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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).
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they may have ongoing TB infection, they may have treatment extended to 9 months (with 24 months of Follow Up) or be withdrawn from the study.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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bedaquiline + PA-824 + Linezolid | Experimental | 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. A reduction in the dose of linezolid (to either 600 mg qd or 300 mg qd), or temporary cessation of linezolid (due to a linezolid-specific toxicity), or of the full regimen per Investigator discretion was allowed for suspected drug related toxicity. Re-introduction of the regimen could be considered post a cessation not greater than 35 consecutive days. If participants had toxicity events related to linezolid prohibiting further treatment with that drug, they could remain on the bedaquiline and pretomanid study IMP if they received the initial total of 1200 mg daily dose of linezolid for at least the first 4 consecutive weeks of treatment and they were smear negative, or with trace/scanty results and judged to be clinically improving by the Investigator. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bedaquiline | Drug | 100mg tablets |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 Months post End of Treatment |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Not provided
Key Inclusion Criteria
Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian).
Body weight of ≥35 kg (in light clothing and no shoes).
Male or female, aged 14 years or above.
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
Karnofsky score < 50 within 30 days prior to entry.
Body Mass index (BMI) < 17 kg/m²
History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.
HIV infected Subjects having a CD4+ count ≤ 50 cells/μL
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.
Significant cardiac arrhythmia requiring medication.
Subjects with the following at Screening:
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.
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.
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment.
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
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| Name | Affiliation | Role |
|---|---|---|
| Morounfolu Olugbosi, MD | Global Alliance for TB Drug Development | Principal Investigator |
| Francesca Conradie, MD | CHRU Themba Lethu Clinic - Helen Joseph Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Task Applied Science - Brooklyn Chest Hospital | Ysterplaat | Cape Town | 7405 | South Africa | ||
| King DinuZulu Hospital Complex |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36804834 | Derived | Solans BP, Imperial MZ, Olugbosi M, Savic RM. Analysis of Dynamic Efficacy Endpoints of the Nix-TB Trial. Clin Infect Dis. 2023 Jun 8;76(11):1903-1910. doi: 10.1093/cid/ciad051. | |
| 34604901 | Derived | Imperial MZ, Nedelman JR, Conradie F, Savic RM. Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis. Clin Infect Dis. 2022 May 30;74(10):1736-1747. doi: 10.1093/cid/ciab699. |
| Label | URL |
|---|---|
| TB Alliance Website | View source |
Not provided
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Bedaquiline + PA-824 + Linezolid | Bedaquiline (Days 1 to 14): 400 mg once daily (4 x bedaquiline 100mg tablets); Bedaquiline (Weeks 3 to 26 or 39*): 200 mg three days a week (2 x bedaquiline 100 mg tablets); plus Pretomanid: (Day 1 through weeks 26 or 39*) 200 mg once daily (1 x pretomanid 200 mg tablet); plus Linezolid: (Day 1 through weeks 26 or 39*) 1200 mg daily (1 x linezolid 600 mg tablet twice daily, later amended to 2 x linezolid 600 mg tablets once daily) *Note - participants received a minimum of 6 months (week 26) of trial treatment. If participants were culture positive or reverted to being culture positive between month 4 and month 6, and their clinical condition suggested they may have ongoing TB infection, the trial treatment could have been extended to 9 months (week 39). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period |
|
| |||||||||||||||||||||
| 6 Month Follow Up Period |
| ||||||||||||||||||||||
| 7 to 24 Month Follow Up Period |
|
Not provided
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan. | Posted | Count of Participants | Participants | 6 Months post End of Treatment |
Day 1 to 24 Months post-End of Treatment.
Adverse events (AEs) collected for all participants who received at least one dose of study treatment. Includes all AEs which started or worsened on or after the first trial drug administration through 14 days after administration.
All-cause mortality reported for participants through 24 Months post-End of Treatment.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Bedaquiline + PA-824 + 600mg BID Linezolid | bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 600mg twice daily . Bedaquiline: 100mg tablets PA-824: 200mg tablets Linezolid: Scored 600mg tablets |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | MedDra 22.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDra 22.1 | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eugene Sun, MD | Global Alliance for TB Drug Development | 212-227-7540 | eugene.sun@tballiance.org |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 16, 2018 | Sep 30, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 11, 2017 | Dec 14, 2023 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| D014397 | Tuberculosis, Pulmonary |
| D014376 | Tuberculosis |
| D018088 | Tuberculosis, Multidrug-Resistant |
| D054908 | Extensively Drug-Resistant Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
Not provided
Not provided
| ID | Term |
|---|---|
| C493870 | bedaquiline |
| C410767 | pretomanid |
| D000069349 | Linezolid |
| ID | Term |
|---|---|
| D000081 | Acetamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000085 | Acetates |
| D000144 |
Not provided
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| PA-824 | Drug | 200mg tablets |
|
|
| Linezolid | Drug | Scored 600mg tablets |
|
|
| 24 Months post End of Treatment |
| 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. | Day 1 through End of Treatment, approximately 6 to 9 months of treatment |
| 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) | Week 4, 6, 8, 12, 16, 26, 39 |
| 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. | Day 1 to 14 days post-End of Treatment |
| 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. | Day 1 to 14 days post-End of Treatment |
| 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". | Day 1 to 14 days post-End of Treatment |
| Sydenham |
| Durban |
| 4001 |
| South Africa |
| Sizwe Tropical Disease Hospital | Sandringham | Johannesburg | 2131 | South Africa |
| 32130813 | Derived | Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, Mendel CM, Egizi E, Moreira J, Timm J, McHugh TD, Wills GH, Bateson A, Hunt R, Van Niekerk C, Li M, Olugbosi M, Spigelman M; Nix-TB Trial Team. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814. |
|
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Height (cm) | total number with height recorded | Mean | Standard Deviation | cm |
|
| Weight (kg) | Mean | Standard Deviation | kg |
|
| BMI (kg/m^2) | Mean | Standard Deviation | kg/m^2 |
|
| CD4 Count (cells/uL) | CD4 count for HIV positive patient (with a CD4 count available) | Mean | Standard Deviation | cells/uL |
|
| Karnofsky Score (%) | Measure Description: Trained clinicians interview participants and grade their ability to perform daily activities using a percent scale where higher scores indicate that the participant is better able to function than lower scores. 100% indicates normal activity with no evidence of disease whereas a score of 70% or lower would indicate that the participant is unable to work and 40% or lower is unable to care for themselves. http://www.npcrc.org/files/news/karnofsky\_performance\_scale.pdf | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Total | Total Participants |
| OG001 | XDR-TB | Extensively Drug-Resistant Tuberculosis (XDR-TB) Population |
| OG002 | TI/NR MDR-TB | Treatment-Intolerant/Nonresponsive Multidrug-Resistant Tuberculosis (TB) Population |
|
|
| 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. | Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan. | Posted | Count of Participants | Participants | 24 Months post End of Treatment |
|
|
|
| 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. | Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan. | Posted | Median | Inter-Quartile Range | Weeks | Day 1 through End of Treatment, approximately 6 to 9 months of treatment |
|
|
|
| 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) | Participants deemed unassessable were excluded from the Modified Intent to Treat (MITT) population as per the analysis plan. | Posted | Count of Participants | Participants | No | Week 4, 6, 8, 12, 16, 26, 39 |
|
|
|
| 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. | Population analyzed contains all participants who received at least 1 dose of study treatment | Posted | Number | events | Day 1 to 14 days post-End of Treatment |
|
|
|
| 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. | The Safety analysis population is defined as all participants who received at least 1 administration of trial treatment. | Posted | Count of Participants | Participants | Day 1 to 14 days post-End of Treatment |
|
|
|
| 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". | The Safety analysis population is defined as all participants who received at least 1 administration of trial treatment. | Posted | Number | events | Day 1 to 14 days post-End of Treatment |
|
|
|
| 5 |
| 44 |
| 13 |
| 44 |
| 44 |
| 44 |
| EG001 | Bedaquiline + PA-824 + 1200mg QD 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 | 3 | 65 | 6 | 65 | 65 | 65 |
| EG002 | Total | Total Population | 8 | 109 | 19 | 109 | 109 | 109 |
| Pulmonary Tuberculosis | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Disseminated Tuberculosis | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Septic Shock | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Tuberculoma of Central Nervous System | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Abdominal Pain Upper | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Haematemesis | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Pancreatitis | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Pancreatitis Haemorrhagic | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Upper Gastrointestinal Haemorrhage | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Abnormal Loss of Weight | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Lactic Acidosis | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Generalized Tonic-Clonic Seizure | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Optic Neuritis | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Seizure | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDra 22.1 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDra 22.1 | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Pneumothorax Spontaneous | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Depression Suicidal | Psychiatric disorders | MedDra 22.1 | Systematic Assessment |
|
| Generalized Anxiety Disorder | Psychiatric disorders | MedDra 22.1 | Systematic Assessment |
|
| Optic Neuropaty | Eye disorders | MedDra 22.1 | Systematic Assessment |
|
| Multiple Organ Dysfunction Syndrome | General disorders | MedDra 22.1 | Systematic Assessment |
|
| Transaminases Increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDra 22.1 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDra 22.1 | Systematic Assessment |
|
| Conjunctivitis allergic | Eye disorders | MedDra 22.1 | Systematic Assessment |
|
| Visual impairment | Eye disorders | MedDra 22.1 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Lower respiratory tract infection | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDra 22.1 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Amylase increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Blood urea increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Electrocardiogram qt prolonged | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Gamma-glutamyltran sferase increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Lipase increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Transaminases increased | Investigations | MedDra 22.1 | Systematic Assessment |
|
| Abnormal loss of weight | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Hyperamylasaemia | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDra 22.1 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Costochondritis | Musculoskeletal and connective tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Neuropathy peripheral | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Peripheral sensory neuropathy | Nervous system disorders | MedDra 22.1 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDra 22.1 | Systematic Assessment |
|
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Pleuritic pain | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDra 22.1 | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDra 22.1 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDra 22.1 | Systematic Assessment |
|
Not provided
Not provided
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012141 | Respiratory Tract Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D023303 | Oxazolidinones |
| D010080 | Oxazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Died |
|
| Week 6 |
|
| Week 8 |
|
| Week 12 |
|
| Week 16 |
|
| End of Treatment |
|
| TEAE Leading To Death |
|
| Serious TEAE (Including Death) |
|
| TEAE Leading To Early Trial Withdrawal |
|
| TEAE Leading To Discontinuation Of One Or All Drugs in the Trial Regimen (Per Investigator) |
|
| TEAE Leading To Interruption Of Trial Drug |
|
| Grade III and/or IV TEAE |
|
| Drug-Related TEAE |
|
| Serious Drug-Related TEAE |
|
| TEAE of Special Interest |
|
| Liver-Related TEAE |
|
| Drug-Related and Liver-Related TEAE |
|
| Serious Liver-Related TEAE |
|
| Haematopoietic Cytopenias |
|
| Haematopoietic Erythropenia |
|
| Haematopoietic Leukopenia |
|
| Haematopoietic Thrombocytopenia |
|
| Haematopoietic Cytopenias Affecting More Than One Type of Blood Cell |
|
| Hepatic Disorders |
|
| Drug-Related Hepatic Disorders - Comprehensive Search |
|
| Liver-Related Investigations, Signs, and Symptoms |
|
| Cholestasis and Jaundice of Hepatic Origin |
|
| Drug-Related Hepatic Disorders - Severe Events Only |
|
| Hepatic Failure, Fibrosis and Cirrhosis and Other Liver Damage-Related Conditions |
|
| Optic Nerve Disorders |
|
| Cardiac Arrhythmias |
|
| Cardiac Arrhythmia Terms (Incl. Bradyarrhythmias and Tachyarrhythmias) |
|
| Bradyarrhythmias (Incl. Conduction Defects and Disorders of Sinus Node Function) |
|
| Conduction Defects |
|
| Disorders of Sinus Node Function |
|
| Tachyarrhythmias (Incl. Supraventricular and Ventricular Tachyarrhythmias) |
|
| Supraventricular Tachyarrhythmias |
|
| Arrhythmia-Related Investigations, Signs, and Symptoms |
|
| Rhabdomyolysis/Myopathy |
|
| Lactic Acidosis |
|
| Acute Pancreatitis |
|
| Convulsions |
|
| #Peripheral Neuropathy |
|
| Headache |
|
| Dizziness |
|
| Dysgeusia |
|
| Chronic Inflammatory Demyelinating Polyradiculoneurpoathy |
|
| Dizziness Postural |
|
| Dystonia |
|
| #Generalized Tonic-Clonic Seizure |
|
| Migraine |
|
| #Optic Neuritis |
|
| #Seizure |
|
| Sinus Headache |
|
| Taste Disorder |
|
| Tension Headache |
|
| #Syncope |
|