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| ID | Type | Description | Link |
|---|---|---|---|
| R21TW011035 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| MRC/UVRI and LSHTM Uganda Research Unit | OTHER |
| London School of Hygiene and Tropical Medicine | OTHER |
| Fogarty International Center of the National Institute of Health | NIH |
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This is a phase II randomized open-label trial of high versus standard dose rifampin (RIF) with or without linezolid (LZD) for the first 4 weeks of treatment for Tuberculosis Meningitis (TBM) at Masaka Regional Referral Hospital in Uganda. Initial randomization will be to high (35 mg/kg/day) versus standard (10 mg/kg/day) dose oral rifampin for the first 4 weeks of intensive therapy. Participants will then undergo a second randomization to linezolid 1200 mg daily versus no linezolid for the first 4 weeks of therapy. The primary aims are (1) to determine the cerebrospinal fluid and plasma pharmacokinetics of adjunctive LZD 1200 mg daily in TBM patients receiving high or standard dose RIF and (2) to evaluate the tolerability of a 4-week course of LZD in TBM patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High Dose RIF with LZD | Experimental | Arm 1 participants will receive high dose oral RIF (35mg/kg/day) and LZD 1200 mg daily for the first 4 weeks of therapy, along with standard doses of Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol (EMB). After 4 weeks, LZD will be discontinued and high dose RIF will return to standard dose for the remainder of treatment. |
|
| Standard dose RIF with LZD | Experimental | Arm 2 participants will receive standard dose RIF, INH, PZA, and EMB along with LZD 1200 mg daily. After 4 weeks, LZD will be discontinued. |
|
| High Dose RIF | Experimental | Arm 3 participants will receive high dose oral RIF (35mg/kg/day) for the first 4 weeks of therapy, along with standard doses of INH, PZA, and EMB. After 4 weeks, high dose RIF will return to standard dose for the remainder of treatment. |
|
| Standard Dose RIF | Active Comparator | Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| LZD | Drug | LZD 1200 mg daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| Drug Clearance (CL/F) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | 4 weeks |
| Volume of Distribution (Vd) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | 4 weeks |
| Plasma Absorption Rate Constant (ka) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | 4 weeks |
| Rate of CSF Uptake (kPC) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | 4 weeks |
| CSF to Plasma Ratio (PC) |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Participants With Grade 3 or Higher Adverse Events (AE). | 4 weeks | |
| Proportion of Participants Who Complete LZD Treatment. | 4 weeks | |
| Modified Rankin Scale (MRS) Performance. |
Not provided
Inclusion Criteria
All participants must have at least one of the following signs/symptoms: headache, irritability, vomiting, fever, neck stiffness, convulsions, focal neurological deficits, altered consciousness, or lethargy. In addition, participants must have CSF glucose to plasma ratio < 0.5 OR positive CSF acid-fast bacilli (AFB) smear OR positive CSF GeneXpert or Xpert Ultra OR clinician intent to initiate TB treatment for suspected TB meningitis.
Definite, probable and possible TBM will be defined as:
Definite TBM is defined by the presence of one or more of the following:
Probable and possible TBM are defined using previously published consensus criteria as shown in Appendix A45.
Exclusion of the most likely alternative diagnoses is also required (e.g., negative cryptococcal antigen). Because culture confirmation is rarely available or often delayed in TBM, patients with probable or possible TBM will be recruited based on these predefined criteria, and CSF will be collected for mycobacterial culture and molecular testing. Classification of participants as definite, probable, or possible TBM will be made retrospectively once all necessary data are available.
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Felicia C Chow, MD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Masaka Regional Referral Hospital/MRC UVRI Uganda Research Unit on AIDS | Masaka | Uganda |
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| ID | Title | Description |
|---|---|---|
| FG000 | High Dose RIF With LZD | Arm 1 participants will receive high dose oral RIF (35mg/kg/day) and LZD 1200 mg daily for the first 4 weeks of therapy, along with standard doses of Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol (EMB). After 4 weeks, LZD will be discontinued and high dose RIF will return to standard dose for the remainder of treatment. LZD: LZD 1200 mg daily High dose RIF: RIF 35 mg/kg/day |
| FG001 | Standard Dose RIF With LZD | Arm 2 participants will receive standard dose RIF, INH, PZA, and EMB along with LZD 1200 mg daily. After 4 weeks, LZD will be discontinued. LZD: LZD 1200 mg daily Standard dose RIF: RIF 10 mg/kg/day |
| FG002 | High Dose RIF | Arm 3 participants will receive high dose oral RIF (35mg/kg/day) for the first 4 weeks of therapy, along with standard doses of INH, PZA, and EMB. After 4 weeks, high dose RIF will return to standard dose for the remainder of treatment. High dose RIF: RIF 35 mg/kg/day |
| FG003 | Standard Dose RIF | Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
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| ID | Title | Description |
|---|---|---|
| BG000 | High Dose RIF With LZD | Arm 1 participants will receive high dose oral RIF (35mg/kg/day) and LZD 1200 mg daily for the first 4 weeks of therapy, along with standard doses of Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol (EMB). After 4 weeks, LZD will be discontinued and high dose RIF will return to standard dose for the remainder of treatment. LZD: LZD 1200 mg daily High dose RIF: RIF 35 mg/kg/day |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Drug Clearance (CL/F) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | Our primary outcomes include only 2 out of the 4 arms (High dose RIF with LZD + Standard Dose with LZD) because only these 2 arms received linezolid (LZD), and the primary outcomes are measures of LZD pharmacokinetics. Thus, the other 2 arms (High dose RIF with No LZD + Standard Dose with No LZD) are not relevant. Additionally, as pre-specified in the protocol, the 2 arms that received LZD (High dose RIF with LZD + Standard Dose with LZD) are combined. | Posted | Mean | 95% Confidence Interval | L/hr | 4 weeks |
|
24 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | High Dose RIF With LZD | Arm 1 participants will receive high dose oral RIF (35mg/kg/day) and LZD 1200 mg daily for the first 4 weeks of therapy, along with standard doses of Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol (EMB). After 4 weeks, LZD will be discontinued and high dose RIF will return to standard dose for the remainder of treatment. LZD: LZD 1200 mg daily High dose RIF: RIF 35 mg/kg/day |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sepsis Secondary to Multiple Pressure Sores | Skin and subcutaneous tissue disorders | Systematic Assessment | Unrelated to Study Drug |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Grade 3 or 4 anemia | Blood and lymphatic system disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Felicia Chow | University of California, San Francisco | (628) 206-4449 | felicia.chow@ucsf.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 3, 2019 | May 21, 2019 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 18, 2022 | Jul 18, 2024 | ICF_001.pdf |
Not provided
| ID | Term |
|---|---|
| D014390 | Tuberculosis, Meningeal |
| ID | Term |
|---|---|
| D016920 | Meningitis, Bacterial |
| D020806 | Central Nervous System Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
Not provided
Not provided
| ID | Term |
|---|---|
| D000069349 | Linezolid |
| D012293 | Rifampin |
| ID | Term |
|---|---|
| D000081 | Acetamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000085 | Acetates |
| D000144 |
Not provided
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| High dose RIF | Drug | RIF 35 mg/kg/day |
|
| Standard dose RIF | Drug | RIF 10 mg/kg/day |
|
Once plasma parameter estimates were finalized, these were fixed and then linked to CSF concentrations via a hypothetical effect compartment with a unidirectional rate of the entry whose rate was described by KPC and an amount, expressed as PC, or a ratio between plasma concentrations and CSF concentrations. Higher values of KPC indicate faster rates of entry, and higher values of PC indicate greater proportions of linezolid entering from the blood into the CSF.
Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).
| 4 weeks |
Measures the degree of disability/dependence on a 6 point scale ranging from 0 (no symptoms) to 6 (death). |
| 4, 12 and 24 weeks |
| Neurocognitive Battery Performance: Wechsler Adult Intelligence Scale-III Digit Symbol (WAIS-III). | The WAIS-III assesses speed of information processing. The test consists of 133 small blank squares separated into 7 rows. Each square consists a number ranging from 1-9 and a blank space below. The participant must pair each number in the square with its corresponding symbol provided in a 'key' above the test over a time limit of 90 or 120 seconds. Scores range from 1-133 where higher scores equal indicate better outcomes. | 12 and 24 weeks |
| Neurocognitive Battery Performance: Color Trails, Part 1 | The Color Trails, part 1 is used to assess attention and working memory. For this test 25 circles each containing a number between 1 and 25 are randomly placed on a sheet of paper. Participants draw a line between circles as quickly as possible in numerical order. Scores are presented as time to completion. Higher values indicate greater impairment. | 12 and 24 weeks |
| Neurocognitive Battery Performance: Color Trails, Part 2 | The Color Trails, part 2 is used to assess executive function. For this test 25 circles each containing either a number between 1 and 13 or a letter between A through L are randomly placed on a sheet of paper. Participants draw a line between circles as quickly as possible alternating between number and letter in ascending order. Scores are presented as time to completion. Higher values indicate greater impairment. | 12 and 24 weeks |
| Neurocognitive Battery Performance: Category Fluency | The Category Fluency test measures executive function and semantic fluency. Participants have 1 minute to name as many categorical items as possible. Scores are presented as the total number of correct names. Lower values indicate greater impairment. | 12 and 24 weeks |
| Neurocognitive Battery Performance: Hopkins Verbal Learning Test-Revised (HVLT-R) | Either the HVLT-R or WHO-UCLA AVLT will be used to assess verbal learning and memory. In the HVLT-R Participants are asked to recall a list of 12 words. It includes four subscales: total recall, delayed recall, retention score, and recognition discrimination index. The total recall score indicates the number of correctly reported words in 3 learning trials, with a subscale ranging from 0-36. The delayed recall subscale, ranging from 0-12, indicates the number of correctly reported words in the delayed recall trial. The retention score represents the score on the delayed recall test divided by the higher of the recall scores from learning trials 2 and 3, multiplied by 100. The recognition discrimination index (RDI) is calculated by subtracting the total false positives score (semantically-related plus semantically un-related) from the total true-positives score obtained in the delayed recognition test. For all subscales, higher values indicate better outcomes. | 12 and 24 weeks |
| Neurocognitive Battery Performance: World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT). | Either the HVLT-R or WHO-UCLA AVLT will be used to assess verbal learning and memory. The WHO-UCLA AVLT includes a 15 word list learned over five trials (subscale from 0-75), an interference trial (subscale from 0-15), and a 20 minute delayed recall trial (subscale from 0-15). A final delayed recognition trial is performed immediately after delayed recall. The retention score represents the score on the delayed recall test divided by the higher of the recall scores from learning trials 2-5, multiplied by 100. The recognition discrimination index (RDI) is calculated by subtracting the total false positives score from the total true-positives score obtained in the delayed recognition test. For all subscales, higher values indicate better outcomes. | 12 and 24 weeks |
| Neurocognitive Battery Performance: Grooved Pegboard Bilateral | The Grooved Pegboard Bilateral test evaluates fine motor ability. One hand at a time, subjects place 25 pegs as quickly as possible in a board with randomly oriented peg holes. Scores for each hand are presented as time to completion. Higher values indicate greater impairment. | 12 and 24 weeks |
| Neurocognitive Battery Performance: Finger Tapping Bilateral | The Finger Tapping Bilateral test evaluates fine motor ability. One hand at a time, subjects tap a lever counter device as quickly as possible within a 10 second time interval. A total of ten trials are conducted, five trials per hand. Trial subscores are presented as the number of taps within the 10 second interval. Trial subscores for each hand are averaged for a total score. Higher values indicate better outcomes. | 12 and 24 weeks |
| Montreal Cognitive Assessment Performance (Conditional). | Completed if participant is unable to undergo the full neurocognitive test battery. The Montreal Cognitive Assessment (MoCA) is a brief cognitive screening tool used to detect mild neurocognitive disability. It assesses six key areas of cognitive ability: short-term memory, visuospatial abilities, executive functions, language, orientation to time and place, and attention, concentration and working memory. The assessment has 11 scored sections, summed for a total score ranging from 0-30 points; a score of 26 or above is considered normal. | 12 and 24 weeks |
| BG001 | Standard Dose RIF With LZD | Arm 2 participants will receive standard dose RIF, INH, PZA, and EMB along with LZD 1200 mg daily. After 4 weeks, LZD will be discontinued. LZD: LZD 1200 mg daily Standard dose RIF: RIF 10 mg/kg/day |
| BG002 | High Dose RIF | Arm 3 participants will receive high dose oral RIF (35mg/kg/day) for the first 4 weeks of therapy, along with standard doses of INH, PZA, and EMB. After 4 weeks, high dose RIF will return to standard dose for the remainder of treatment. High dose RIF: RIF 35 mg/kg/day |
| BG003 | Standard Dose RIF | Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Living with HIV infection | Count of Participants | Participants |
|
Includes arm 1 (Linezolid, high dose rifampicin) and arm 2 (Linezolid, standard dose rifampicin) |
|
|
| Primary | Volume of Distribution (Vd) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | Our primary outcomes include only 2 out of the 4 arms (High dose RIF with LZD + Standard Dose with LZD) because only these 2 arms received linezolid (LZD), and the primary outcomes are measures of LZD pharmacokinetics. Thus, the other 2 arms (High dose RIF with No LZD + Standard Dose with No LZD) are not relevant. Additionally, as pre-specified in the protocol, the 2 arms that received LZD (High dose RIF with LZD + Standard Dose with LZD) are combined. | Posted | Mean | 95% Confidence Interval | L | 4 weeks |
|
|
|
| Primary | Plasma Absorption Rate Constant (ka) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | Our primary outcomes include only 2 out of the 4 arms (High dose RIF with LZD + Standard Dose with LZD) because only these 2 arms received linezolid (LZD), and the primary outcomes are measures of LZD pharmacokinetics. Thus, the other 2 arms (High dose RIF with No LZD + Standard Dose with No LZD) are not relevant. Additionally, as pre-specified in the protocol, the 2 arms that received LZD (High dose RIF with LZD + Standard Dose with LZD) are combined. | Posted | Mean | 95% Confidence Interval | per hour (hr^-1) | 4 weeks |
|
|
|
| Primary | Rate of CSF Uptake (kPC) | Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | Our primary outcomes include only 2 out of the 4 arms (High dose RIF with LZD + Standard Dose with LZD) because only these 2 arms received linezolid (LZD), and the primary outcomes are measures of LZD pharmacokinetics. Thus, the other 2 arms (High dose RIF with No LZD + Standard Dose with No LZD) are not relevant. Additionally, as pre-specified in the protocol, the 2 arms that received LZD (High dose RIF with LZD + Standard Dose with LZD) are combined. | Posted | Mean | 95% Confidence Interval | per hour (hr^-1) | 4 weeks |
|
|
|
| Primary | CSF to Plasma Ratio (PC) | Once plasma parameter estimates were finalized, these were fixed and then linked to CSF concentrations via a hypothetical effect compartment with a unidirectional rate of the entry whose rate was described by KPC and an amount, expressed as PC, or a ratio between plasma concentrations and CSF concentrations. Higher values of KPC indicate faster rates of entry, and higher values of PC indicate greater proportions of linezolid entering from the blood into the CSF. Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability). | Our primary outcomes include only 2 out of the 4 arms (High dose RIF with LZD + Standard Dose with LZD) because only these 2 arms received linezolid (LZD), and the primary outcomes are measures of LZD pharmacokinetics. Thus, the other 2 arms (High dose RIF with No LZD + Standard Dose with No LZD) are not relevant. Additionally, as pre-specified in the protocol, the 2 arms that received LZD (High dose RIF with LZD + Standard Dose with LZD) are combined. | Posted | Mean | 95% Confidence Interval | ratio | 4 weeks |
|
|
|
| Secondary | Proportion of Participants With Grade 3 or Higher Adverse Events (AE). | Not Posted | 4 weeks | Participants |
| Secondary | Proportion of Participants Who Complete LZD Treatment. | Not Posted | 4 weeks | Participants |
| Secondary | Modified Rankin Scale (MRS) Performance. | Measures the degree of disability/dependence on a 6 point scale ranging from 0 (no symptoms) to 6 (death). | Not Posted | 4, 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: Wechsler Adult Intelligence Scale-III Digit Symbol (WAIS-III). | The WAIS-III assesses speed of information processing. The test consists of 133 small blank squares separated into 7 rows. Each square consists a number ranging from 1-9 and a blank space below. The participant must pair each number in the square with its corresponding symbol provided in a 'key' above the test over a time limit of 90 or 120 seconds. Scores range from 1-133 where higher scores equal indicate better outcomes. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: Color Trails, Part 1 | The Color Trails, part 1 is used to assess attention and working memory. For this test 25 circles each containing a number between 1 and 25 are randomly placed on a sheet of paper. Participants draw a line between circles as quickly as possible in numerical order. Scores are presented as time to completion. Higher values indicate greater impairment. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: Color Trails, Part 2 | The Color Trails, part 2 is used to assess executive function. For this test 25 circles each containing either a number between 1 and 13 or a letter between A through L are randomly placed on a sheet of paper. Participants draw a line between circles as quickly as possible alternating between number and letter in ascending order. Scores are presented as time to completion. Higher values indicate greater impairment. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: Category Fluency | The Category Fluency test measures executive function and semantic fluency. Participants have 1 minute to name as many categorical items as possible. Scores are presented as the total number of correct names. Lower values indicate greater impairment. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: Hopkins Verbal Learning Test-Revised (HVLT-R) | Either the HVLT-R or WHO-UCLA AVLT will be used to assess verbal learning and memory. In the HVLT-R Participants are asked to recall a list of 12 words. It includes four subscales: total recall, delayed recall, retention score, and recognition discrimination index. The total recall score indicates the number of correctly reported words in 3 learning trials, with a subscale ranging from 0-36. The delayed recall subscale, ranging from 0-12, indicates the number of correctly reported words in the delayed recall trial. The retention score represents the score on the delayed recall test divided by the higher of the recall scores from learning trials 2 and 3, multiplied by 100. The recognition discrimination index (RDI) is calculated by subtracting the total false positives score (semantically-related plus semantically un-related) from the total true-positives score obtained in the delayed recognition test. For all subscales, higher values indicate better outcomes. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT). | Either the HVLT-R or WHO-UCLA AVLT will be used to assess verbal learning and memory. The WHO-UCLA AVLT includes a 15 word list learned over five trials (subscale from 0-75), an interference trial (subscale from 0-15), and a 20 minute delayed recall trial (subscale from 0-15). A final delayed recognition trial is performed immediately after delayed recall. The retention score represents the score on the delayed recall test divided by the higher of the recall scores from learning trials 2-5, multiplied by 100. The recognition discrimination index (RDI) is calculated by subtracting the total false positives score from the total true-positives score obtained in the delayed recognition test. For all subscales, higher values indicate better outcomes. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: Grooved Pegboard Bilateral | The Grooved Pegboard Bilateral test evaluates fine motor ability. One hand at a time, subjects place 25 pegs as quickly as possible in a board with randomly oriented peg holes. Scores for each hand are presented as time to completion. Higher values indicate greater impairment. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Neurocognitive Battery Performance: Finger Tapping Bilateral | The Finger Tapping Bilateral test evaluates fine motor ability. One hand at a time, subjects tap a lever counter device as quickly as possible within a 10 second time interval. A total of ten trials are conducted, five trials per hand. Trial subscores are presented as the number of taps within the 10 second interval. Trial subscores for each hand are averaged for a total score. Higher values indicate better outcomes. | Not Posted | 12 and 24 weeks | Participants |
| Secondary | Montreal Cognitive Assessment Performance (Conditional). | Completed if participant is unable to undergo the full neurocognitive test battery. The Montreal Cognitive Assessment (MoCA) is a brief cognitive screening tool used to detect mild neurocognitive disability. It assesses six key areas of cognitive ability: short-term memory, visuospatial abilities, executive functions, language, orientation to time and place, and attention, concentration and working memory. The assessment has 11 scored sections, summed for a total score ranging from 0-30 points; a score of 26 or above is considered normal. | Not Posted | 12 and 24 weeks | Participants |
| 3 |
| 9 |
| 5 |
| 9 |
| 0 |
| 9 |
| EG001 | Standard Dose RIF With LZD | Arm 2 participants will receive standard dose RIF, INH, PZA, and EMB along with LZD 1200 mg daily. After 4 weeks, LZD will be discontinued. LZD: LZD 1200 mg daily Standard dose RIF: RIF 10 mg/kg/day | 3 | 11 | 5 | 11 | 4 | 11 |
| EG002 | High Dose RIF | Arm 3 participants will receive high dose oral RIF (35mg/kg/day) for the first 4 weeks of therapy, along with standard doses of INH, PZA, and EMB. After 4 weeks, high dose RIF will return to standard dose for the remainder of treatment. High dose RIF: RIF 35 mg/kg/day | 5 | 10 | 6 | 10 | 4 | 10 |
| EG003 | Standard Dose RIF | Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day | 4 | 10 | 6 | 10 | 3 | 10 |
|
| Drug-Induced Liver Injury | Hepatobiliary disorders | Systematic Assessment | Related to Study Drug |
|
| Stevens-Johnson Syndrome R/O Exfoliative Dermatitis Induced by Initiation of Zidovudine | Skin and subcutaneous tissue disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Sepsis With Chest and Urinary Tract Focus | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Fever With Hyponatremia and Hypokalemia | Blood and lymphatic system disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Hospitalization for Dehydration | Blood and lymphatic system disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Possible Aspiration Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Sepsis With Acute Kidney Injury | Renal and urinary disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Aspiration Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Sepsis With Chest Focus Complicated with Acute Kidney Injury and Electrolyte Imbalance | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Possible Neuro-Syphilis and Severe Hyponatremia | Nervous system disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Severe Malaria with Severe Anemia and Urinary Tract Infection | Infections and infestations | Systematic Assessment | Unrelated to Study Drug |
|
| Severe Malaria and Severe Anemia | Infections and infestations | Systematic Assessment | Unrelated to Study Drug |
|
| Aspiration | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Acute Kidney Injury Secondary to Sepsis with Chest Focus | Renal and urinary disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Severe Sepsis Secondary to Multi-Drug Resistant Bacteremia | Infections and infestations | Systematic Assessment | Unrelated to Study Drug |
|
| Severe Sepsis with Skin Focus Possible Acute Pulmonary Embolus | Skin and subcutaneous tissue disorders | Systematic Assessment | Unrelated to Study Drug |
|
| TB Meningitis with Moderate Hyponatremia | Blood and lymphatic system disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Sepsis Secondary to Infected Decubitus Ulcer and Respiratory Failure Following Aspiration Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Sepsis | General disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Possible Hypoglycemia | Blood and lymphatic system disorders | Systematic Assessment | Unrelated to Study Drug |
|
| Grade 3 or 4 hyponatremia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Grade 3 or 4 elevated total bilirubin | Hepatobiliary disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D007239 | Infections |
| D020306 | Tuberculosis, Central Nervous System |
| D000092225 | Tuberculosis, Extrapulmonary |
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D002494 | Central Nervous System Infections |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008581 | Meningitis |
| D000090862 | Neuroinflammatory Diseases |
| Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D023303 | Oxazolidinones |
| D010080 | Oxazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |