Adjunctive Linezolid for the Treatment of Tuberculous Meningitis

Study Overview
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Brief Summary
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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.

Official Title
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Pharmacokinetics and Tolerability of Adjunctive Linezolid for the Treatment of Tuberculous Meningitis

Conditions
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Tuberculosis, Meningeal

Intervention / Treatment
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* Drug: LZD
* Drug: High dose RIF
* Drug: Standard dose RIF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age > 18 years Written informed consent from participant or proxy Definite, probable, possible, or suspected TBM diagnosis wherein the patient is being committed to a full course of anti-TB treatment for TBM in the setting of routine care. 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: Acid- fast bacilli (AFB) seen in the CSF, M tuberculosis cultured from CSF, or a CSF M tuberculosis-positive nucleic acid amplification test (e.g., Gene Xpert Ultra) performed within 14 days of entry AFB seen in the context of histological changes consistent with tuberculosis in the brain with suggestive symptoms or signs and CSF changes. Probable and possible TBM are defined using previously published consensus criteria as shown in Appendix A45. Probable TBM is defined as a total score of ≥12 when neuroimaging is available or total score of ≥10 when neuroimaging is unavailable. At least two points should either come from CSF or cerebral imaging criteria. Possible TBM is defined as a total score of 6-11 when neuroimaging is available, or total score of 6-9 when neuroimaging is unavailable. 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 >5 doses of TB treatment received within previous 5 days Discontinued TB treatment in prior 14 days Known current/previous drug resistant TB infection Known allergy to RIF, INH, PZA, EMB, LZD Previous treatment of TB or TBM with LZD Concomitant or planned use of monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, HIV protease inhibitors, or any other drug with significant interaction with RIF, LZD, or any TB drugs (see Appendices C and D) Women who are pregnant or breastfeeding, or women or men of reproductive potential who are unwilling to use at least one reliable form of barrier contraception or to abstain from sexual activity while receiving study drug treatment and for 30 days after stopping study treatment. Acceptable forms of contraception include: condoms (male or female) with or without a spermicidal agent, or diaphragm or cervical cap with spermicide. Hormonal contraception is not recommended as it may be ineffective due to induction of metabolism when receiving rifampicin. Unwillingness to be an inpatient for 2 weeks for initial treatment or to attend follow up clinic visits Lack of informed consent from participant or next of kin/caregiver Serum creatinine >1.8 times upper limit of normal, hemoglobin <7.0 g/dL for men, <6.5 g/dL for women, platelet count <50,000/mm3, absolute neutrophil count <600/mm3, alanine aminotransferase (ALT) >3 times the upper limit of normal, total bilirubin >2 times the upper limit of normal. Severe peripheral neuropathy defined by Grade 3 symptoms AND vibratory loss OR absent ankle jerks for participants able to undergo the Brief Peripheral Neuropathy Screen (see Appendix B). Contraindication to LP, including PLT <50 cells/mm3 or unequal pressures between intracranial compartments (e.g., due to mass lesion, non-communicating hydrocephalus), or unwillingness to undergo or consent to LP

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose RIF with LZD<br>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. | Drug: LZD<br>* LZD 1200 mg daily<br>* Other names: Linezolid;Drug: High dose RIF<br>* RIF 35 mg/kg/day<br>|
| Experimental: Standard dose RIF with LZD<br>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. | Drug: LZD<br>* LZD 1200 mg daily<br>* Other names: Linezolid;Drug: Standard dose RIF<br>* RIF 10 mg/kg/day<br>|
| Experimental: High Dose RIF<br>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. | Drug: High dose RIF<br>* RIF 35 mg/kg/day<br>|
| Active Comparator: Standard Dose RIF<br>Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB. | Drug: Standard dose RIF<br>* RIF 10 mg/kg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebrospinal Fluid (CSF) and Plasma LZD Pharmacokinetic Parameters | CSF to plasma ratio | 4 weeks | 
| Cerebrospinal Fluid (CSF) and Plasma LZD Pharmacokinetic Parameters | Rate of CSF uptake | 4 weeks | 
| Cerebrospinal Fluid (CSF) and Plasma LZD Pharmacokinetic Parameters | Plasma absorption rate constant (Ka) | 4 weeks | 
| Cerebrospinal Fluid (CSF) and Plasma LZD Pharmacokinetic Parameters | Drug clearance (CI/F) | 4 weeks | 
| Cerebrospinal Fluid (CSF) and Plasma LZD Pharmacokinetic Parameters | Volume of distribution (Vd) | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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 |