Pharmacokinetics and Tolerability of Adjunctive Linezolid for the Treatment of Tuberculous Meningitis
Phase: PHASE2
Conditions: Tuberculosis, Meningeal
Sponsor: University of California, San Francisco

 
 
ALTER Protocol 
 
STUDY TITLE: Pharmacokinetics and tolerability of Adjunctive Linezolid for the Treatment of 
tubERculous meningitis (ALTER): a Phase II trial, open-label, randomized trial 
 
STUDY SPONSOR: University of California, San Francisco 
 
FUNDING MECHANISM: NIH/Fogarty International Center R21TW011035 (PI: Chow) 
 
INVESTIGATORS: 
 
Principal Investigator: Felicia Chow, University of California, San Francisco.  
 
Co-investigator: Payam Nahid, University of California, San Francisco 
 
Co-investigator: Rada Savic, University of California, San Francisco 
 
Co-investigator & Site PI: Freddie Mukasa Kibengo, MRC/UVRI and London School of Hygiene and 
Tropical Medicine Uganda Research Unit  
 
Co-investigator: Fiona Cresswell, MRC/UVRI and London School of Hygiene and Tropical Medicine 
Uganda Research Unit 
 
Study Coordinator: Yofesi Nikweri, MRC/UVRI and London School of Hygiene and Tropical 
Medicine Uganda Research Unit  
 
VERSION NUMBER: 1.0 
DATE: April 3, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
2 
 
 
 
Pharmacokinetics and tolerability of Adjunctive Linezolid for the Treatment of tubERculous meningitis 
(ALTER): a Phase II trial, open-label, randomized trial 
 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with the standards of the International 
Conference on Harmonization Guideline for Good Clinical Practice (E6); Institutional Review 
Board/Ethics Committee determinations; all applicable in-country, state, and local laws and 
regulations; and other applicable requirements and institutional policies. 
 
 
 
Principal Investigator: _____________________________________________________ 
Print/Type 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
 
 
 
 
 
 
 
 
 
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
3 
TABLE OF CONTENTS 
SIGNATURE PAGE .................................................................................................................... 2 
PARTICIPATING SITES ............................................................................................................. 7 
INVESTIGATORS ...................................................................................................................... 7 
SCHEMA ................................................................................................................................. 8-9 
1.0 
Background and study rationale ................................................................................. 9-11 
2.0  
Hypotheses ................................................................................................................... 11 
2.1 
Primary Objective .......................................................................................................... 11 
2.2 
Primary Endpoint .......................................................................................................... 11 
2.3 
Secondary Objectives .............................................................................................. 11-12 
2.4 
Secondary Endpoints .................................................................................................... 12 
3.0 
STUDY POPULATION .................................................................................................. 12 
 
3.1     Inclusion Criteria ............................................................................................ 12-13 
 
3.2     Exclusion Criteria ................................................................................................ 13 
 
3.3     Late Exclusion Criteria ........................................................................................ 13 
4.0 
STUDY DESIGN ........................................................................................................... 14 
4.1 
Study Enrollment Procedures ........................................................................................ 15 
 
4.1.1      Identification of participants ............................................................................. 15 
 
4.1.2      Enrollment visit ................................................................................................ 15 
 
4.1.3      Informed consent ........................................................................................ 15-16 
 
4.1.4      Assessment of capacity to provide informed consent ...................................... 16 
 
4.1.5      Surrogate consent by next of kin/caregiver ...................................................... 16 
 
4.1.6      Illiterate/unable to provide signature ................................................................ 16 
 
4.1.7      Randomization ........................................................................................... 16-17 
  
4.1.4      Co-enrollment guidelines ................................................................................. 17 
5.0 
STUDY TREATMENT ................................................................................................... 17 
5.1       Administration .......................................................................................................... 18-19 
5.2       Acquisition .................................................................................................................... 19 
5.3       Product Storage and Stability ........................................................................................ 19 
5.4       Study Product Accountability ......................................................................................... 19 
5.5       Concomitant Medications ......................................................................................... 19-20 
5.6       Adjunctive corticosteroids.............................................................................................. 20 
5.7       Antiretroviral therapy ..................................................................................................... 20 
6.0 
CLINICAL AND LABORATORY EVALUATIONS .......................................................... 20 
6.1 
Schedule of evaluations ........................................................................................... 20-21 
6.2 
Timing for evaluations ................................................................................................... 22 

ALTER 
Draft version 1.0 
4/3/19 
 
 
4 
 
6.2.1      Screening evaluations ..................................................................................... 22 
 
6.2.2      Entry evaluations ............................................................................................. 22 
 
6.2.3      Discontinuation evaluations ............................................................................. 22 
 
6.2.4      Sick visits ................................................................................................... 22-23 
6.3 
Instructions for evaluations ............................................................................................ 23 
 
6.3.1      Complete medical history ................................................................................ 23 
 
6.3.2      Symptom assessment ..................................................................................... 23 
 
6.3.3      Medication history ........................................................................................... 23 
 
6.3.4      Assessment of adherence ............................................................................... 23 
 
6.3.5      Complete physical exam ................................................................................. 23 
 
6.3.6      Targeted physical exam ............................................................................. 23-24 
 
6.3.7      Neurologic exam and Glasgow Coma Scale .................................................... 24 
 
6.3.8      MRC TBM disease grade ................................................................................ 24 
 
6.3.9      Brief peripheral neuropathy screen .................................................................. 24 
 
6.3.10    Vision testing ................................................................................................... 24 
 
6.3.11    Neurocognitive testing ..................................................................................... 24 
 
6.3.12    Functional outcomes ....................................................................................... 24 
 
6.3.13    Laboratory assessments ............................................................................ 24-25 
 
6.3.14    Lumbar puncture ............................................................................................. 25 
 
6.3.15    TB laboratory diagnostics and microbiology ............................................... 25-26 
 
6.3.16    Chext x-ray ...................................................................................................... 26 
 
6.3.17    Computed tomagraphy imaging ....................................................................... 26 
 
6.3.18    Pharmacokinetic studies .................................................................................. 26 
 
6.3.19    Storage of M. tuberculosis isolates .................................................................. 26 
 
6.3.20    Storage of biospecimens ............................................................................ 26-27 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ........................................................ 27 
7.1 
Definition of Adverse Events ......................................................................................... 27 
7.2 
Adverse Event Collection Requirements for this Study .................................................. 27 
7.3 
Reporting requirements for the study ............................................................................ 28 
7.4 
Expected disease-related events .................................................................................. 28 
7.5 
Evaluation of events ...................................................................................................... 28 
 
7.5.1    Assessment of seriousness .......................................................................... 28-29 
 
7.5.2    Assessment of severity...................................................................................... 29 
 
7.5.3    Assessment of causality .................................................................................... 29 
 
7.5.4    Assessment of expectedness ............................................................................ 29 

ALTER 
Draft version 1.0 
4/3/19 
 
 
5 
7.6 
Recording of AEs .......................................................................................................... 30 
7.7 
Reporting of SAEs......................................................................................................... 30 
7.8 
Independent Safety Committee ................................................................................ 30-31 
8.0 
CLINICAL MANAGEMENT ISSUES ............................................................................. 31 
8.1  
Toxicity Management .................................................................................................... 31 
 
8.1.1    Liver toxicity ...................................................................................................... 31 
 
8.1.2    Hematological toxicity ................................................................................... 31-32 
 
8.1.3    Gastrointestinal toxicity ..................................................................................... 32 
 
8.1.4    Neurotoxicity ..................................................................................................... 32 
 
8.1.5    Rash.................................................................................................................. 32 
 
8.1.6    Other toxicities .................................................................................................. 33 
 
8.1.7    Criteria for temporary discontinuation of study therapy ................................. 33-34 
8.2 
Management of CNS tuberculomas .............................................................................. 34 
8.3  
Management of Resistant TBM ..................................................................................... 34 
8.4 
Management of Participants with Suspicion of Relapse Post-treatment or New Neurological 
Event............................................................................................................................. 34 
8.5  
Management of Pregnancy ...................................................................................... 34-35 
8.6 
Management of ART ..................................................................................................... 35 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 35 
9.1 
Permanent and Premature Treatment Discontinuation .................................................. 35 
9.2 
Premature Study Discontinuation ............................................................................. 35-36 
10.0 
STATISTICAL CONSIDERATIONS .............................................................................. 36 
10.1 
Sample size planning .................................................................................................... 36 
10.2 
Planned analyses ..................................................................................................... 36-37 
11.0 
DATA COLLECTION AND MONITORING .................................................................... 37 
11.1 
Records to Be Kept ....................................................................................................... 37 
11.2 
Clinical Site Monitoring and Record Availability ............................................................. 37 
11.3 
Role of data management ............................................................................................. 37 
11.4 
Data collection, entry, and retention  ........................................................................ 37-38 
11.5 
Protocol violations ......................................................................................................... 38 
11.6 
Laboratory quality control .............................................................................................. 38 
12.0 
ETHICS AND PROTECTION OF HUMAN SUBJECTS ................................................. 38 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ................................... 38 
12.2 
Participant Confidentiality .............................................................................................. 38 
12.3 
Study Discontinuation .............................................................................................. 38-39 
12.4 
Future use of stored specimens .................................................................................... 39 

ALTER 
Draft version 1.0 
4/3/19 
 
 
6 
 
12.5 
Conflict of interest ......................................................................................................... 39 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 39 
14.0 
REFERENCES ........................................................................................................ 40-43 
APPENDIX A:  STAGING CRITERIA FOR PROBABLE AND POSSIBLE TUBERCULOUS 
MENINGITIS .....................................................................................................................  
APPENDIX B:  BRIEF PERIPHERAL NEUROPATHY SCREENING TOOL .................................  
APPENDIX C:  RIFAMPICIN DRUG INTERACTIONS ..................................................................  
APPENDIX D:  LINEZOLID DRUG INTERACTIONS ....................................................................  
APPENDIX E:  CONSENT FORMS ..............................................................................................  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
7 
PARTICIPATING SITES 
 
ALTER will recruit 60 participants from Masaka Regional Referral Hospital in Masaka, Uganda over 
approximately 1.5 years. 
 
INVESTIGATORS 
 
 
Principal Investigator:  
Felicia Chow, MD, MAS 
University of California, San Francisco  
Building 1, Room 101, Box 0870 
1001 Potrero Avenue 
San Francisco, CA 94110 
Phone: +1 415-206-4449 
E-mail: felicia.chow@ucsf.edu  
 
Co-investigator 
Payam Nahid, MD, MPH 
University of California, San Francisco 
San Francisco General Hospital 
1001 Potrero Avenue, 5K1 
San Francisco, CA 94110 
Phone: +1 415-206-5464  
E-mail: pnahid@ucsf.edu 
 
Co-investigator/Pharmacometrician: 
Rada Savic, PhD 
UCSF School of Pharmacy and Medicine 
Department of Bioengineering and Therapeutic 
Sciences 
University of California San Francisco 
1550 4th Street Box 2911 
San Francisco, CA 94143-2911 
Phone: +1 415-502-0640 
E-mail: rada.savic@ucsf.edu 
 
 
Co-investigator and Site PI: 
Freddie Mukasa Kibengo, MBChB, MMED, 
FCP (ECSA) 
MRC/UVRI & London School of Hygiene  
and Tropical Medicine Uganda Research Unit  
P.O. Box 49 Entebbe, Uganda 
Phone: +256 481 421211 
E-mail: freddie.kibengo@mrcuganda.org 
 
Co-investigator: 
Fiona Cresswell, MBChB, BSc, MRCP, 
DTM&H 
MRC/UVRI & London School of Hygiene and 
Tropical Medicine Uganda Research Unit 
Keppel Street, London, WC1E 7HT              
Phone: +256 793 420173                                      
E-mail: fiona.cresswell@lshtm.ac.uk  
Study Coordinator/ Study Physician 
Yofesi Nikweri, MBChB 
MRC/UVRI and London School of Hygiene and 
Tropical Medicine Uganda Research Unit 
P.O. Box 49 Entebbe, Uganda 
Phone: +256 481 421211 
E-mail: yofesi.nikweri@mrcuganda.org 
 
 
 
 
 
 
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
8 
 
SCHEMA 
 
Pharmacokinetics and tolerability of Adjunctive Linezolid for the Treatment of tubERculous meningitis 
(ALTER): a Phase II trial, open-label, randomized trial 
 
DESIGN  
 
ALTER is a phase II randomized, open-label trial using a factorial design of high 
 
 
 
or standard dose rifampicin with or without linezolid for the first 4 weeks of 
 
 
 
treatment for tuberculous meningitis (TBM). Initial randomization will be to high 
 
 
 
(35 mg/kg/day) versus standard (10 mg/kg/day) dose oral rifampicin for 4  
 
 
 
weeks. After randomization to high versus standard dose rifampicin,  
 
 
 
participants will undergo a second randomization to linezolid 1200 mg daily 
 
 
 
versus no linezolid for 4 weeks.   
DURATION 
24 weeks 
 
SAMPLE SIZE 
60 participants 
 
POPULATION 
Participants with definite, probable, or possible TBM, aged ≥ 18 years 
 
SETTING 
Masaka Regional Referral Hospital, Masaka, Uganda 
 
STRATIFICATION 
Participants will be randomized with stratification by HIV status and stage of 
disease (Grade 1 vs. 2 and 3), as defined by the modified British Medical 
Research Council criteria.  
 
REGIMEN  
Participants will first be randomized 1:1 to: 
 
 
High dose rifampicin 35 mg/kg for 4 weeks vs. standard dose rifampicin 10 
mg/kg  
 
 
Participants will then be randomized 1:1 to: 
 
 
Linezolid 1200 mg daily for 4 weeks vs. no linezolid (see Table 1) 
 
 
In addition, all participants will receive standard treatment for TBM with 
isoniazid 5 mg/kg/day, pyrazinamide 25 mg/kg/day, ethambutol 20 mg/kg/day, 
corticosteroids (IV dexamethasone 0.4 mg/kg/day for 1 week, 0.3 mg/kg/day for 
1 week, followed by a prednisone taper over 6 weeks), and vitamin B6 50 mg 
daily. After the first 4 weeks of therapy, participants in the high dose rifampicin 
arm (Arm A) will receive standard dose oral rifampicin (10 mg/kg/day) for 
another 11 months as per national guidelines. 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
9 
 
Table 1: Study regimens 
R, rifampicin; H, isoniazid; Z, pyrazinamide; E, ethambutol; L, linezolid 
 
 
 
1.0 BACKGROUND AND STUDY RATIONALE 
Although TBM is the most devastating form of TB, it has largely been neglected in the global 
health research agenda. Even with appropriate therapy up to 50% of patients with TBM die, most 
within the first month after presentation.1-3 Of those who survive, neurologic disability is common.4-6 
Despite these bleak outcomes, a paucity of data exists on the optimal approach to TBM treatment, 
including for people living with HIV (PLWH). 
 
A targeted approach to TBM management must leverage drugs that penetrate the CNS. In the 
absence of large-scale trials, the same standard drug regimens and dosing used for pulmonary TB—
rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for two months 
(intensive therapy), followed by RIF and INH in the continuation phase—are empirically employed for 
TBM, except with a longer continuation phase to complete 9 to 12 months of therapy. This generic 
approach assumes that the efficacy of TB drugs is equivalent at all sites of infection, disregarding the 
unique challenges of infection of the CNS.7 Effective drugs for TBM must penetrate the blood brain 
barrier (BBB) and remain in the CNS to achieve bactericidal drug concentrations.8 
 
Rifampicin plays an essential role in the treatment of TBM. Of standard TB drugs, INH and PZA 
have good CNS penetration, while diffusion is poor for RIF, EMB, and streptomycin, particularly in the 
absence of meningeal inflammation.8,9 RIF is essential for the treatment of TBM, as evidenced by the 
fact that those infected with rifampicin-resistant Mycobacterium tuberculosis strains have a near-
universal fatal outcome, even with treatment with second-line drugs in resource-rich settings.10. 
However, RIF has poor cerebrospinal fluid (CSF) penetration, with reported CSF concentrations often 
reaching less than 10% of those in plasma. Furthermore, standard oral RIF dosing for TBM rarely 
exceeds the minimum inhibitory concentration (MIC) against M. tuberculosis in the CSF.8 Increasing 
the systemic dose of RIF is one strategy to improve CNS drug concentrations. A Phase II open label 
randomized trial in Indonesia demonstrated 50% reduction in TBM mortality with high dose IV RIF 
(600 mg/day).2 Higher RIF exposure in the CSF was strongly associated with survival.11 In contrast, a 
TBM trial in Vietnam found no significant difference in mortality with high dose oral RIF (15 mg/kg), 
although the lack of efficacy may have been due to inadequate dosing, as oral bioavailability is about 
50% of IV RIF.12,13 In a dose-finding study in Indonesia, an oral RIF dose of 1350 mg (about 30 
mg/kg) was safe and resulted in a large increase in plasma and CSF exposures (Dian et al), with a 
trend toward lower mortality among those with definite TBM.14 High dose RIF is a promising strategy 
to improve outcomes in TBM.  
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
10
Higher doses of RIF are well tolerated with a favorable safety profile. We will randomize 
participants to high (35 mg/kg) versus standard dose (10 mg/kg) oral RIF. The most common side 
effect of RIF is harmless red discoloration of bodily fluid (urine, tears and CSF). Other well-recognized 
side effects of RIF include gastrointestinal upset, rash, flu-like syndrome and thrombocytopenia. Drug-
induced liver injury occurs in 20% HIV-infected patients on TB treatment. The drugs most commonly 
implicated are INH, PZA, and RIF. However, transaminitis is only seen in 0-2.5% of patients treated 
with RIF monotherapy, so INH and PZA are the most likely culprits. RIF oral doses as high as 40 
mg/kg once daily for 14 days and doses of 35 mg/kg for up to 12 weeks have been safe and well-
tolerated in clinical trials15,16. In the ReDEFINE dose-finding study, oral RIF as high as 30 mg/kg daily 
(1350 mg) for 30 days were well tolerated without any increase in the incidence of adverse effects14.  
 
Several linezolid characteristics favor its use as adjunctive therapy for TBM. Although RIF is the 
cornerstone of treatment of TBM, even with higher dosing to overcome poor CSF penetration, 
adjunctive therapies that enhance the potential benefit of high dose RIF may be needed to improve 
outcomes of TBM. Of new or repurposed drugs in the development pipeline for TB, many coming into 
clinical use (e.g., bedaquiline, delamanid) are highly protein bound and thus may not freely penetrate 
the BBB.7,17 Linezolid (LZD), a member of the oxazolidinone family with in vitro activity against TB,18-22 
combines superb CNS penetration and excellent oral bioavailability.9,23-25 LZD has been included as 
salvage therapy for drug resistant (DR) TB.26 In extensively DR (XDR) pulmonary TB, 89% receiving 
LZD achieved culture sterility by 6 months.27 Acquired resistance was uncommon and occurred late, 
suggesting a high barrier to LZD resistance. Of 30 patients receiving 6 months of LZD 1200 mg, 
bedaquiline, and pretomanid for DR TB in the Nix-TB trial, 75% achieved culture sterility by 8 weeks.28 
Although LZD has largely been used for DR TB, it may also be valuable for drug susceptible TB. Few 
data are available on LZD use in TBM,29 and none from randomized trials. In retrospective studies, 
LZD 600 mg BID in adults and 10 mg/kg every 8 hours for children was associated with better 
neurologic outcomes and lower mortality.30,31 
Cumulative toxicity is less of a concern when adjunctive LZD is administered for a short 
duration.32-34 LZD’s narrow therapeutic window has tempered the enthusiasm for its therapeutic utility 
for TB. While most treatment-limiting toxicities, including myelosuppression, gastrointestinal (GI) 
symptoms and optic neuropathy, are reversible, some, including a painful, sensory-predominant 
neuropathy, may be permanent.35,36 LZD toxicity is driven by both dose and duration.37 In 796 patients 
with gram-positive bacterial infections on LZD 600 mg BID, hematologic toxicities correlated with 
treatment duration, occurring in 5% of patients on LZD for 2 to 4 weeks. Peripheral neuropathy 
occurred in only 3 individuals with a mean treatment duration of 95 days.38 Among 85 patients with 
DR TB on LZD, the majority of AEs occurred after 2 months.33 Of 33 patients on LZD 1200 mg for 
XDR TB, anemia and GI symptoms were common (~50%) but necessitated discontinuation in only 2 
patients within the first month.39 No cases of peripheral or optic neuropathy occurred before 2 months. 
We will use a short course of adjunctive LZD, which has not been studied in a randomized trial for 
TBM, early in intensive therapy to augment bactericidal activity during the logarithmic growth phase of 
TB while minimizing cumulative toxicity.  
 
Linezolid and the CSF compartment  
CSF to plasma concentration ratios of 0.6 to >0.9 support good to excellent CNS penetration of LZD. 
However, the distribution of LZD in the CSF, from small studies of mostly neurosurgical patients, 
varies substantially. After a one-time dose of LZD 600 mg IV, mean CSF maximum concentrations 

ALTER 
Draft version 1.0 
4/3/19 
 
 
11
(Cmax) ranged from 5.1 to 6.6 ug/mL. At steady state, CSF Cmax was 1.3 to 7.1 and up to 10.8 μg/mL, 
and minimum concentrations (Cmin) were <0.2 to 3.1 and up to 6.1 μg/mL. The ability to achieve 
adequate CSF concentrations for sufficient duration has been inconsistent. One study found CSF LZD 
concentrations were >4 μg/mL for the entire dosing interval, while in another few patients reached 
concentrations >1 μg/mL. The minimum inhibitory concentration for 90% of isolates (MIC90) is 
generally <0.5 μg/mL. 
 
Although studies have suggested that lower LZD doses may be effective for TB,34,40,41 a dose-ranging 
trial demonstrated doses >600 mg daily are required for optimal effect.42 A higher systemic dose will 
increase the likelihood of achieving adequate concentrations in the CSF, particularly with LZD and 
RIF drug-drug interactions. We will use LZD 1200 mg daily to maximize peak concentrations while 
reducing troughs, which correlate with mitochondrial toxicity and AEs.42,43 No dose adjustment is 
needed for renal or hepatic impairment or older age.44 We will give LZD for the 1st 4 weeks of 
intensive therapy to enhance bactericidal activity in the early rapid growth phase when mortality is 
highest, while minimizing duration-dependent toxicity. 
 
A critical consideration in determining optimal LZD dosing for TBM is LZD RIF drug-drug 
interactions. As RIF is a potent inducer of hepatic cytochrome P450 (CYP450) enzymes and efflux 
mechanisms (e.g., P-glycoprotein transport system), RIF can lower drug concentrations with potential 
loss of efficacy. In addition, with repeated administration, RIF induces enzymes resulting in a 
decrease in its own concentrations. Although LZD metabolism is independent of CYP450, increased 
LZD clearance has been observed when given with RIF, with reduced LZD concentrations of up to 
30% in healthy volunteers and greater in ill patients. These studies have focused on plasma PK, while 
the impact of RIF on LZD CSF pharmacokinetics is unknown. We have a unique opportunity to 
evaluate LZD pharmacokinetics when administered with RIF in TBM patients, in whom various factors 
(e.g. meningeal inflammation, corticosteroids, critical illness) may influence LZD concentrations. This 
will be critical to establishing optimal LZD dosing for a Phase III efficacy trial.  
STUDY RATIONALE  
The current mortality associated with TBM is unacceptably high, particularly among PLWH in low and 
middle-income countries. The highest proportion of deaths occurs within the first month after TBM 
treatment initiation, indicating that this time period is critically important when considering improved 
treatment strategies. RIF, the most important drug in the treatment of TBM, seldom reaches minimal 
inhibitory concentration for M.tb in CSF, which is likely to jeopardize therapy. Furthermore, mortality 
rates in the aforementioned favorable Indonesian trial still exceeded 33% in the high dose RIF arm, 
arguing that adjunctive therapies may be needed to further enhance the potential benefit of high dose 
RIF. Adjunctive linezoild in the first month of TBM treatment, when the highest proportion of deaths 
occurs, may allow us to augment bactericidal activity during the critical rapid growth phase of TB while 
minimizing cumulative toxicity. Because of drug-drug interactions (DDI), evaluating LZD 
pharmacokinetics (PK) when administered with RIF will be critical to establishing optimal LZD dosing 
for an efficacy trial. In this trial, we will examine CSF and plasma LZD PK in the presence of high or 
standard dose RIF and will evaluate LZD safety and tolerability in TBM patients living with HIV from 
an African population, correlating adverse events (AEs) with LZD exposures. 
 
2.0 HYPOTHESIS 
CSF and plasma LZD PK exposure parameters will be lower when administered with high dose 
compared with standard dose RIF.  

ALTER 
Draft version 1.0 
4/3/19 
 
 
12
 
2.1 PRIMARY OBJECTIVE 
To determine the CSF and plasma PK of LZD 1200 mg daily in TBM patients receiving high or 
standard dose RIF. 
 
2.2 PRIMARY ENDPOINTS  
CSF and plasma LZD PK parameters, including CSF to plasma ratio, rate of CSF uptake, and plasma 
absorption rate constant (ka), drug clearance (Cl/F), volume of distribution (Vd). 
 
2.3 SECONDARY OBJECTIVE 
1. To evaluate the safety and tolerability of 4 weeks of LZD 1200 mg for the treatment of TBM.  
2. To determine if LZD exposures in the CSF and plasma predict linezolid AEs. 
3. To compare longitudinal neurocognitive and functional outcomes in participants randomized to 
linezolid versus no LZD for the treatment of TBM. 
4. To determine if LZD exposures in CSF and plasma predict neurocognitive and functional outcomes. 
 
2.4 SECONDARY ENDPOINTS 
1. Proportion of participants with Grade 3 or higher AEs at 4 weeks 
2. Proportion of participants who complete LZD treatment 
3. Exposure-response (PK-PD) relationship, with LZD as predictor and Grade 3 or higher AE as 
outcome variable 
4. Modified Rankin Scale (death, severe disability, moderately severe, moderate disability, slight 
disability, no significant disability, no symptoms) at 12 and 24 weeks 
5. Montreal Cognitive Assessment (MoCA) or neurocognitive battery performance at 12 and 24 weeks 
6. Exposure-response (PK-PD) relationship, with linezolid as predictor and Modified Rankin Scale as 
outcome variable 
 
3.0 STUDY POPULATION 
A total of 60 adults with definite, probable, or possible TBM, aged 18 years or older from Masaka 
Regional Referral Hospital.  
 
3.1 Inclusion criteria 
 
1. Age > 18 years 
 
2. Written informed consent from participant or proxy 
 
3. 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: 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
13
Definite TBM is defined by the presence of one or more of the following45:  
 
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. 
3.2 Exclusion criteria 
 
1. >5 doses of TB treatment received within previous 5 days 
 
2. Discontinued TB treatment in prior 14 days 
 
3. Known current/previous drug resistant TB infection 
 
4. Known allergy to RIF, INH, PZA, EMB, LZD 
 
5. Previous treatment of TB or TBM with LZD 
 
6. 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) 
 
7. 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.  
 
8.  Unwillingness to be an inpatient for 2 weeks for initial treatment or to attend follow up clinic visits 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
14
9. Lack of informed consent from participant or next of kin/caregiver 
 
10. 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.  
 
11. 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).  
 
12. 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 
 
3.3 Late exclusion (exclusion after enrollment) 
 
1. Confirmed drug-resistant MTB infection: Resistance testing will be performed on all M. tuberculosis 
isolates from cerebrospinal fluid or other specimens obtained prior to randomization. If a participant is 
confirmed to have drug resistant infection, defined as resistance to one or more first-line  TB 
medications or linezolid, they will be excluded from the study. If drug resistance is confirmed through 
phenotypic susceptibility testing, results may not become available until after a participant is enrolled, 
at which point  they would meet criteria for late exclusion.   
 
2. Identification of an alternative cause of meningitis: If CSF or other laboratory or pathology results 
return after a participant is enrolled indicating an alternative (or secondary) cause of meningitis, they 
would meet criteria for late exclusion.  
Participants who meet criteria for late exclusion will discontinue study treatment but remain on study. 
These participants will be replaced in order to maintain a balanced number of participants per arm.  
 
4.0 STUDY DESIGN 
This is an open-label, randomized clinical trial with a factorial design. 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. We will use a computer generated permuted block 
randomization (block size = 2 or 4) stratified by TBM grade (1 vs 2 and 3), given the association 
between TBM severity and mortality. The trial is open label, although we will endeavor for research 
staff assessing adverse events, neurocognitive and functional outcomes, and PK data to be blinded. 
 
Initiation of high or standard dose oral rifampicin and linezolid or no linezolid will begin immediately 
(within 24 hours) after randomization. In addition, all participants will receive a standard backbone of 
oral TB treatment with INH 5 mg/kg/day, PZA 25 mg/kg/day, EMB 20 mg/kg/day, corticosteroids (IV 
dexamethasone 0.4 mg/kg/day for week 1, 0.3 mg/kg/day for week 2, followed by a prednisone taper 
over 6 weeks), and vitamin B6 50 mg daily. After the first 4 weeks of therapy, participants will receive 
standard dose oral RIF (10 mg/kg/day) for another 11 months along with standard treatment for TBM 
per national guidelines. Patients admitted to Masaka Regional Referral Hospital who meet eligibility 
criteria will be invited to participate.  
 
4.1  
Study enrollment procedures 
Prior to implementation of this protocol, and any subsequent amendments, sites must have the 
protocol and the protocol consent form approved by their local institutional review board (IRB)/ethics 
committee and any other applicable regulatory entity. Site-specific informed consent forms must also 
be reviewed and approved by the local IRB/ethics committee. Once a candidate for study entry has 

ALTER 
Draft version 1.0 
4/3/19 
 
 
15
been identified, details will be carefully discussed with the participant. The participant (or, when 
necessary, the next of kin/caregiver if the participant lacks capacity to provide consent) will be asked 
to read and sign the approved protocol consent form. Participants from whom a signed informed 
consent has been obtained may be screened and enrolled, if they otherwise qualify. Participants who 
are enrolled through a next of kin/caregiver will provide consent once they regain capacity to consent. 
 
4.1.1.  Identification of participants and screening 
Patients presenting to Masaka Regional Referral Hospital with suspected TBM will be identified by 
ward doctors. As part of routine clinical care they will undergo HIV test and lumbar puncture (LP), 
which can be done by the ward medical team or by the study team.  
o In most cases, the ward medical team will perform the initial LP as part of routine care. 
However, study personnel can also perform the LP, if needed. If the participant has undergone 
a diagnostic LP as part of routine care, a repeat LP for screening is not necessarily required.  
o If the LP has already been performed as part of routine care, after consent has been obtained, 
study personnel will facilitate the necessary diagnostic testing of the previously collected CSF.  
o If persons are referred from outside health care facilities with appropriate documentation of 
TBM per study inclusion criteria, they will be eligible; however these persons must have a LP 
with a full diagnostic CSF analysis performed at the site approved laboratory after study 
consent is obtained to exclude alternative diagnoses. 
o Screening evaluations, which can be performed as part of routine care, are outlined in the 
Schedule of Evaluations (Table 5) 
Additional consent will be sought for long-term storage of samples, including blood and CSF. In this 
case, samples will be stored indefinitely, unless the participant asks for them to be destroyed. 
Participants may also give limited consent to the collection and testing of samples for the purposes of 
this research only, after which the samples will be destroyed. 
 
4.1.2  Enrollment visit 
 
 
 
 
 
 
 
 
 
 
The enrollment visit will be Day 1 of the study, which will correspond to the first day of study drug. 
During the enrollment visit, clinical history, examination findings and available laboratory results or 
radiology will be reviewed to ensure inclusion criteria are met and no exclusion criteria are present. 
The enrollment CRF will be completed. If participants meet entry criteria, they will be invited to 
participate in the clinical trial. After informed consent has been obtained, the participant will be 
allocated a study participant number and randomized to treatment allocation.  
4.1.3  Informed consent 
TBM is a medical emergency requiring prompt treatment so it is not necessary to wait for complete 
screening LP results before initiating TBM treatment and enrolling into the trial. The proximity to the 
screening visit will depend on the time required to make a provisional diagnosis of TBM. In most 
cases, there will be clear supporting evidence of TBM by clinical and/or CSF findings, whereas in 
other cases further investigation (e.g. to find evidence of extra-meningeal TB or perform brain 
imaging) may be required. Participants will not have their emergent diagnostic or medical care 
delayed.  
All informed consent forms will be read in full to potential study participants. The consent forms will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. The potential participant or their surrogate must be given sufficient time to review and 
ask questions. After sufficient time for consideration, study participants will sign all applicable consent 
forms prior to performance of any study-related procedures or administration of study-related 
medications. Study personnel obtaining consent must also sign the consent form. A copy of the 
consent form will be given to the participant or surrogate but if she/he does not want to keep a copy, it 
will be kept at the study site on behalf of the participant. 

ALTER 
Draft version 1.0 
4/3/19 
 
 
16
 
4.1.4 Assessment of capacity to provide informed consent 
Potential participants will be evaluated by study personnel (medical officer or nurse) to determine if 
they have the capacity to provide consent. The Glasgow Coma Scale (GCS) will be used to assess 
level of consciousness and neurological status. Only participants with a GCS of 15 will be able to 
provide consent. In addition to having a GCS of 15, participants must also demonstrate understanding 
of the purpose and risks and benefits of the study and participate in a detailed review of the consent 
form with a trained study team member. If the study team member deems the participant’s 
comprehension of the study to be appropriate, the participant will be able to provide consent. 
Otherwise, surrogate consent from the participant’s next of kin/caregiver will be sought. 
 
4.1.5 Surrogate Consent by a Next of Kin/Caregiver 
A potential participant who lacks the capacity to provide informed consent due to altered mental status 
(e.g., confusion, somnolence, unconsciousness), which may be present in more than 50% of TBM 
patients, may be considered if they have a designated surrogate caregiver/next of kin who can 
consent on their behalf. The designated surrogate is a next of kin or caregiver who has the ability to 
provide consent for the participant’s participation in this research protocol.  
If participants regain the capacity to give consent, information will be provided to them and written 
informed consent will be sought for continuation in the trial. If a participant declines to give consent for 
continuation in the trial, they will be withdrawn. For participants enrolled by surrogate consent, 
capacity will be assessed regularly prior to hospital discharge and at clinic follow up visits.  
 
4.1.6 Illiterate/Unable to Provide Signature 
A participant who speaks and understands the language of the informed consent document, but does 
not read and write, can be enrolled in the study by "making their mark" or via a thumbprint on the 
informed consent document. In this event, an impartial, literate third party, which excludes study team 
members, must witness the entire consent process and sign the informed consent document.  The 
witness’s name, signature, and relationship must be recorded on the informed consent document.  
 
4.1.7 Randomization 
At study entry and prior to the 4th dose of TB treatment, participants will first be randomized by a 
computer-generated permutated block randomization (block size of 2 or 4) with a 1:1 randomization to 
high (35 mg/kg) versus standard dose (10 mg/kg) rifampicin. A second 1:1 randomization will then be 
performed to linezolid 1200 mg daily or no linezolid. Randomization will be stratified by British Medical 
Research Council (BMRC) TBM disease grade (Table 2), determined at the time of consent, given the 
association between worse disease severity and higher mortality1.    
Table 2. British Medical Research Council (BMRC) TBM disease grade 
GRADE I 
Glasgow coma score 15, no focal neurological signs 
GRADE II 
Glasgow coma score 11–14 with or without focal neurological sign or 
Glasgow coma score 15 with focal neurological signs 
GRADE III 
Glasgow coma score < 10 with or without focal neurological signs 
 
The randomization schedules will be provided to the site pharmacy in a listed sequence. The 
sequential, unique randomization code will be recorded on the study entry CRF to assure there is no 

ALTER 
Draft version 1.0 
4/3/19 
 
 
17
skipping of the randomization order. All randomized participants will initiate their allocated study TB 
treatment within 24 hours of randomization and ideally the same day. For participants from whom 
informed consent has been obtained, but who are deemed ineligible or who do not enroll into the 
protocol, a Screening Failure form must be completed and entered into the database. 
4.1.8 Co-enrollment Guidelines  
Participants may be co-enrolled in observational studies but not in other interventional trials.  
5.0 
STUDY TREATMENT  
Participants will be randomized in a factorial design to receive one of the following regimens shown in 
Table 3. 
 
Table 3: Study treatment regimens 
Arm 
Weeks 1-4 
Weeks 5-8* 
Weeks 9-24* 
A 
R35HZEL 
 
 
R10HZE 
 
 
 
R10H 
 
B  
R10HZEL 
C 
R35HZE 
D 
R10HZE 
Abbreviations: R, RIF; H, INH; Z, PZA; E, EMB; L, LZD;  
*After the first 4 weeks of therapy, participants will receive treatment for TBM as per national 
guidelines.  
 
Corticosteroid dosing: All participants will receive adjunctive corticosteroids, in addition to 
pyridoxine 50 mg daily.  
 
 
Week 1: Dexamethasone IV 0.4 mg/kg/day  
 
Week 2: Dexamethasone IV 0.3 mg/kg/day 
 
Week 3: Prednisone PO 60 mg/day 
 
Week 4: Prednisone PO 50 mg/day 
 
Week 5: Prednisone PO 40 mg/day 
 
Week 6: Prednisone PO 30 mg/day 
 
Week 7: Prednisone PO 20 mg/day 
 
Week 8: Prednisone PO 10 mg/day 
 
5.1 
Administration 
The intervention period will be for the first 4 weeks of TB therapy, after which all participants will 
receive the same standard therapy for TBM as per national guidelines. 
Table 4: Treatment administration by weight bands through study period 
 
Intervention period 
Standard intensive phase 
Standard continuation phase 
Week 
1 
2 
3 
4 
5 to 8 
10 
12 
16 
20 
24 

ALTER 
Draft version 1.0 
4/3/19 
 
 
18
 
The study pharmacist will dispense medication according to study arm and weight and will log all 
medication dispensed, the date, participant identification number and participant initials. 
Intervention period: Weeks 1-4 
Arm A: Fixed-dose combination tablets according to weight bands (Table 4) will be dispensed 
with additional 300 mg oral RIF tablets to equal a RIF dose of ~35mg/kg/day, along with 
standard dose INH ~5 mg/kg, PZA ~25 mg/kg, and EMB ~20 mg/kg. LZD 1200 mg daily will be 
dispensed as two 600 mg tablets. Participants will receive intact tablets or via nasogastric tube. If 
participants are discharged before the 4-week intervention period, they will be discharged with an 
adequate supply of study drug to last until the week 4 visit. Participants will be weighed at each visit 
and TB drug dose will be adjusted as necessary. Fixed dose combination antituberculous therapy will 
be prescribed through routine care pathways initially via the hospital and subsequently via linked TB 
clinics according to national guidelines. 
Arm B: Fixed-dose combination tablets according to weight bands (Table 4) will be dispensed 
 
 
 
Arm 
A 
 
 
 
Standard co-formulated TB treatment with additional 300mg  
Weight 
Number of           
RHZE tabs 
(150/75/400/275 mg) 
Additional 
R 300mg 
tablets 
Total R  
dose (mg) 
30-37 kg 
2 tabs 
3 tabs 
1200 
38-54 kg 
3 tabs 
4 tabs 
1650 
55-70 kg 
4 tabs 
5 tabs 
2100 
≥ 71 kg 
5 tabs 
6 tabs 
2550 
rifampicin tablets 
 
PLUS Linezolid (600 mg) 2 tablets 
 
 
Standard intensive phase in all 
participants, as per national 
guidelines 
Weight 
Number of RHZE tabs:   
(150/75/400/275 mg) 
30-37 kg 
2 tabs 
38-54 kg 
3 tabs 
55-70 kg 
4 tabs 
≥ 71 kg 
5 tabs 
 
 
 
 
Standard continuation phase in all 
participants, as per national 
guidelines 
 
Weight 
RH tabs 
(150/75mg) 
RH tabs 
(300/150mg) 
30-37 kg 
2 tabs 
 
38-54 kg 
3 tabs 
 
55-70 kg 
 
2 tabs 
≥ 71 kg 
 
2 tabs 
 
 
 
 
Arm 
B 
Standard co-formulated TB treatment  
Weight 
Number of RHZE tablets:   
(150 / 75 / 400 / 275 mg) 
30-37 kg 
2 tabs 
38-54 kg 
3 tabs 
55-70 kg 
4 tabs 
≥ 71 kg 
5 tabs 
 
 
 
 
 
 
 
PLUS Linezolid (600 mg) 2 tablets 
 
 
 
 
 
 
Arm 
C 
Standard co-formulated TB treatment with additional 300mg  
Weight 
Number of           
RHZE tabs 
(150/75/400/275 mg) 
Additional 
R 300mg 
tablets 
Total R  
dose (mg) 
30-37 kg 
2 tabs 
3 tabs 
1200 
38-54 kg 
3 tabs 
4 tabs 
1650 
55-70 kg 
4 tabs 
5 tabs 
2100 
≥ 71 kg 
5 tabs 
6 tabs 
2550 
rifampicin tablets 
 
 
 
 
Arm 
D 
 
 
 
Standard co-formulated TB treatment  
 
Weight 
Number of RHZE tablets:   
(150 / 75 / 400 / 275 mg) 
30-37 kg 
2 tabs 
38-54 kg 
3 tabs 
55-70 kg 
4 tabs 
≥ 71 kg 
5 tabs 
 
 
 
 
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
19
to equal standard dosing for TBM treatment: oral RIF ~10 mg/kg, INH ~5 mg/kg, PZA ~25 
mg/kg, EMB ~20 mg/kg. LZD 1200 mg daily will be dispensed as two 600 mg tablets. 
Participants will receive intact tablets or via nasogastric tube. If participants are discharged before the 
4-week intervention period, they will be discharged with an adequate supply of study drug to last until 
the week 4 visit. Participants will be weighed at each visit and TB drug dose will be adjusted as 
necessary. Fixed dose combination antituberculous therapy will be prescribed through routine care 
pathways initially via the hospital and subsequently via at TB clinics according to national guidelines. 
Arm C: Fixed-dose combination tablets according to weight bands (Table 4) will be dispensed 
with additional 300 mg oral RIF tablets to equal a RIF dose of ~35mg/kg/day, along with 
standard dose INH ~5 mg/kg, PZA ~25 mg/kg, and EMB ~20 mg/kg. Participants will receive intact 
tablets or via nasogastric tube. If participants are discharged before the 4-week intervention period, 
they will be discharged with an adequate supply of study drug to last until the week 4 visit. 
Participants will be weighed at each visit and TB drug dose will be adjusted as necessary. Fixed dose 
combination antituberculous therapy will be prescribed through routine care pathways initially via the 
hospital and subsequently via linked TB clinics according to national guidelines. 
Arm D: Fixed-dose combination tablets according to weight bands (Table 4) will be dispensed 
to equal standard dosing for TBM treatment: oral RIF ~10 mg/kg, INH ~5 mg/kg, PZA ~25 
mg/kg, EMB ~20 mg/kg. Participants will receive intact tablets or via nasogastric tube. If participants 
are discharged before the 4-week intervention period, they will be discharged with an adequate supply 
of study drug to last until the week 4 visit. Participants will be weighed at each visit and TB drug dose 
will be adjusted as necessary. Fixed dose combination antituberculous therapy will be prescribed 
through routine care pathways initially via the hospital and subsequently via TB clinics according to 
national guidelines. 
Standard intensive phase: Weeks 5-8  
For the remainder of the standard intensive phase of treatment, all participants in all arms will receive 
standard treatment as per Ugandan national guidelines (Table 4), which recommend a total of 8 
weeks of 4-drug therapy with RIF, INH, PZA, and EMB. Where isoniazid monoresistance or another 
clinical indication exists for alternative regimen this should be discussed with the treating clinician and 
PI.    
Standard continuation phase: Weeks 9-24  
For the continuation phase of treatment during the study period, all participants in all arms will receive 
standard treatment as per Ugandan national guidelines (Table 4), which recommend an additional 10 
months of RIF and INH. After the study period ends at 24 weeks, participants will continue to receive 
routine care through TB clinic. Where isoniazid monoresistance or another clinical indications exist for 
alternative regimen this should be discussed with the treating clinician and PI.   
5.2  
Acquisition 
The study will provide all TB medications for the first 4 weeks that are not part of current standard of 
care. This includes single drug formulation of rifampicin 300 mg tablets (Brand Name Rifacos, 
Cosmos Ltd), along with linezolid 600 mg tablets (Brand Name Lizolid, Star Pharmaceuticals Ltd), 
both of which will be purchased locally. Fixed-dose combination tablets will be supplied by the clinical 
site as part of routine care from a licensed nationally approved source.  
5.3.  
Product Storage and Stability 
The study medication will be stored at the site’s secure pharmacy. All drugs will be protected from 
light and stored at room temperature (at or below 25⁰C in adherence with manufacturers’ instructions 
and documented on a temperature log in the pharmacy). If study medication has expired, it will be 
destroyed according to the local regulations. At the conclusion of the trial study medication will be 

ALTER 
Draft version 1.0 
4/3/19 
 
 
20
destroyed.  
 
5.4 
Study Product Accountability 
The site pharmacist is required to maintain complete records of all dispensed study medications. 
Clinical personnel involved in the dispensation and administration of study drugs will adhere to Good 
Clinical Practice guidelines. Compliance with the protocol will be assessed via on-going quality 
assurance monitoring. A record of study medication final accountability and destruction will be kept 
and filed throughout. 
5.5  
Concomitant Medications 
All concomitant prescription medications will be recorded on medication CRFs. Concomitant 
medications that are prohibited for the duration of the study due to known interactions with rifampicin 
include protease inhibitors (ritonavir, atazanavir, lopinavir), as rifampicin substantially reduces 
concentrations, which may result in loss of antiviral efficacy and development of HIV resistance. Due 
to a substantial reduction in the concentration of atovaquone, clarithromycin, digoxin, posaconazole, 
quinine, and voriconazole, rifampicin should also not be used concurrently with any of these drugs. 
There is not a danger in taking these medications; however, clinical investigators are advised to use 
alternatives for these medications. Monoamine oxidase inhibitors and selective serotonin reuptake 
inhibitors are also prohibited due to interactions with linezolid, in addition to tricyclic and other anti-
depressant, lithium, carbamazepine, diphenhydramine, atypical antipsychotics, and anti-Parkinsonian 
medications (see Appendices C and D). Patients using systemic hormonal contraceptives should 
change to a non-hormonal method during rifampicin therapy. Barrier contraception is required for 
sexually active women of childbearing potential. 
5.6 
Adjunctive Corticosteroids 
Adjunctive corticosteroid treatment has been shown to improve survival in TBM and is recommended 
for all patients with CNS TB according to WHO guidelines. Persons in Strongyloides stercoralis 
endemic regions are recommended to receive albendazole 400 mg orally twice daily for three days to 
reduce the risk of Strongyloides hyperinfection.  
5.7 
Antiretroviral Therapy 
In a randomized trial of TBM participants in Vietnam, immediate ART did not improve survival and 
was associated with significantly more grade 4 adverse events compared with delayed ART initiation 
at 8 weeks.46 As there is no available evidence that earlier ART confers a survival advantage, the 
international standard for ART initiation in persons living with HIV with TBM is currently at about 8 
weeks.46 HIV-infected participants not already receiving ART will be recommended to initiate ART at 
about 8 weeks after TB treatment initiation according to international guidelines. For persons on ART 
presenting with virologic failure, they would switch regimens at about 8 weeks after initiation of TB 
treatment. Appropriate counselling will be undertaken in HIV clinics. ART regimens will be prescribed 
and provided per National HIV Treatment Guidelines. HIV-infected participants will receive 
cotrimoxazole prophylaxis, unless allergic. We expect that the majority of our HIV-infected participants 
will not be receiving ART at TBM presentation; according to WHO guidelines they will be offered ART 
8 weeks after starting TB treatment. Earlier initiation of ART is associated with an increase in adverse 
events and does not reduce mortality.36 Early ART is associated with immune reconstitution 
inflammatory syndrome (IRIS), which can be fatal in TBM. Patients who are culture positive for M. 
tuberculosis from CSF at TBM diagnosis are also at increased risk of TBM-IRIS.37  
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
21
 
6.0  
CLINICAL AND LABORATORY EVALUATIONS 
6.1  
Schedule of evaluations (Table 5) 
 
Table 5: Schedule of evaluations 
Evaluation 
 
 
Screena 
Entry 
(Day 1) 
Day 
2 
Wk 
1 
Wk 
2 
Wk 
3 
Wk  
4 
Wk 
8 
Wk 
12 
Wk 
18 
Wk 24 
Sick 
visit, Rx 
fail, 
relapse 
Early 
with-
drawal 
Visit window (days) 
 
 
+/- 1 
+/-1 
+/-2 
+/-2 
+/-2 
+/-
7 
+/-
7 
+/-14 
+/-14 
 
 
Complete medical history 
 

 



 
 
 
 
 


Symptom assessment 
 

 



 
 
 
 
 


Medication review 
 

 



 
 
 
 
 


Adherence assessment 
 

 



 
 
 
 
 


Complete physical exam 
 

 



 
 
 
 
 


Targeted exam 
 

 



 
 
 
 
 


Neurologic exam with 
Glasgow Coma Scale 
 

 



 
 
 
 
 


MRC TBM disease grade 













Brief peripheral 
neuropathy screen 
 

 



 
 
 
 
 


Vision testing 
 

 



 
 
 
 
 


Neurocognitive testing 
 

 



 
 
 
 
 


Patient Health  
Questionnaire-9 
 

 



 
 
 
 
 


Modified Rankin Scale 
 

 



 
 
 
 
 


Hematologyb 
 
 
 



 
 
 
 
 
 if 
indicated
 if 
indicated
Chemistriesb 
 

 



 
 
 
 
 
 if 
indicated
 if 
indicated
Liver function testsb,c 
 

 



 
 
 
 
 
 if 
indicated
 if 
indicated
Pregnancy test 
 
As clinically indicated 
Documentation of HIV  
 

 



 
 
 
 
 


CD4 count 
 

 



 
 
 
 
 
 if 
indicated
 if 
indicated
Lumbar puncture for CSF 
cell count, glucose, 
protein, AFB smear and 
cultured 
 

 



 op-
tional if 
out-
patient 
 
 
 
 
 if 
indicated 
 if 
indicated
CSF Xpert Ultra 
 

 



 if LP 
done 
 
 
 
 


Chest x-rayd 
 

 



 
 
 
 
 


Head CT scan  
 if 
indicated 

 



 
 
 
 
 
 if 
indicated
 if 
indicated
Plasma PKe 
 

 



 
 
 
 
 


CSF PKe 
 

 



 
 
 
 
 


Stored TB isolate 
 

 



 
 
 
 
 


Stored plasma 
 

 



 
 
 
 
 


Stored CSF 
 

 



 
 
 
 
 


aScreening evaluations can occur as part of routine care
bCan defer at entry if screening labs obtained within 72 hours prior to entry
cInclude hepatitis B surface antigen, hepatitis C antibody, and INR if ALT abnormal.  
dCan use chest x-ray and lumbar puncture performed as part of routine clinical care within 14 days prior to screening. Repeat 
lumbar puncture must be performed if AFB smear, culture, or Xpert Ultra were not performed prior to screening. 
eIntensive PK sampling at Day 2, sparse sampling at Week 2; CSF PK at Week 4 if LP performed

ALTER 
Draft version 1.0 
4/3/19 
 
 
22
6.2 
Timing of evaluations 
6.2.1 Screening Evaluations  
Screening evaluations must occur prior to the participant starting any study medications,  treatments, 
or interventions. Screening evaluations to determine eligibility must be completed within 14 days prior 
to study entry unless otherwise specified. For participants from whom informed consent has been 
obtained but who are deemed ineligible or who do not enroll into the study, they will be logged as a 
screening failure. Participants who meet the enrollment criteria will be randomized to the study. 
6.2.2 Entry Evaluations 
Entry evaluations must occur within 14 days of the first screening evaluation unless otherwise 
specified. Participants should begin treatment ideally on the day of but at most 24 hours after 
randomization. 
 
6.2.3 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All CRFs must be completed and keyed for the period up to and including the entry visit. Participants 
who do not start study treatment will be taken off study with no further evaluations required. 
 
Premature Treatment Discontinuation Evaluations  
Participants who prematurely discontinue study treatment permanently will have premature 
discontinuation evaluations performed as noted in Section 6.1 as soon as possible after stopping 
study treatment, but no later than 14 days after stopping treatment. If the participant discontinues 
treatment prematurely, the participant will be encouraged to continue on study and receive all 
evaluations per 6.1 Schedule of Events. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue participation in the study should have the premature study 
discontinuation evaluations noted in Section 6.1 performed as soon as possible.  
 
Evaluations for Participants Who Die 
All CRFs must be completed and keyed for the period up to the week of death. 
 
 
6.2.4 Sick visit  
After discharge from the hospital, participants will be encouraged to attend the clinic for unscheduled 
visits if they experience symptomatic deterioration where they will be assessed by the study doctor. If 
the suspected reason for deterioration is a drug reaction, AE CRF and reporting will be completed. 
Other clinical problems will be managed as appropriate. If patients are sick enough to require hospital 
admission for investigation and management, the study team will closely monitor their clinical 
condition while they are managed by the medical staff on the inpatient service. 
 
Procedures to be performed during unscheduled sick visit include:  
 
Symptom assessment history  
 
Medication review 
 
Targeted physical examination and neurologic examination 
 
Laboratory evaluation as clinically appropriate 
 
Lumbar puncture as clinically appropriate 

ALTER 
Draft version 1.0 
4/3/19 
 
 
23
 
Head CT scan and other radiology testing as clinically appropriate 
 
6.3  
Instructions for evaluations 
6.3.1  Complete medical history  
A complete medical history, including history of tuberculosis, AIDS-defining conditions, diabetes 
mellitus, cardiovascular disease, cancer, hepatitis, or any neurologic disease (e.g., ischemic stroke, 
intraparenchymal hemorrhage, subarachnoid hemorrhage, traumatic brain injury, epilepsy/seizures, 
CNS infections) must be recorded. Any allergies to medications and their formulations must also be 
documented. 
6.3.2 Symptom assessment 
At entry, record on the CRFs all signs/symptoms occurring within 30 days prior to entry. After entry, all 
Grade ≥2 signs/symptoms, any signs/symptoms regardless of grade that lead to a change in 
treatment, that meet expedited or serious adverse event guidelines, or are defined by the protocol as 
reportable events that require detailed event reporting. 
6.3.3 Medication history and review 
A medication history, including alternative therapies and/or dietary supplements, must be present, 
including start and stop dates. After entry, all concomitant medications, including alternative therapies 
and/or dietary supplements, must be recorded on the CRFs.  
Record all TB medication modifications, including initial doses, participant-initiated and/or protocol-
mandated modifications, and inadvertent and deliberate interruptions of ≥7 days since the last visit. 
Record any permanent discontinuation of treatment. 
All modifications to antiretroviral medications will be recorded on the CRF, including actual start dates 
and stop dates, initial doses, and inadvertent and deliberate interruptions of ≥7 days since the last 
visit. Record any permanent discontinuation of antiretroviral treatment.  
6.3.4 Assessment of adherence 
Participants will be hospitalized for the first 2 weeks of therapy, during which directly observed therapy 
will occur. After 2 weeks, participants can be discharged at the discretion of the inpatient physician. 
Once discharged, adherence will be assessed at in-person follow up visits by self-report (or by proxy 
report) and pill counts. Study staff will also endeavor to contact participants weekly by phone for 
remotely observed therapy.  
6.3.5 Complete physical exam 
A complete physical examination will be performed at screening and is to include, at a minimum, an 
examination of the skin, head, mouth, and neck; auscultation of the chest; cardiac exam; abdominal 
exam; examination of the lower extremities for edema. The complete physical exam will also include 
height, weight and vital signs (temperature, pulse, respiration rate, and blood pressure). 
6.3.6 Targeted physical exam 
A targeted physical examination performed as scheduled in section 6.1 is to include weight and vital 
signs (temperature, pulse, respiration rate, and blood pressure), and is to be driven by any previously 

ALTER 
Draft version 1.0 
4/3/19 
 
 
24
identified or new adverse event/targeted condition that the participant has experienced since the 
previous study visit. 
6.3.7 Neurologic exam and Glasgow Coma Scale  
Neurologic exam to include, at a minimum, examination of mental status, cranial nerves, tone, power, 
reflexes, sensation, and coordination, and assessment of the Glasgow Coma Scale (GCS), will be 
performed as per section 6.1.  
6.3.8 MRC TBM disease grade 
Tuberculous meningitis stage will be defined using a modified British Medical Research Council 
system: 
 
Grade 1 - GCS 15, no focal neurological signs 
 
Grade 2 - GCS 11-14, or GCS 15 with focal neurological signs 
 
Grade 3 - GCS <10 
6.3.9 Brief Peripheral Neuropathy Screen 
Study staff will administer the Brief Peripheral Neuropathy Screen, a validated neuropathy screening 
tool for HIV,47 to participants who are able to provide subjective information regarding symptoms and 
participate in sensory testing.  
6.3.10 Vision testing 
Visual acuity (Snellen chart), color vision (Ishihara plates), and contrast sensitivity (Pelli-Robson 
chart) testing will be performed in participants who are able to participate. 
6.3.11 Neurocognitive testing 
Neurocognitive testing will be performed as scheduled in 6.1 on individuals who are able to 
participate. The battery will take approximately 45 minutes to an hour to complete: 
Neurocognitive Test Battery 
 
Wechsler Adult Intelligence Scale-III Digit Symbol (Speed of Information Processing) 
 
Color Trails 1 (Attention/Working Memory)  
 
Color Trails 2 (Executive Function) 
 
Category Fluency (Executive Function) 
 
Hopkins Verbal Learning Test-Revised or WHO-UCLA Auditory Verbal Learning Test (Verbal 
Learning and Memory) 
 
Grooved Pegboard Bilateral, Finger-tapping Bilateral (Fine Motor) 
For participants unable to undergo the full test battery, we will attempt to perform the Montreal 
Cognitive Assessment (MOCA). We will endeavor to have staff assessing neurocognitive and 
functional outcomes to be blinded to treatment arm.  
6.3.12 Functional outcomes 
Participants will also be assigned to a Modified Rankin Scale level using the structured interviewer 
questionnaire. In addition we will collect data on disability and depression using the WHO Disability 
Assessment 2.0 and the Patient Health Questionnaire (PHQ-9). 
6.3.13 Laboratory assessments 

ALTER 
Draft version 1.0 
4/3/19 
 
 
25
At screening and entry all laboratory values must be recorded on the CRF. For post-entry 
assessments, record on the CRF all laboratory values regardless of grade. Blood samples will be 
collected via venous blood draw. 
Hematology 
A complete blood count, including hemoglobin, white blood cell count (WBC), differential WBC (to 
include only neutrophils, lymphocytes, and monocytes), absolute neutrophil count (ANC), and platelet 
count will be performed. 
Liver Function Tests 
AST and/or ALT; total and direct bilirubin; and alkaline phosphatase will be performed. 
Blood Chemistry 
Sodium, potassium, bicarbonate, and creatinine will be performed.  
Pregnancy Test 
For women of reproductive potential: Serum or urine -HCG may be used (urine test must have a 
sensitivity of <25 mIU/mL).  
Documentation of HIV infection 
HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test kit at any time prior 
to entry and confirmed by a licensed Western blot or a second antibody test by a method other than 
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load. Two or more 
HIV-1 RNA viral loads of >1,000 copies/mL are also acceptable as documentation of HIV-1 infection, 
or documentation of HIV diagnosis in the medical record by a healthcare provider. 
CD4+ for participants living with HIV 
Obtain absolute CD4+ count and percentages at entry unless the results are available within 14 days 
prior to entry.  
Other laboratory testing 
Additional laboratory tests can be undertaken at the discretion of the physician with agreement of the 
site PI. 
6.3.14 Lumbar Puncture 
Lumbar puncture (LP) will be performed as per section 6.1. Prior to LP, participants must have 
platelets ≥50,000 cells/mm3 measured within 72 hours prior to the LP and no contraindication to LP 
per the treating clinician. Opening pressure in the lateral decubitus position will be measured by 
manometry, when possible, and recorded. CSF cell count, glucose, protein, and AFB smear and 
culture will be performed. Repeat lumbar puncture must be performed if AFB culture and/or Xpert 
Ultra are not performed on the CSF obtained during routine care used for screening.  
6.3.15 TB Laboratory Diagnostics and Microbiology 
AFB smear and culture 
CSF will be used for cell count, glucose, protein, direct smear examination by Ziehl-Neelsen (ZN) 
stain, and culture (in conventional solid medium and/or Becton Dickinson Mycobacterial Growth 

ALTER 
Draft version 1.0 
4/3/19 
 
 
26
Indicator Tube (MGIT) liquid culture).  
CSF Xpert Ultra 
Xpert Ultra will be performed on collected CSF. If the Xpert Ultra machine is unavailable, we will store 
the CSF until Xpert Ultra becomes available.  
Resistance testing  
Molecular and phenotypic resistance testing for participants with positive CSF culture will be 
performed on CSF samples. Participants with RIF resistance on molecular testing will be excluded. If 
participants are determined to have resistant infection based on phenotypic testing after enrollment, 
they will be taken off study treatment but will continue to be followed. Participants in whom resistance 
is identified after the 4 weeks of LZD will be referred to clinic for management of resistant TB 
infection. Their CSF and plasma samples and collected data will be analyzed, unless the participant 
chooses to withdraw from the study.   
To assess response to treatment, development of complications and other outcome measures 
participants will be reviewed daily by the clinical research team while hospitalized. GCS and focal 
neurological signs will be recorded daily on the CRFs during the inpatient stay. Participants may be 
discharged at the discretion of the attending physician.  
6.3.16 Chest X-Ray 
A chest x-ray should be performed at screening unless one performed as part of routine clinical care 
within the previous 14 days is available for review.   
6.3.17  Computed Tomography Imaging  
CT brain and other radiological tests can be undertaken at the discretion of the physician with 
agreement of the site PI. 
6.3.18 Pharmacokinetic studies 
CSF sampling via lumbar puncture (LP) will occur at Day 2 (with intensive plasma sampling 0, 2, 4, 8 
hours after dosing) and Day 14 (with sparse plasma sampling at one time point), with an LP at Day 28 
(Week 4) +/- 2 days for RIF and LZD PK that may by optional for participants who are no longer 
hospitalized. Participants will be randomized to CSF sampling at an early (0-2 hours), medium (2-6 
hours), or late (6-8 hours) interval after drug administration. After centrifugation, specimens will be 
stored at -80C for batched analysis.  
6.3.19 Storage of M. tuberculosis bacterial isolates 
Any M. tuberculosis bacterial isolates from screening, as well as isolates cultured from specimens 
obtained after screening will be stored. Isolates should be labeled with study identification number and 
collection date, and not with participant name.  
 
6.3.20 Storage of biospecimens 
Blood and CSF specimens will be stored from consenting participants. Specimens collected for 
storage will be labeled with study identification number and collection date, and will not be labeled 
with participant name. Specimens will be stored at the site and shipped in batches to the US-based 
team for testing. Additionally, samples should be collected a) if failure or relapse is suspected and the 
participant is evaluated at an unscheduled or sick visit or b) if a participant voluntarily withdraws from 
the study. Participant consent for collection and storage of specimens will be part of the study consent 

ALTER 
Draft version 1.0 
4/3/19 
 
 
27
form which will be administered during the entry visit, with an independent signature line.  
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
7.1 
Definition of Adverse Events 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or diagnosis that occurs in a study participant during the conduct of the study 
REGARDLESS of the attribution (i.e., relationship of event to medical treatment/study product/device 
or procedure/intervention). This includes any occurrence that is new in onset or aggravated in severity 
or frequency from the baseline condition. 
7.2 
Adverse Event Collection Requirements for this Study  
All AEs must be recorded on the CRFs if any of the following criteria have been met. 
 
All Grade 3 to 5 AEs 
 
All AEs that led to a change in study treatment/intervention regardless of grade 
 
All AEs meeting serious adverse event definition or expedited adverse event reporting 
requirement 
All AEs that are reported must have their severity graded. AEs will be graded according to the Division 
of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table), Corrected Version 2.1, July 2017, which can be found on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables  
Serious Adverse Events (SAEs) 
A SAE is defined as any untoward medical occurrence that: 
 
Results in death 
 
Is life-threatening  
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity  
 
Is a congenital anomaly/birth defect 
 
Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. 
 
All pre-existing conditions present at study entry must be clearly documented on the CRF at entry. 
If the frequency, intensity, or the character of the condition worsens to Grade 3 to 5 level during the 
reporting period, the event should be defined as an AE.  
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
28
7.3.  
Reporting Requirements for this Study 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in Version 
2.0 of the DAIDS EAE Manual, which is available on the RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-
daids. 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be 
used for this study from the time of enrollment through week 8 for all participants. For the 
remainder of the trial, only SAEs which are judged by the site as having a reasonable 
possibility of being related to study drug (SARs) should be reported. 
 
The study agents for which expedited reporting is required are: rifampicin and linezolid 
 
The expedited AE reporting period for this study is the entire study duration of 24 weeks for an 
individual participant (from study enrollment until study completion or discontinuation of the 
participant from study participation for any reason). 
 
7.4 
Expected disease-related events 
This study population, with TB and advanced HIV, are both critically ill and profoundly 
immunosuppressed will have a complicated clinical course. Opportunistic and nosocomial infections 
are expected. Disease-related events will be frequent and include: 
 
Death due to TBM (~40% enrolled participants). Will always be reported as an SAE.  
 
Disability due to TBM. Will not be reported as an AE. 
 
TBM-IRIS events and symptoms. Will not be reported as an AE. 
 
Neurological complications of TBM, including tuberculoma, infarct, seizures, headache due to 
raised ICP. Will not be reported as an AE. 
 
Other opportunistic infections. Will not be reported as an AE. 
 
Nosocomial infections, including hospital acquired pneumonias or aspiration pneumonias. Will 
not be reported as an AE. 
 
Expected disease-related events do not require reporting unless the severity of the event was 
considered to be unexpected.  
7.5 
Evaluation of events 
The PI and site PI will monitor the conduct and safety of the study via regular summaries of accrual 
rates, deaths, SAEs, AEs, and study discontinuation, as appropriate.  
The PI and/or site PI will evaluate all SAEs received for seriousness, expectedness and causality. 
Investigator reports of suspected unexpected serious adverse reactions (SUSAR) will be reviewed 
and those that are SUSARs identified and reported to the regulatory authorities.  
7.5.1  Assessment of Seriousness 
When an AE occurs the investigator must first assess whether the AE is serious or not using the 
definition in Section 7.2. If the event is serious and not only related to disease progression it must be 
reported within 24 hours of the investigator becoming aware of the event. The regulatory authorities  

ALTER 
Draft version 1.0 
4/3/19 
 
 
29
 
must then be notified within 7 days.  
7.5.2 Assessment of Severity 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS 
AE Grading Table), Corrected Version 2.1, July 2017, must be used to determine severity of events 
and is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables.  
7.5.3  Assessment of Causality  
The investigator must determine causality in relation to rifampicin and linezolid, based on temporal 
relationship and clinical judgment. The degree of certainty about causality will be assigned using the 
definitions in Table 6. If causality is assessed as unrelated or unlikely to be related it is classed as an 
SAE. If the event is possibly, probably or definitely related, then the event is classed a serious 
adverse reaction (SAR).  
 
7.5.4 Assessment of Expectedness 
If there is at least a possible involvement of the trial treatment, the investigator must assess the 
expectedness of the event. An unexpected adverse reaction (UAR) is one not previously reported in 
summary of product characteristics or more severe than previously reported. If an SAR is assessed 
as unexpected, it becomes a SUSAR, Expected disease-related events will not be reportable as 
SUSARs.  
Side-effects of rifampicin and linezolid should be checked in the latest version of the summary of 
product characteristics at: http://www.medicines.org.uk/emc  
Table 6: Assigning type of SAE through causality  
Relationship 
Description 
SAE Type 
Unrelated 
The AE is completely independent of study drug administration, and/or evidence exists that the 
event is definitely related to another aetiology. There must be an alternative, definitive aetiology 
documented. 
Unrelated 
SAE 
Unlikely  
A clinical event, including an abnormal laboratory test result, whose temporal relationship to 
drug administration makes a causal relationship improbable (e.g., the event did not occur within 
a reasonable time after administration of the trial medication) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the subject’s clinical 
condition, other concomitant treatments). 
Unrelated 
SAE 
Possible 
There is some evidence to suggest a causal relationship (e.g., the event occurred within a 
reasonable time after administration of the trial medication).  However, the influence of other 
factors may have contributed to the event (e.g., the subject’s clinical condition, other 
concomitant events). Although an adverse drug event may rate only as “possibly related” soon 
after discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related”, as appropriate – for example should a re-challenge 
occur with the same effect. 
SAR 
Probable 
There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. 
The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
sequence to administration of the drug, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal (de-challenge).  
SAR 
Definite 
There is clear evidence to suggest a causal relationship and other possible contributing factors 
can be ruled out. The clinical event, including an abnormal laboratory test result, occurs in a 
plausible time relationship to drug administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug (de-challenge) 
should be clinically plausible. The event must be pharmacologically definitive, with use of a 
satisfactory re-challenge procedure, if necessary or appropriate 
SAR 
 
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
30
 
7.6 
Recording of AEs 
The objective of the AE endpoint is to assess linezolid drug toxicity when administered with high and 
standard dose rifampicin among this critically ill population with high mortality. AEs grade 3-5 will be 
recorded via the AE recording CRF. The clinical course of each event should be followed until 
resolution, stabilization, or until it has been determined that the study treatment is not the cause. All 
unresolved AEs at study termination should be followed until the events are resolved, otherwise 
explained.  
 
Asymptomatic laboratory abnormalities are not reportable AEs. However, abnormal laboratory results 
constitute an AE if the abnormality: 
 
is associated with a serious adverse event (e.g. death, hospitalization) 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests, (other than repeat lab check), or 
 
is considered by the investigator to be of clinical significance 
7.7 
Reporting of SAEs 
The PI and site PI should be notified of all SAEs within 24 hours of the investigator becoming aware of 
the event. The AE CRF must be completed. Investigators should notify the PI and site PI of all SAEs 
occurring from the time of randomization until 28 days after the last protocol treatment administration 
(through Week 8). SARs and SUSARs must be reported until trial closure.  
The study site is responsible for the reporting of SAEs, SUSARs, and other SARs to the regulatory 
authorities and the research ethics committees, as appropriate. The PI and/or site PI will review all 
SAE reports. SAEs and SUSARs must be then reported to the competent authorities within 7 days.  
Reporting will be submitted to the local IRB as per their specified reporting requirements. Copies of 
each report and documentation of IRB notification and receipt will be kept in the regulatory binder. At 
the time of the initial report, the study identifier, participant identification number, date of event, 
description of event, relationship to linezolid or rifampicin, intervention if any, working diagnosis, and 
current vital status will be provided.  
Within the 7 days of the initial report (or concurrently), the investigator will provide further information 
on the AE Reporting CRF in the form of a written narrative. This will be documented along with any 
other diagnostic information that will assist understanding of the event.  Significant new information on 
on-going SAEs will be provided promptly to the study sponsor and local IRB. Serious AEs that are still 
on-going at the end of the reporting period must be followed up to determine the final outcome. Grade 
3-4 AEs that are not serious and unrelated to the investigational medicinal product will be reported in 
aggregate in a safety report. 
 
7.8 
Independent Data Safety Committee 
The study will undergo interim review by the appointed Data Safety and Monitoring Board, which will 
include expertise in statistics, clinical trials, and HIV/TB co-infection, after 30 participants have 
completed the Week 8 visit, or no more than nine months after the enrollment of the first study 
participant. An interim review may also be convened if a concern is identified by the PI, site PI, other 
study team member in consultation with the team, IRB, or regulatory authorities. The DSMB will be 
separate from the investigators and will have full access to all accumulating data on safety and 
efficacy. The DSMB can also modify the frequency of interim analysis.  
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
31
Criteria for participant management, dose interruptions, modifications, and discontinuation of 
treatment are mandated only for toxicities attributable to study-provided drugs. The PI and site PI 
must be notified within 24 hours regarding toxicities that result in a change in study treatment 
(including transient or permanent discontinuation) during the study-defined treatment period (first 4 
weeks).  
 
8.1  
Toxicity Management 
 
Only toxicities Grade 3 or higher related to study medications provided through the study (linezolid, 
rifampicin) will be considered in the toxicity management section. For toxicities potentially attributed to 
one or more of the study medications, one or more of the study medications may be held or 
permanently discontinued. 
 
8.1.1 Liver toxicity 
 
A liver toxicity management plan will be implemented if either of the criteria outlined below are met: 
 
 
ALT > 5x the upper limit of normal (ULN) 
 
ALT > 3x ULN with signs or symptoms suggestive of clinical hepatitis including one or more of 
the following: nausea, vomiting, abdominal pain, dark or clay colored stools, unexplained 
fever, jaundice, liver tenderness, or hepatomegaly 
 
Management plan: 
1. Discontinue pyrazinamide  
2. Assess for use of other hepatotoxic drugs and discontinue potentially hepatotoxic, non-
essential medications (e.g., co-trimoxazole, fluconazole) 
3. Repeat ALT, bilirubin, and INR every 2 (+/-1) days 
4. If the transaminases fall to <5x ULN and symptoms resolve, continue treatment without 
pyrazinamide.  
5. If the transaminases do not fall to <5x ULN or bilirubin is >2.0 mg/dL or INR >1.5, or 
symptoms worsen, stop rifampicin and isoniazid, and start alternative regimen for TB 
meningitis (e.g., streptomycin and fluoroquinolone).  
6. Continue to follow ALT every 2 (+/-1) days until stable. If the ALT return to <2x ULN and 
symptoms resolve, rifampicin will be restarted. If ALT remain stable after a minimum of 7 
days, isoniazid will be restarted, and streptomycin and fluoroquinolone stopped. 
7. Continue to follow ALT every 2 (+/-1) days until stable. If ALT begin to rise again to >5x ULN 
after reintroduction of either rifampicin or isoniazid, stop the offending medication. Depending 
on which medication has to be stopped (or potentially both), treat with 1) streptomycin, 
fluoroquinolone, and ethambutol OR 2) rifampicin, fluoroquinolone, and ethambutol OR 3) 
isoniazid, fluoroquinolone, and ethambutol.  
8.1.2 Hematological toxicity 
 
A hematological toxicity management plan will be implemented if any of the following criteria are met: 
 
Hemoglobin < 7.0 g/dL for men, <6.5 g/dL for women 
 
Platelets <50,000/mm3  
 
Absolute neutrophil count <600/mm3 
 
Management plan: 
1. Discontinue linezolid 

ALTER 
Draft version 1.0 
4/3/19 
 
 
32
2. Assess for use of other myelosuppressive medications and discontinue non-essential 
medications (e.g., co-trimoxazole) 
3. Repeat blood count will be performed every 2 (+/-1) days until stable. If the abnormal 
hematological parameter(s) returns to Grade <2 and any associated symptoms resolve, 
linezolid 1200 mg can be restarted.  
4. Continue to follow blood count every 2 (+/-1) days until stable. If after restarting linezolid, the 
abnormal hematological parameter returns to the above criteria, linezolid should again be 
discontinued.  
5. Continue to follow blood count every 2 (+/-1) days until stable. If the abnormal hematololgical 
parameter(s) returns to Grade <2 and any associated symptoms resolve, linezolid can be 
restarted at 600 mg daily.  
6. Continue to follow blood count every 2 (+/-1) days until stable. If after restarting linezolid, the 
abnormal hematological parameter returns to the above criteria, linezolid should be 
discontinued permanently.  
8.1.3 Gastrointestinal toxicity 
Study treatment will be stopped for any Grade 3 or higher gastrointestinal adverse events, including 
nausea, vomiting, diarrhea, or loss of appetite with weight loss. If a participant develops Grade 3 or 4 
GI symptoms, rifampicin will be discontinued first until symptoms have resolved to Grade <2, at which 
point it can be reintroduced. If GI symptoms do not improve after discontinuing rifampicin, linezolid will 
be discontinued until symptoms have resolved to Grade <2, at which point it can be reintroduced.  
8.1.4 Neurotoxicity 
Mild to moderate headache is an expected adverse reaction linezolid, whereas peripheral neuropathy 
and optic neuropathy are expected to be relatively uncommon over a 4-week treatment period. Study 
treatment will be stopped for any Grade 3 or higher neurologic adverse events, including neuropathy 
or visual changes. If participants develop signs/symptoms of optic neuropathy, we will endeavor to 
have them evaluated by an ophthalmologist in Masaka if safe and logistically feasible. If a participant 
develops Grade 3 or higher symptoms, linezolid will be discontinued for up to 14 days until symptoms 
have resolved to Grade <2, at which point linezolid 1200 mg can be reintroduced. 
 
8.1.5 Rash 
Mild to moderate rash is a potential adverse reaction to rifampicin or linezolid. Participants with a 
Grade 1 or 2 rash may continue study medications at the site investigator’s discretion. The participant 
should be advised to contact the site investigator immediately if there is any worsening of the rash, if 
any systemic signs or symptoms worsen, or if mucosal involvement develops. Study treatment should 
be discontinued in participants who develop Grade 3 or higher rash. Participants will be followed off 
study treatment, on study. Participants should be treated as clinically appropriate and followed until 
resolution of the AE. If the etiology of the rash can be definitely diagnosed as being unrelated to study 
medications and due to a specific medical event or a concomitant non-study medication, routine 
management should be performed and documentation of the diagnosis provided. 

ALTER 
Draft version 1.0 
4/3/19 
 
 
33
8.1.6 Other toxicities 
Grade 2 toxicities: For grade 2 toxicities, the participant will be followed more carefully, with 
additional laboratory and/or clinic visits as necessary, and the study drugs temporarily held at the 
investigator's discretion.  
Grade 3 toxicities: For any grade 3 toxicity that, in the investigator’s judgment is due to rifampicin or 
linezolid, the causative drug should be held. The clinician should rule out other possible causes of the 
symptoms before discontinuing study medication. When possible, concomitant medications should be 
held first at the discretion of the investigator if he/she suspects they are contributing to the toxicity. 
Depending on the nature and severity of the toxicity, the degree to which it resolves, and/or the 
emergence of alternative explanations for the toxicity or the subject’s deterioration, the study drugs(s) 
may be restarted at the discretion of the investigator.    
Grade 4 toxicities: Any participant with grade 4 renal, hepatic, cardiac, hematological, or neurologic 
toxicity will be immediately discontinued from study therapy. The laboratory test or clinical finding in 
question will be reassessed as soon as possible. The repeat test will guide management of the event 
as follows: 
1. If the repeat assessment shows toxicity of grade 3 or lower, and if the participant has 
continued to receive study drugs between the two testing dates, then the participant will be 
managed according to the appropriate toxicity level of the repeat test. 
2. If the repeat test shows toxicity of grade 3 or lower, and if the participant has not received 
study drugs between the two testing dates, then the participant will be managed at the 
discretion of the investigator with regard to the re-administration of study drugs, and otherwise 
according to the toxicity level of the repeat test. 
3. If the repeat test shows grade 4 toxicity, then the participant will be permanently discontinued 
from study medications unless a clear alternative cause for the toxicity has been identified, in 
which case, re-administration of study drugs may be considered but only with prior approval 
from the PI and site PI. Further treatment of TB will be directed by the investigator and treating 
clinician on an individualized basis. The participant will continue to be followed for study 
monitoring purposes (as are other participants who make a permanent departure). 
For other grade 4 toxicities, the study drugs will be temporarily held and may be restarted or 
permanently stopped at the discretion of the investigator. For all toxicities that are treatment-emergent 
and that require the study therapy to be temporarily or permanently discontinued, relevant clinical and 
laboratory tests will be obtained as clinically indicated and repeated as needed until final resolution or 
stabilization of the toxicity. 
Temporary or permanent discontinuation of study drugs: Certain events or conditions may 
necessitate temporary or permanent discontinuation of the study medication. Participants who 
experience such events or conditions, however, will still be "on study" and will be followed until study 
completion. Any participant for whom the study medication is temporarily discontinued will be 
restarted on study medication as soon as possible. Study regimens will be discontinued and non-
study regimens will be used with continued study follow-up for participants who fail to respond to 
study therapy either clinically and/or bacteriologically, for participants in whom treatment-emergent 
drug toxicity warrants discontinuation of study therapy. If study drugs are permanently discontinued, 
further TB therapy will be administered at the investigator and treating clinicians’ discretion. 
8.1.7 Criteria for temporary discontinuation of study therapy 

ALTER 
Draft version 1.0 
4/3/19 
 
 
34
 
Development of a toxicity that, depending on its nature and severity, requires temporary 
discontinuation of the study medication until the toxicity resolves as indicated in the preceding 
toxicity management section. 
 
Development of another medical condition that makes the administration of the study drug 
inadvisable. The decision to discontinue temporarily the study medication in this situation will 
be at the investigator's discretion. The period during which the participant is off study 
medication will be as short as clinically possible. 
8.2 
Management of CNS tuberculomas 
Participants with radiologic evidence of a CNS tuberculoma or other mass lesion on initial head CT or 
MRI are eligible for the study. Participants who develop a CT or MRI-confirmed CNS tuberculoma or 
other mass lesion after enrollment can remain on study treatment. In both circumstances, the duration 
of therapy and corticosteroids can be modified at the discretion of the investigator and treating 
clinician.   
8.3  
Management of Resistant TBM  
Participants with known current or previous drug resistant TB infection will be excluded from the trial. 
If participants are determined to have resistant infection based on phenotypic testing after enrollment, 
they may discontinue study treatment at the discretion of the investigators and treating clinicians but 
will remain “on study” for follow up evaluations as per the schedule of events, including:  
 
Symptom assessment since last study visit. 
 
Targeted physical exam, including neurologic exam with GCS 
 
Medication review 
 
Adherence questionnaire, including documentation of all doses received 
 
Neuropathy and vision testing 
 
Neurocognitive and functional outcome assessment  
8.4 
Management of Participants with Suspicion of Relapse Post-treatment or New 
Neurological Event 
All efforts should be made to complete the assessments listed below as soon as possible: 
 
Symptom assessment  
 
Targeted physical exam, including neurologic exam with GCS 
 
Medication review 
 
Adherence questionnaire, including documentation of all doses received 
 
Blood draw for a complete blood count and chemistries including LFTs if indicated 
 
Brain imaging if indicated 
 
CSF specimen for protein, cell count, differential, glucose, gram stain, bacterial culture, AFB 
smear and culture, and Xpert Ultra. Positive culture isolates will be sent for drug susceptibility 
testing for M. tuberculosis 
 
Whole blood and plasma collected for storage 
8.5  
Management of Pregnancy  

ALTER 
Draft version 1.0 
4/3/19 
 
 
35
If a participant becomes pregnant during the study, she will be discontinued from study medications 
and will continue treatment of her TB according to local standards of care, to a prenatal care program 
for management of her pregnancy according to local standards of care, and to their local HIV clinic. 
Participants who become pregnant during the study will be followed through the end of the study 
period. At the end of the pregnancy, the outcome and AEs for the participant and the infant will be 
recorded. If a participant has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then the study team should request permission to contact her regarding 
pregnancy outcomes at the end of pregnancy. If the information is obtained, pregnancy outcomes will 
be recorded at the end of the pregnancy.  
All four first line antituberculous drugs have an excellent safety record in pregnancy and are not 
associated with human fetal malformations. The effects of higher dose rifampicin and linezolid on the 
developing human fetus are unknown. For this reason, women of childbearing potential must agree to 
use adequate barrier contraception or abstinence for the duration of study participation. Women of 
childbearing-potential will have a pregnancy test prior to enrollment. Should a woman become 
pregnant while participating in this study, she should inform study staff immediately. Female 
participants of “childbearing potential” are defined as women who have reached menarche or who 
have not been post-menopausal for at least 24 consecutive months or have not undergone surgical 
sterilization. Hormonal contraception is not recommended because it will not be effective due to 
induction of metabolism when receiving rifampicin. This information will be discussed with female 
participants when their mental status normalizes at the time they are re-consented.  
8.6  
Management of ART  
During the trial HIV therapy will be provided in partnership with local HIV services through Masaka 
Regional Referral Hospital. For those participants already on effective first-line ART at presentation, it 
will be continued. In participants on a failing first-line ART-regimen, it will be switched after the 
intensive phase of TB treatment in accordance with local guidelines. Patients on a protease-inhibitor 
based regimen at presentation are not eligible to be enrolled into the trial due to the drug interactions. 
 
9.0 
CRITERIA FOR DISCONTINUATION 
9.1 
Permanent and Premature Treatment Discontinuation 
 
Drug toxicity that is possibly, probably or definitely related to high-dose rifampicin or linezolid, 
and that requires permanent discontinuation of any of these drugs 
 
Confirmed drug-resistant MTB infection 
 
Another infection cause found that is not MTB 
 
Sustained non-adherence that, in the opinion of the investigator, warrants early 
discontinuation. 
 
Requirement for prohibited concomitant medications. 
 
Pregnancy or breastfeeding. 
 
Request by participant or next of kin/caregiver to terminate treatment.  
 
Clinical reasons believed life threatening by the physician, even if not addressed in the toxicity 
section of the protocol 
Participation is entirely voluntary so participants may choose to discontinue the trial treatment at any 
point without penalty. Participants should be encouraged to remain in the trial for the purpose of 
follow-up and data analysis.  Where study drug is discontinued or the dose is modified it should be 
recorded in the follow-up CRF.  
9.2 
Premature Study Discontinuation 

ALTER 
Draft version 1.0 
4/3/19 
 
 
36
 
Request of a medical provider or investigator if they think the study is no longer in the best 
interest of the participant. 
 
The participant or next of kin/caregiver refuses further follow-up evaluations (i.e., withdraws 
continued consent to participate). 
 
At the discretion of the IRB and other regulatory authorities as part of their duties to ensure 
that research participants are protected, or the industry supporter or its designee. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Sample size estimation  
Sample size calculations for the PK analyses are based on different study designs (varying number of 
participants and time points) using clinical trial simulations. We used the stochastic simulation-
estimate “sse” methodology for clinical trial simulation and re-estimation to determine sample sizes 
required to evaluate key PK parameters with precision adequate to determine optimal dosing for a 
future efficacy trial of LZD. This methodology simulates the data from a planned trial with a proposed 
design (e.g., number of participants) followed by the estimation of the parameters under the true and 
alternative models. This is repeated a minimum of 1000 times to estimate PK parameters, standard 
errors and inter-individual variability. With 30 participants receiving LZD, we will be able to estimate 
PK parameters with required precision of relative standard errors <10% for typical values and <25% 
for random effects (inter-individual variability). For the evaluation of LZD adverse events, if we 
assume 40% of participants in the LZD arm and 10% in the no LZD arm will experience 
myelosuppression,78,84 the planned sample size of 60 participants (n=30 per arm) will provide at least 
80% power to detect a similar or greater difference in the frequency of myelosuppression between 
arms at a significance level of 0.05. Given the modest sample size, we recognize that we may not 
have adequate power to compare the frequency of myelosuppression in participants on LZD and 
standard versus high dose RIF; however, if the frequency of myelosuppression in participants on LZD 
and high dose RIF (n=20) is anticipated as ~25%, the 90% confidence interval of this estimate is 10% 
to 46% with a precision of 18%.  
10.2  Planned analyses 
The primary outcomes will be CSF and plasma LZD PK parameters, including CSF to plasma ratio, 
rate of CSF uptake, and plasma absorption rate constant (ka), drug clearance (Cl/F), volume of 
distribution (Vd). We will employ a model-based approach using non-linear mixed effects modeling in 
NONMEM to estimate plasma and CSF PK parameters based on simultaneous analysis of all plasma 
and CSF drug concentration data.74 We will perform post-hoc Bayesian predictions of secondary LZD 
PK parameters, including Cmax, time to Cmax, AUC0-24, and elimination half-life in plasma and in CSF. 
Based on this approach, we will characterize the dynamic uptake of LZD in the CSF when 
administered with high and standard dose RIF over 4 weeks and derive a dosing algorithm for LZD to 
achieve target exposures through simulations. Pharmacodynamic breakpoints for LZD against TB are 
not established, but we will use target AUC0-24, AUC/MIC, T>MIC for LZD of 160 μg*hr/mL, 100, and 
85%, respectively.23,75,76 We will use sparse sampling to estimate the AUC curve based on CSF 
sampling early, at steady state, and before LZD discontinuation.77  
For the LZD adverse event evaluation, the primary outcome will be a dichotomous measure of Grade 
3 or higher (yes/no) myelosuppression (e.g., anemia, thrombocytopenia, leukopenia) during the 4 
weeks of therapy. A secondary outcome will be LZD discontinuation or dose reduction (yes/no) for any 
AE. We will compare the frequency of myelosuppression between the LZD and no LZD arms across 
RIF dosing with the Cochran-Mantel-Haenszel test, which accounts for stratified randomization. Within 

ALTER 
Draft version 1.0 
4/3/19 
 
 
37
the LZD arm, we will explore differences in the frequency of myelosuppression between the standard 
and two high dose RIF arms combined by a chi-square test. We will use an exposure-response model 
using logistic regression to test if the probability of myelosuppression and LZD discontinuation is 
related to PK measurements, including Cmin, Cmax and AUC0-24. 
 
11.0 
DATA COLLECTION AND MONITORING  
11.1 
Records to be Kept 
Case report forms (eCRFs) will be provided for each participant. Participants must not be identified by 
name on any CRFs. Participants will be identified by a participant identification number (PID). 
11.2 
Clinical Site Monitoring and Record Availability 
The PI and site PI will visit the site to review individual participant records, including consent forms, 
CRFs, supporting data, laboratory specimen records, and medical records (physicians’ progress 
notes, nurses’ notes, participants’ hospital charts), to ensure protection of study participants, 
compliance with the protocol, and accuracy and completeness of records. The monitors also will 
inspect sites’ regulatory files to ensure that regulatory requirements are being followed and sites’ 
pharmacies to review product storage and management. 
The site investigator will also make study documents (e.g., consent forms, drug distribution forms, 
CRFs) and pertinent hospital or clinic records readily available for inspection by the local IRB, study 
sponsors, or other designated local, US, and international regulatory authorities for confirmation of the 
study data. 
Study data forms will be digitally scanned for permanent record keeping and to enable rapid resolution 
of any discrepancies. The DSMB and regulatory inspectors will have full access to source documents. 
The following data will be verifiable from source documents: 
o Signed consent forms 
o Dates of assessments including dates specimens were processed in the laboratory 
o Eligibility and baseline values for all participants  
o Clinical endpoints 
o Adverse events 
o Participant clinical and laboratory data 
o Study drug compliance 
o Pharmacy logs for dispensing / returns of study drugs 
o Concomitant medication 
11.3 
Role of Data Management 
The study paper-based CRF is the primary data collection instrument for the study. All data requested 
on the CRF will be recorded. Entering study data on CRFs will be performed in a timely fashion by the 
site. 
 
11.4 
Data collection, Entry and Retention 
Data collection is the responsibility of the study staff under the supervision of the PI and site PI. The 
investigator is responsible for ensuring accuracy, completeness, legibility and timeliness of data   

ALTER 
Draft version 1.0 
4/3/19 
 
 
38
collection and entry. The investigator will retain study essential source documents for 20-years after 
the completion of the study, as per Ugandan guidelines. Digital images of the source documents will 
be retained for an indefinite period.  
11.5 
Protocol violations 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements with an 
impact on patient safety or scientific integrity. The noncompliance may be either on the part of the 
participant, the investigator or study site staff. Corrective actions are to be developed by the PI and 
implemented promptly. It is the responsibility of the site to be vigilant, to identify and report deviations 
within 5 working days on the deviation. All deviations must be addressed in source documents and 
sent to local IRB as per their guidelines.  
As this trial duration is 24 weeks, reportable deviations include: 
1) Participant Eligibility Criteria 
2) Informed Consent 
3) Randomization Procedures 
4) Administration of Study Investigational medicine 
11.6 
Laboratory Quality Control 
All laboratory work will be undertaken in accredited laboratories with internal and external validation 
procedures.  
12.0 
ETHICS AND PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted according to the international standards of Good Clinical Practice 
(International Conference on Harmonization guidelines), Declaration of Helsinki, and International 
Ethical Guidelines for Biomedical Research Involving Human Subjects, applicable national 
government regulations, and Institutional research policies and procedures. All investigators must 
have received human subject protection and GCP training prior to human subject involvement. 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol, the informed consent documents, and any subsequent modifications will be reviewed 
and approved by the appropriate IRB/ethics committees. A signed consent form will be obtained from 
the participant (or proxy for participants who cannot consent for themselves). The consent form will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be given to the participant or proxy and if they are 
unwilling to keep a copy, it will be kept at the study site on their behalf. 
12.2 
Participant Confidentiality 
All participant-related information, including laboratory specimens, CRFs, and other records will be 
kept confidential and identified by participant ID only to maintain confidentiality. All records will be kept 
in a secure, locked location and only research staff will have access to the records. All computerized 
databases will identify participants by numeric codes only, and will be password-protected. Clinical 
information will not be released without written permission of the participant, except as necessary for 
monitoring by local, US, or international regulatory authorities as part of their duties, or the study 
sponsor.   

ALTER 
Draft version 1.0 
4/3/19 
 
 
39
12.3 
Study Discontinuation 
The study may be discontinued at any time by the IRB, study sponsor, independent DSMB, or other 
regulatory agencies as part of their duties to ensure that research participants are protected.  
12.4  Future Use of Stored Specimens 
If additional storage consent has been given residual participant specimens will be stored for future 
research. Specimens to be stored include CSF and blood.  
12.5  Conflict of Interest 
No conflict of interest exists by any investigator.  Any investigator who develops a new conflict of 
interest will disclose this to their relevant institutional oversight board and to the study sponsor.  
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
All publications and presentations relating to the study will be authorized by the trial 
investigators. Named authors will include at least the trial's PI, site PI, co-investigators, and 
statistician.  Members of the DSMB will be listed as contributors if published in a journal where this 
does not conflict with the journal's policy.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ALTER 
Draft version 1.0 
4/3/19 
 
 
40
14.0 
REFERENCES 
1. 
Wilkinson RJ, Rohlwink U, Misra UK, et al. Tuberculous meningitis. Nat Rev Neurol 
2017;13(10):581–98.  
2. 
Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin and 
moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. 
Lancet Infect Dis 2013;13(1):27–35.  
3. 
Sütlaş PN, Unal A, Forta H, Senol S, Kirbaş D. Tuberculous meningitis in adults: review of 61 
cases. Infection 2003;31(6):387–91.  
4. 
Torok ME, Bang ND, Chau TTH, et al. Dexamethasone and Long-Term Outcome of 
Tuberculous Meningitis in Vietnamese Adults and Adolescents. PLoS ONE 2011;6(12):e27821.  
5. 
Heemskerk AD, Nguyen MTH, Dang HTM, et al. Clinical Outcomes of Patients With Drug-
Resistant Tuberculous Meningitis Treated With an Intensified Antituberculosis Regimen. CLIN 
INFECT DIS 2017;65(1):20–8.  
6. 
Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological sequelae of tuberculous 
meningitis: a multivariate analysis. Eur J Neurol 2007;14(1):33–7.  
7. 
Donald PR. Chemotherapy for Tuberculous Meningitis. N Engl J Med 2016;374(2):179–81.  
8. 
Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. 
Tuberculosis 2010;90(5):279–92.  
9. 
Nau R, Sorgel F, Eiffert H. Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-
Brain Barrier for Treatment of Central Nervous System Infections. Clin Microbiol Rev 
2010;23(4):858–83.  
10. 
Marais S, Pepper DJ, Schutz C, Wilkinson RJ, Meintjes G. Presentation and outcome of 
tuberculous meningitis in a high HIV prevalence setting. PLoS ONE 2011;6(5):e20077.  
11. 
Brake te L, Dian S, Ganiem AR, et al. Pharmacokinetic/pharmacodynamic analysis of an 
intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis. 
International Journal of Antimicrobial Agents 2015;45(5):496–503.  
12. 
Heemskerk AD, Bang ND, Mai NTH, et al. Intensified Antituberculosis Therapy in Adults with 
Tuberculous Meningitis. N Engl J Med 2016;374(2):124–34.  
13. 
Mai NTH, Thwaites GE. Recent advances in the diagnosis and management of tuberculous 
meningitis. Curr Opin Infect Dis 2017;30(1):123–8.  
14. 
Dian S, Yunivita V, Ganiem AR, et al. Double-Blind, Randomized, Placebo-Controlled Phase II 
Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis. Antimicrob 
Agents Chemother 2018;62(12):581–12.  
15. 
Boeree MJ, Heinrich N, Aarnoutse R, et al. High-dose rifampicin, moxifloxacin, and SQ109 for 
treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis 
2017;17(1):39–49.  
16. 
Boeree MJ, Diacon AH, Dawson R, et al. A Dose-Ranging Trial to Optimize the Dose of 

ALTER 
Draft version 1.0 
4/3/19 
 
 
41
Rifampin in the Treatment of Tuberculosis. Am J Respir Crit Care Med 2015;191(9):1058–65.  
17. 
Akkerman OW, Odish OFF, Bolhuis MS, et al. Pharmacokinetics of Bedaquiline in 
Cerebrospinal Fluid and Serum in Multidrug-Resistant Tuberculous Meningitis. CLIN INFECT 
DIS 2015;:civ921–2.  
18. 
Alcala L, Ruiz-Serrano MJ, Perez-Fernandez Turegano C, et al. In Vitro Activities of Linezolid 
against Clinical Isolates of Mycobacterium tuberculosis That Are Susceptible or Resistant to 
First-Line Antituberculous Drugs. Antimicrob Agents Chemother 2003;47(1):416–7.  
19. 
Huang TS, Liu YC, Sy CL, Chen YS, Tu HZ, Chen BC. In Vitro Activities of Linezolid against 
Clinical Isolates of Mycobacterium tuberculosis Complex Isolated in Taiwan over 10 Years. 
Antimicrob Agents Chemother 2008;52(6):2226–7.  
20. 
Richter E, Rusch-Gerdes S, Hillemann D. First Linezolid-Resistant Clinical Isolates of 
Mycobacterium tuberculosis. Antimicrob Agents Chemother 2007;51(4):1534–6.  
21. 
Prammananan T, Chaiprasert A, Leechawengwongs M. In vitro activity of linezolid against 
multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant (XDR)-TB isolates. 
International Journal of Antimicrobial Agents 2009;33(2):190–1.  
22. 
Yang C, Lei H, Wang D, et al. In vitro activity of linezolid against clinical isolates of 
Mycobacterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains 
from Beijing, China. Jpn J Infect Dis 2012;65(3):240–2.  
23. 
Di Paolo A, Gori G, Tascini C, Danesi R, Del Tacca M. Clinical Pharmacokinetics of 
Antibacterials in Cerebrospinal Fluid. Clin Pharmacokinet 2013;52(7):511–42.  
24. 
Myrianthefs P, Markantonis SL, Vlachos K, et al. Serum and Cerebrospinal Fluid 
Concentrations of Linezolid in Neurosurgical Patients. Antimicrob Agents Chemother 
2006;50(12):3971–6.  
25. 
Beer R, Engelhardt KW, Pfausler B, et al. Pharmacokinetics of Intravenous Linezolid in 
Cerebrospinal Fluid and Plasma in Neurointensive Care Patients with Staphylococcal 
Ventriculitis Associated with External Ventricular Drains. Antimicrob Agents Chemother 
2006;51(1):379–82.  
26. 
Chowdri HR, Gugliotta JL, Berardi VP, et al. Borrelia miyamotoi infection presenting as human 
granulocytic anaplasmosis: a case report. Ann Intern Med 2013;159(1):21–7.  
27. 
Lee M, Lee J, Carroll MW, et al. Linezolid for Treatment of Chronic Extensively Drug-Resistant 
Tuberculosis. N Engl J Med 2012;367(16):1508–18.  
28. 
Bloch KC, Glaser C. Diagnostic approaches for patients with suspected encephalitis. Curr 
Infect Dis Rep 2007;9(4):315–22.  
29. 
Alsleben N, Garcia-Prats AJ, Hesseling AC, Willemse M, Donald PR, Schaaf HS. Successful 
Treatment of a Child With Extensively Drug-Resistant Tuberculous Meningitis. J Pediatric Infect 
Dis Soc 2015;4(3):e41–4.  
30. 
Sun F, Ruan Q, Wang J, et al. Linezolid manifests a rapid and dramatic therapeutic effect for 
patients with life-threatening tuberculous meningitis. Antimicrob Agents Chemother 

ALTER 
Draft version 1.0 
4/3/19 
 
 
42
2014;58(10):6297–301.  
31. 
Li H, Lu J, Liu J, Zhao Y, Ni X, Zhao S. Linezolid is Associated with Improved Early Outcomes 
of Childhood Tuberculous Meningitis. Pediatr Infect Dis J 2016;35(6):607–10.  
32. 
Sotgiu G, Centis R, D'Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing 
regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. European 
Respiratory Journal 2012;40(6):1430–42.  
33. 
Migliori GB, Eker B, Richardson MD, et al. A retrospective TBNET assessment of linezolid 
safety, tolerability and efficacy in multidrug-resistant tuberculosis. European Respiratory 
Journal 2009;34(2):387–93.  
34. 
Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a 
systematic review and meta-analysis [Review article]. Int J Tuberc Lung Dis 2012;16(4):447–
54.  
35. 
Gould K. Clinical update on linezolid in the treatment of Gram-positive bacterial infections. IDR 
2012;:87–16.  
36. 
Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral neuropathy associated with 
prolonged use of linezolid. Lancet Infect Dis 2004;4(8):528–31.  
37. 
Maartens G, Benson CA. Linezolid for Treating Tuberculosis: A Delicate Balancing Act. EBIOM 
2015;2(11):1568–9.  
38. 
Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the 
treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-
use program. CLIN INFECT DIS 2003;36(2):159–68.  
39. 
Tang S, Hao X, Zhang X, et al. Efficacy, safety and tolerability of linezolid for the treatment of  
XDR-TB: a study in China. 2014;:1–10.  
40. 
Srivastava S, Magombedze G, Koeuth T, et al. Linezolid Dose That Maximizes Sterilizing Effect 
While Minimizing Toxicity and Resistance Emergence for Tuberculosis. Antimicrob Agents 
Chemother 2017;61(8):e00751–17–12.  
41. 
Koh WJ, Kwon OJ, Gwak H, et al. Daily 300 mg dose of linezolid for the treatment of intractable 
multidrug-resistant and extensively drug-resistant tuberculosis. J Antimicrob Chemother 
2009;64(2):388–91.  
42. 
Nuermberger E. Evolving strategies for dose optimization of linezolid for treatment of 
tuberculosis. Int J Tuberc Lung Dis 2016;20(12):48–51.  
43. 
Song T, Lee M, Jeon H-S, et al. Linezolid Trough Concentrations Correlate with Mitochondrial 
Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant 
Tuberculosis. EBIOM 2015;2(11):1627–33.  
44. 
MacGowan AP. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy 
volunteers and patients with Gram-positive infections. Journal of Antimicrobial Chemotherapy 
2003;51(90002):17ii–25.  

ALTER 
Draft version 1.0 
4/3/19 
 
 
43
45. 
Marais S, Thwaites G, Schoeman JF, et al. Tuberculous meningitis: a uniform case definition 
for use in clinical research. 2010. p. 803–12. 
46. 
Torok ME, Yen NTB, Chau TTH, et al. Timing of initiation of antiretroviral therapy in human 
immunodeficiency virus (HIV)--associated tuberculous meningitis. CLIN INFECT DIS 
2011;52(11):1374–83.  
47. 
Cherry CL, Wesselingh SL, Lal L, McArthur JC. Evaluation of a clinical screening tool for HIV-
associated sensory neuropathies. Neurology 2005;65(11):1778–81.