Trial Outcomes & Findings for Adjunctive Linezolid for the Treatment of Tuberculous Meningitis (NCT NCT04021121)

NCT ID: NCT04021121

Last Updated: 2024-10-01

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 40 participants
• Primary outcome timeframe: 4 weeks
• Results posted on: 2024-10-01

Participant Flow

Participant milestones

Measure	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	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	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	Standard Dose RIF Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day
Overall Study STARTED	9	11	10	10
Overall Study COMPLETED	6	8	5	6
Overall Study NOT COMPLETED	3	3	5	4

Reasons for withdrawal

Measure	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	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	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	Standard Dose RIF Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day
Overall Study Death	3	3	5	4

Baseline Characteristics

Adjunctive Linezolid for the Treatment of Tuberculous Meningitis

Baseline characteristics by cohort

Measure	High Dose RIF With LZD n=9 Participants 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	Standard Dose RIF With LZD n=11 Participants 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	High Dose RIF n=10 Participants 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	Standard Dose RIF n=10 Participants Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day	Total n=40 Participants Total of all reporting groups
Age, Continuous	39 years n=5 Participants	35 years n=7 Participants	38 years n=5 Participants	33 years n=4 Participants	37 years n=21 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	8 Participants n=7 Participants	6 Participants n=5 Participants	6 Participants n=4 Participants	22 Participants n=21 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	18 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	9 Participants n=5 Participants	11 Participants n=7 Participants	10 Participants n=5 Participants	10 Participants n=4 Participants	40 Participants n=21 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Living with HIV infection	9 Participants n=5 Participants	11 Participants n=7 Participants	9 Participants n=5 Participants	10 Participants n=4 Participants	39 Participants n=21 Participants

PRIMARY outcome

Timeframe: 4 weeks

Population: 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.

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).

Outcome measures

Measure	Linezolid n=18 Participants Includes arm 1 (Linezolid, high dose rifampicin) and arm 2 (Linezolid, standard dose rifampicin)
Drug Clearance (CL/F)	6.24 L/hr Interval 5.305 to 7.175

PRIMARY outcome

Timeframe: 4 weeks

Population: 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.

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).

Outcome measures

Measure	Linezolid n=18 Participants Includes arm 1 (Linezolid, high dose rifampicin) and arm 2 (Linezolid, standard dose rifampicin)
Volume of Distribution (Vd)	24.97 L Interval 14.024 to 35.976

PRIMARY outcome

Timeframe: 4 weeks

Population: 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.

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).

Outcome measures

Measure	Linezolid n=18 Participants Includes arm 1 (Linezolid, high dose rifampicin) and arm 2 (Linezolid, standard dose rifampicin)
Plasma Absorption Rate Constant (ka)	0.35 per hour (hr^-1) Interval 0.173 to 0.527

PRIMARY outcome

Timeframe: 4 weeks

Population: 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.

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).

Outcome measures

Measure	Linezolid n=18 Participants Includes arm 1 (Linezolid, high dose rifampicin) and arm 2 (Linezolid, standard dose rifampicin)
Rate of CSF Uptake (kPC)	0.382 per hour (hr^-1) Interval 0.278 to 0.486

PRIMARY outcome

Timeframe: 4 weeks

Population: 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.

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).

Outcome measures

Measure	Linezolid n=18 Participants Includes arm 1 (Linezolid, high dose rifampicin) and arm 2 (Linezolid, standard dose rifampicin)
CSF to Plasma Ratio (PC)	.5381 ratio Interval 0.46 to 0.616

SECONDARY outcome

Timeframe: 4 weeks

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 4 weeks

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 4, 12 and 24 weeks

Measures the degree of disability/dependence on a 6 point scale ranging from 0 (no symptoms) to 6 (death).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 and 24 weeks

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.

Outcome measures

Outcome data not reported

Adverse Events

High Dose RIF With LZD

Serious events: 5 serious events

Other events: 0 other events

Deaths: 3 deaths

Standard Dose RIF With LZD

Serious events: 5 serious events

Other events: 4 other events

Deaths: 3 deaths

High Dose RIF

Serious events: 6 serious events

Other events: 4 other events

Deaths: 5 deaths

Standard Dose RIF

Serious events: 6 serious events

Other events: 3 other events

Deaths: 4 deaths

Serious adverse events

Measure	High Dose RIF With LZD n=9 participants at risk 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	Standard Dose RIF With LZD n=11 participants at risk 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	High Dose RIF n=10 participants at risk 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	Standard Dose RIF n=10 participants at risk Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day
Skin and subcutaneous tissue disorders Sepsis Secondary to Multiple Pressure Sores	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks
Hepatobiliary disorders Drug-Induced Liver Injury	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks
Skin and subcutaneous tissue disorders Stevens-Johnson Syndrome R/O Exfoliative Dermatitis Induced by Initiation of Zidovudine	11.1% 1/9 • Number of events 1 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Respiratory, thoracic and mediastinal disorders Sepsis With Chest and Urinary Tract Focus	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks
Blood and lymphatic system disorders Fever With Hyponatremia and Hypokalemia	0.00% 0/9 • 24 weeks	9.1% 1/11 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Blood and lymphatic system disorders Hospitalization for Dehydration	11.1% 1/9 • Number of events 1 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Respiratory, thoracic and mediastinal disorders Possible Aspiration Pneumonia	0.00% 0/9 • 24 weeks	9.1% 1/11 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Renal and urinary disorders Sepsis With Acute Kidney Injury	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks
Respiratory, thoracic and mediastinal disorders Aspiration Pneumonia	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks
Respiratory, thoracic and mediastinal disorders Sepsis With Chest Focus Complicated with Acute Kidney Injury and Electrolyte Imbalance	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks
Nervous system disorders Possible Neuro-Syphilis and Severe Hyponatremia	11.1% 1/9 • Number of events 1 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Infections and infestations Severe Malaria with Severe Anemia and Urinary Tract Infection	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks
Infections and infestations Severe Malaria and Severe Anemia	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/9 • 24 weeks	9.1% 1/11 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks
Renal and urinary disorders Acute Kidney Injury Secondary to Sepsis with Chest Focus	11.1% 1/9 • Number of events 1 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Infections and infestations Severe Sepsis Secondary to Multi-Drug Resistant Bacteremia	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks
Skin and subcutaneous tissue disorders Severe Sepsis with Skin Focus Possible Acute Pulmonary Embolus	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks
Blood and lymphatic system disorders TB Meningitis with Moderate Hyponatremia	11.1% 1/9 • Number of events 1 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Respiratory, thoracic and mediastinal disorders Sepsis Secondary to Infected Decubitus Ulcer and Respiratory Failure Following Aspiration Pneumonia	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	0.00% 0/10 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks
General disorders Sepsis	0.00% 0/9 • 24 weeks	9.1% 1/11 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks
Blood and lymphatic system disorders Possible Hypoglycemia	0.00% 0/9 • 24 weeks	9.1% 1/11 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks	0.00% 0/10 • 24 weeks

Other adverse events

Measure	High Dose RIF With LZD n=9 participants at risk 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	Standard Dose RIF With LZD n=11 participants at risk 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	High Dose RIF n=10 participants at risk 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	Standard Dose RIF n=10 participants at risk Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. Standard dose RIF: RIF 10 mg/kg/day
Blood and lymphatic system disorders Grade 3 or 4 anemia	0.00% 0/9 • 24 weeks	9.1% 1/11 • Number of events 1 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	20.0% 2/10 • Number of events 2 • 24 weeks
Blood and lymphatic system disorders Grade 3 or 4 hyponatremia	0.00% 0/9 • 24 weeks	27.3% 3/11 • Number of events 3 • 24 weeks	40.0% 4/10 • Number of events 4 • 24 weeks	30.0% 3/10 • Number of events 3 • 24 weeks
Hepatobiliary disorders Grade 3 or 4 elevated total bilirubin	0.00% 0/9 • 24 weeks	0.00% 0/11 • 24 weeks	10.0% 1/10 • Number of events 1 • 24 weeks	0.00% 0/10 • 24 weeks

Additional Information

Dr. Felicia Chow

University of California, San Francisco

Phone: (628) 206-4449

Email: felicia.chow@ucsf.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place