis and Jaundice of Hepatic Origin | 5 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Liver-Related Investigations, Signs, and Symptoms | 40 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Failure, Fibrosis and Cirrhosis and Other Liver Damage-Related Conditions | 2 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Comprehensive Search | 42 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Disorders of Sinus Node Function | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Hepatic Disorders | 42 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Acute Pancreatitis | 3 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Tachyarrhythmias (Incl. Supraventricular and Ventricular Tachyarrhythmias) | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Cytopenias Affecting More Than One Type of Blood Cell | 5 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Supraventricular Tachyarrhythmias | 1 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Thrombocytopenia | 6 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Peripheral Neurpoathy | 88 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Arrhythmia-Related Investigations, Signs, and Symptoms | 6 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Leukopenia | 12 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Rhabdomyolysis/Myopathy | 11 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Haematopoietic Erythropenia | 40 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Convulsions | 2 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmias | 12 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Optic Nerve Disorders | 14 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Lactic Acidosis | 8 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Cardiac Arrhythmia Terms (Incl. Bradyarrhythmias and Tachyarrhythmias) | 7 Participants |
| Total | Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest | Drug-Related Hepatic Disorders - Severe Events Only | 2 Participants |
Secondary
Number of Treatment Emergent Adverse Events (TEAEs)
Treatment-emergent adverse events (TEAEs): adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. Grade I, II, III, IV TEAEs: DMID grade is indicated as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life-threatening). TEAEs of special interest based on Section 7.3 of the protocol. Liver-related adverse events: any adverse event with a High Level Group Term of HEPATIC AND BILIARY NEOPLASMS BENIGN, HEPATIC AND HEPATOBILIARY DISORDERS, HEPATOBILIARY DISORDERS CONGENITAL, HEPATOBILIARY NEOPLASMS MALIGNANT AND UNSPECIFIED, HEPATOBILIARY INVESTIGATIONS or HEPATOBILIARY THERAPEUTIC PROCEDURES.
Time frame: Day 1 to 14 days post-End of Treatment
Population: Population analyzed contains all participants who received at least 1 dose of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Drug-Related TEAE | 5 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related TEAE | 387 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 658 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Discontinuation Of One Or All Drugs in the Trial Regimen (Per Investigator) | 16 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE of Special Interest | 157 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Death | 5 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Early Trial Withdrawal | 5 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Liver-Related TEAE | 1 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Grade III and/or IV TEAE | 49 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related and Liver-Related TEAE | 22 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Interruption Of Trial Drug | 40 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (Including Death) | 16 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Liver-Related TEAE | 27 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Grade III and/or IV TEAE | 77 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE of Special Interest | 158 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related TEAE | 319 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Drug-Related TEAE | 7 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (Including Death) | 20 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Early Trial Withdrawal | 6 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Death | 5 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 633 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Discontinuation Of One Or All Drugs in the Trial Regimen (Per Investigator) | 23 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Liver-Related TEAE | 0 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Interruption Of Trial Drug | 41 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related and Liver-Related TEAE | 33 events |
| XDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Liver-Related TEAE | 38 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 491 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Death | 6 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (Including Death) | 24 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Early Trial Withdrawal | 7 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Discontinuation Of One Or All Drugs in the Trial Regimen (Per Investigator) | 19 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Interruption Of Trial Drug | 46 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Grade III and/or IV TEAE | 65 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related TEAE | 298 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Drug-Related TEAE | 9 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE of Special Interest | 132 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Liver-Related TEAE | 27 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related and Liver-Related TEAE | 23 events |
| TI/NR MDR-TB | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Liver-Related TEAE | 0 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Grade III and/or IV TEAE | 61 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE of Special Interest | 183 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Liver-Related TEAE | 38 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Interruption Of Trial Drug | 35 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related and Liver-Related TEAE | 32 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Discontinuation Of One Or All Drugs in the Trial Regimen (Per Investigator) | 20 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Death | 4 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Liver-Related TEAE | 1 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Early Trial Withdrawal | 4 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 800 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (Including Death) | 12 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related TEAE | 408 events |
| 1200 mg QD Linezolid | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Drug-Related TEAE | 3 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Drug-Related TEAE | 12 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Serious Liver-Related TEAE | 1 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE of Special Interest | 315 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Interruption Of Trial Drug | 81 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Death | 10 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Early Trial Withdrawal | 11 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Grade III and/or IV TEAE | 126 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Liver-Related TEAE | 65 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 1291 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related and Liver-Related TEAE | 55 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | TEAE Leading To Discontinuation Of One Or All Drugs in the Trial Regimen (Per Investigator) | 39 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Drug-Related TEAE | 706 events |
| Total | Number of Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (Including Death) | 36 events |
Secondary
Proportion of Participants With Sputum Culture Conversion to Negative Status
Proportion of participants with sputum culture conversion to negative status for those positive at baseline at 4, 6, 8, 12, 16, and End of Treatment (26 or 39 weeks)
Time frame: Week 4, 6, 8, 12, 16, 26, 39
Population: Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Positive | 0 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Positive | 3 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Positive | 53 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Negative | 84 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Died | 5 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Died | 1 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Died | 6 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Negative | 83 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Negative | 57 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Positive | 1 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Positive | 15 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Died | 6 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Positive | 32 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Died | 4 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Negative | 71 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Negative | 37 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Negative | 82 Participants |
| Total | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Died | 0 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Negative | 37 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Negative | 25 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Positive | 35 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Died | 0 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Positive | 10 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Died | 4 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Negative | 53 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Positive | 2 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Died | 5 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Negative | 55 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Positive | 0 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Died | 5 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Negative | 55 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Positive | 0 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Positive | 22 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Died | 1 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Negative | 46 Participants |
| XDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Died | 5 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Negative | 29 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Negative | 29 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Positive | 18 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Positive | 0 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Negative | 25 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Died | 0 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Negative | 20 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 8 | Positive | 5 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | End of Treatment | Died | 1 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Positive | 10 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Negative | 28 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Died | 0 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Positive | 1 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Died | 0 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 4 | Negative | 12 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 16 | Died | 1 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 12 | Positive | 1 Participants |
| TI/NR MDR-TB | Proportion of Participants With Sputum Culture Conversion to Negative Status | Week 6 | Died | 0 Participants |
Secondary
Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment.
Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative. Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline. Clinical failure: A change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death. Note: Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart. Participants who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit.
Time frame: 24 Months post End of Treatment
Population: Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Total | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. | Unfavourable (treatment failure) | 10 Participants |
| Total | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. | Favourable (treatment success) | 96 Participants |
| XDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. | Favourable (treatment success) | 61 Participants |
| XDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. | Unfavourable (treatment failure) | 8 Participants |
| TI/NR MDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. | Favourable (treatment success) | 35 Participants |
| TI/NR MDR-TB | Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. | Unfavourable (treatment failure) | 2 Participants |
Secondary
Time to Sputum Culture Conversion to Negative Status Through the Treatment Period
Median time (in weeks) to culture negative status (first of 2 negative cultures without an intervening positive culture), MITT analysis.
Time frame: Day 1 through End of Treatment, approximately 6 to 9 months of treatment
Population: Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Total | Time to Sputum Culture Conversion to Negative Status Through the Treatment Period | 6 Weeks |
| XDR-TB | Time to Sputum Culture Conversion to Negative Status Through the Treatment Period | 6 Weeks |
| TI/NR MDR-TB | Time to Sputum Culture Conversion to Negative Status Through the Treatment Period | 6 Weeks |