Tuberculosis MeningitisPhase 2LASER-TBMNCT03927313
Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM
A Phase 2 study testing Linezolid, High dose rifampicin and Aspirin in people with Tuberculosis Meningitis and HIV-1-infection, run by University of Cape Town at 4 sites in South Africa.
Trial summary
LASER-TBM is a parallel group, randomized, multi-arm phase IIa trial evaluating the safety of increased dose rifampicin (RIF) plus linezolid (LZD), with or without aspirin (ASA), for the treatment of HIV-infected adults with tuberculous meningitis (TBM). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis Meningitis, HIV-1-infection
- What is being tested?
- Linezolid, High dose rifampicin and Aspirin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 4 sitesSouth Africa
- Study dates
- 12 Jun 2019to 31 Mar 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- HIV-1 seropositivity by rapid test, confirmed by enzyme-linked immunosorbent assay (regardless of Antiretroviral Therapy (ART) status);
- Age 18 years or older;
- Tuberculous meningitis defined as 'possible', 'probable' or 'definite' as per published case definitions
Who cannot join
- Rifampicin-resistant M. tb detected in any microbiological specimen;
- History of allergy or hypersensitivity to H, E, R and Z, LZD or ASA;
- Received more than 5 days of antitubercular therapy in the 30 days prior to screening;
- Received a dose of ASA or any other NSAID within 2 weeks of screening;
- CSF unobtainable by lumbar puncture or another procedure;
- Evidence of bacterial or cryptococcal meningitis;
Show all 19Show fewer
- Severe concurrent uncontrolled opportunistic infection including but not limited to active cytomegalovirus-associated disease, Kaposi sarcoma, Pneumocystis jirovecii pneumonia, HIV related or unrelated malignancy or gastrointestinal bleeding;
- Any other form of immunosuppressive therapy including antineoplastic and biologic agents apart from corticosteroids;
- Is pregnant in the third trimester;
- Peripheral neuropathy scoring Grade 3 or above on Brief Peripheral Neuropathy Score
- Any disease or condition in which the use of the standard TB drugs or any of their components is contraindicated, including but not limited to allergy to any TB drug or their components;
- The presence of one or more of the following:
- Estimated glomerular filtration rate (eGFR) < 20ml/min/1.73m2 (using the Cockcroft-Gault equation)
- International normalised ration (INR) > 1.4 and/or clinical evidence of liver failure or decompensated cirrhosis
- Hemoglobin < 8.0 g/dL
- Platelets < 50 x109 /L
- Neutrophils < 0.5 x 109 cells/L;
- The patient has any disease or condition in which any of the medicinal products listed in the section pertaining to prohibited medication is used and cannot be safely stopped;
- The patient has a known or suspected, current or history of drug abuse, within the past 2 years, that is, in the opinion of the investigators, sufficient to compromise the safety or cooperation of the patient.
Trial locations and contacts
4 sites in 1 country.
South Africa4 sites
Mitchells Plain Hospital
Cape Town, Western Cape, 7786
Groote Schuur Hospital
Cape Town, Western Cape, 7925
New Somerset Hospital
Cape Town, Western Cape, 8001
Livingstone Hospital
Port Elizabeth, Eastern Cape, 6020
About this study
Official title: Phase IIA Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid With or Without Aspirin, for HIV-associated Tuberculous Meningitis
LASER-TBM is a parallel group, randomized, multi-arm phase IIa trial evaluating the safety of increased dose rifampicin (RIF) plus linezolid (LZD), with or without aspirin (ASA), for the treatment of HIV-infected adults with tuberculous meningitis (TBM). The study will recruit 100 HIV-infected adults with TBM across four sites in South Africa.
The primary endpoint is the occurrence of solicited treatment-related adverse events.
Read more
Secondary endpoints include death and disability (including neurocognitive impairment), radiological outcomes, and the occurrence of immune reconstitution inflammatory syndrome (IRIS).
A nested pharmacokinetic (PK) substudy aims to:
- Describe the plasma and cerebrospinal fluid (CSF) PK of LZD and high dose RIF.
- Evaluate the relationship between drug exposures, toxicity and efficacy.
- Compare exposures between intravenous and oral RIF administration.
- Investigate the impact of high dose RIF on LZD and dolutegravir (DTG).
Read the detailed description
HIV-1 infected adults with newly-diagnosed TBM (n = 100) will be recruited from four public-sector hospitals in Cape Town and Port Elizebeth, South Africa. Participants will be randomised across two experimental (n = 30 each) and one standard of care (n = 40) arms. Treatment will be provided in all arms for 56 days, after which participants will be referred back to public sector facilities to complete standard therapy for HIV-associated TBM.
The primary objective of the study is to investigate the safety of enhanced antimicrobial therapy including increased dose RIF and LZD with or without adjunctive aspirin added to standard therapy for TBM in HIV-1 infected adults.
Secondary objectives are;
- To determine cerebrospinal fluid M.tb culture positivity and Gene Xpert® Ultra positivity at baseline and at 3 and 28 days post treatment by allocation.
- To evaluate the effect of aspirin and enhanced tuberculosis treatment on the incidence of immune reconstitution syndrome in participants starting antiretroviral therapy.
- To evaluate the effect of high dose rifampicin and linezolid, with and without aspirin on the transcriptional signature derived from whole blood and cerebrospinal fluid RNA sequencing, as well as the metabolomic and proteomic profiles, in tuberculous meningitis.
- To evaluate the effect of high dose rifampicin and linezolid with and without aspirin on central nervous system imaging in conjunction with clinical, immunological and transcriptional profiling.
- To store biological samples for future analysis of potential biomarkers of treatment efficacy and/or novel diagnostic assays.
- To determine i) whether host genotype, including LTA4H genotype, influences therapeutic effect of aspirin in HIV-TBM and ii) the pharmacogenetic influence on rifampicin and linezolid exposures and toxicity.
All participants will receive antitubercular chemotherapy and corticosteroids as standard of care as per national South African guidelines. Participants allocated to experimental arms 2 and 3 will receive additional rifampicin (total oral dose 35 mg/kg/day) plus oral linezolid 1200mg daily for the first 28 days, reduced to 600 mg daily for the next 28 days. Those randomized to experimental arm 3 will also receive oral aspirin 1000 mg daily.
All consenting LASER-TBM participants in experimental arms (n = 60) will undergo a second randomisation to receive either oral (35mg/kg) or IV (20mg/kg) rifampicin at the time of study entry. This sub-study is powered to demonstrate bioequivalence at day 3 of administration, after which all participants will be continued on oral rifampicin dosed at 35mg/kg.
Trial participation will be for 180 days post-randomization: primary safety endpoints and secondary efficacy endpoints will be evaluated at day 56; additional secondary endpoints will be evaluated at day 180.
There are seven scheduled study visits. The first six of thee will occur within the first 56 days, with an additional structured interview at 6 months. All visits will involve a clinical assessment including specified clinical outcome measures to assess functional and cognitive disability. Phlebotomy will be performed at study visits within the first 56 days to monitor for pre-specified parameters of drug safety (haematology, biochemistry) as well as to collect blood for downstream transcriptomic, proteomic and metabolomic analysis. Lumbar puncture will take place at day 3 and day 28. Cerebrospinal fluid will be analysed for Mycobacterium tuberculosis culture and Gene Xpert® Ultra cycle threshold values. Cerebrospinal fluid (CSF) will be stored for downstream transcriptomic, proteomic and metabolomic analysis. Baseline and day 56 brain imaging will be performed in all study participants.
All enrolled participants will undergo sparse plasma PK sampling at the Day 28 and Day 56 visits.
Cerebrospinal fluid (CSF) will be collected from all participants for determination of linezolid and rifampicin concentrations on Days 3 and 28. The timing of the Day 3 lumbar puncture will be randomised to intervals of 1 - 3, 3 - 6, 6 - 10, and 24 hours after observed antitubercular drug dosing in order to construct a concentration-time profile for the population. A single sample will be collected at each time interval. A second lumbar puncture will take place at the Day 28 visit, to coincide with the 4-hour plasma PK sample.
All participants (n=100) will be offered participation in the intensive sampling component of the PK sub-study at the time of randomization to the main study. Intensive plasma sampling will take place at the Day 3 study visit. Serial venous blood samples will be collected through a peripheral intravenous catheter pre-dose, and at 0.5, 1, 2, 3, 6, 8 - 10, and 24 hours after witnessed drug intake and an overnight fast. Sparse sampling will be performed at Day 3 for participants who decline intensive sampling or in whom this fails.
- Conditions
- Tuberculosis Meningitis, HIV-1-infection
- Being tested
- Linezolid, High dose rifampicin, Aspirin, Standard of Care anti-tuberculous therapy, Dexamethasone
- Keywords
- TB meningitis, HIV
- Medical subject headings
- Tuberculosis, Meningeal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LinezolidDrug
For both experimental arms: 1.2g linezolid 28 days, followed by 600mg linezolid for 28 days
High dose rifampicinDrug
For both experimental arms: additional 25mg/kg (making a total of 35mg/kg) rifampicin, for the first 56 days of treatment
AspirinDrug
For only one of the experimental arms: 1000mg of aspirin daily for 56 days.
Standard of Care anti-tuberculous therapyDrug
10mg/kg oral rifampicin, 5mg/kg oral isoniazid, 15mg/kg oral ethambutol, 25mg/kg oral pyrazinamide daily for 56 days.
DexamethasoneDrug
Dexamethasone according to doses of Thwaites criteria for the first 8 weeks of anti-tuberculous treatment. Doses differ according to participants Medical Research Council (MRC) grade. Given orally if participant can swallow and intravenously if they cannot.
| Study group | Role | What they receive |
|---|---|---|
| Standard of care anti-tubercular therapy | Active comparator | Standard of care anti-TB treatment. (10 mg/kg oral rifampicin, 5 mg/kg oral isoniazid, 15 mg/kg oral ethambutol and 25 mg/kg oral pyrazinamide daily for 2 months as fixed dose combination tablets (followed by 10 mg/kg oral rifampicin and 5 mg/kg isoniazid daily for 4-7 months in routine care after study completed)). Receives: Drug: Standard of Care anti-tuberculous therapy; Drug: Dexamethasone |
| Intensified anti-tubercular therapy | Experimental | Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days). Receives: Drug: Linezolid; Drug: High dose rifampicin; Drug: Standard of Care anti-tuberculous therapy; Drug: Dexamethasone |
| Intensified anti-tubercular therapy plus aspirin | Experimental | Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days),
Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment) Receives: Drug: Linezolid; Drug: High dose rifampicin; Drug: Aspirin; Drug: Standard of Care anti-tuberculous therapy; Drug: Dexamethasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants in each arm who develop treatment related adverse events (AEs).
The amount of participants who develop any of the following treatment related adverse events by the time they have been on treatment for 56 days will be counted: Peripheral neuropathy, optic neuropathy, anaemia, neutropaenia, thrombocytopaenia, upper gastro-intestinal haemorrhage, intracerebral haemorrhage, drug-induced liver injury.
Measured: 56 days
Secondary outcomes (10)
Death and disability after 56 days on treatment.
A comparison will be made of the proportion of participants in each arm who died, and their grade of disability will be compared according to Modified Rankin Scoring.
Measured: 56 days
Death at day 56 and day 180.
In all arms: the number of participants who have died at Day 56 will be compared to those that have died at Day 180.
Measured: 180 days
Number of participants who are disabled.
Comparison of level of disability of participants at 56 and 180 days, stratifying by Medical Research Council grade.
Measured: 180 days
Number of participants who develop Grade 3 or Grade 4 adverse events (AEs).
In all 3 arms: comparison of the number of participants who develop Grade 3 or Grade 4 adverse events (according to Division of AIDS (DAIDS) criteria) by the time they have been on treatment or 56 days.
Measured: 56 days
Number of participants in whom experimental drugs had to be stopped.
At 56 days on treatment, the number of participants in the experimental arms in whom rifampicin, linezolid and/or aspirin had to be stopped.
Measured: 56 days
Linezolid toxicity
To note the presence of the following adverse events in all participants in the experimental arms: peripheral neuropathy, optic neuropathy, anaemia, neutropaenia, thrombocytopaenia and hyperlactataemia.
Measured: 56 days
Major bleeding events.
To note at 6 months, the amount of participants who develop upper gastro-intestinal or intra-cerebral haemorrhage after receiving 1000mg daily aspirin as part of the trial.
Measured: 180 days
Cerebrospinal fluid culture conversion.
To compare in the different arms, between lumbar punctures done at day 3 and day 28, the time to automated liquid culture positivity and Gene-Xpert ultra threshold values (for mycobacterium tuberculosis) of cerebrospinal fluid.
Measured: Day 28 and day 56
The occurrence of TBM-immune reconstitution inflammatory syndrome
The amount of participants in all 3 arms who develop paradoxical tuberculosis immune reconstitution, as defined by th modified INSHI criteria.
Measured: 56 days
Changes on brain imaging
To compare at day 56, in participants who had brain imaging at baseline, changes in brain imaging at day 56.
Measured: Day 56
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2019
- Study start12 Jun 2019
- Primary completion30 Mar 2021
- Study completion31 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Tuberculosis MeningitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Phase IIA, randomized, active-controlled, open label, parallel-group trial
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Cape Town
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Robert J Wilkinson, University of Cape Town
- Investigators
- Robert J Wilkinson, PhD, Principal investigator, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape TownSean Wasserman, MMed, Principal investigator, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape TownGraeme Meintjes, PhD, Principal investigator, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape TownJohn Black, MBChB, Principal investigator, Department of Medicine, University of Cape Town and Walter Sisal UniversityAngharad G Davis, Dr, Study chair, 1. Faculty of Life Sciences, University College London, UK 2. Department of Medicine, University of Cape Town, Observatory 7925, Republic of South Africa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03927313
- Sponsor's protocol ID
- LASER-TBM
- Acronym
- LASER-TBM
- Status last verified
- Sep 2021
- First submitted
- 26 Mar 2019
- Last updated
- 28 Sep 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
Abdelgawad N, Wasserman S, Abdelwahab MT, Davis A, Stek C, Wiesner L, Black J, Meintjes G, Wilkinson RJ, Denti P. Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis. J Infect Dis. 2024 Apr 12;229(4):1200-1208. doi: 10.1093/infdis/jiad413.
PubMed 37740554Davis AG, Wasserman S, Stek C, Maxebengula M, Jason Liang C, Stegmann S, Koekemoer S, Jackson A, Kadernani Y, Bremer M, Daroowala R, Aziz S, Goliath R, Lai Sai L, Sihoyiya T, Denti P, Lai RPJ, Crede T, Naude J, Szymanski P, Vallie Y, Banderker IA, Moosa MS, Raubenheimer P, Candy S, Offiah C, Wahl G, Vorster I, Maartens G, Black J, Meintjes G, Wilkinson RJ. A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial. Clin Infect Dis. 2023 Apr 17;76(8):1412-1422. doi: 10.1093/cid/ciac932.
PubMed 36482216Davis AG, Wasserman S, Maxebengula M, Stek C, Bremer M, Daroowala R, Aziz S, Goliath R, Stegmann S, Koekemoer S, Jackson A, Lai Sai L, Kadernani Y, Sihoyiya T, Liang CJ, Dodd L, Denti P, Crede T, Naude J, Szymanski P, Vallie Y, Banderker I, Moosa S, Raubenheimer P, Lai RPJ, Joska J, Nightingale S, Dreyer A, Wahl G, Offiah C, Vorster I, Candy S, Robertson F, Meintjes E, Maartens G, Black J, Meintjes G, Wilkinson RJ. Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM]. Wellcome Open Res. 2021 Jun 1;6:136. doi: 10.12688/wellcomeopenres.16783.1. eCollection 2021.
PubMed 34286103Wasserman S, Davis A, Stek C, Chirehwa M, Botha S, Daroowala R, Bremer M, Maxebengula M, Koekemoer S, Goliath R, Jackson A, Crede T, Naude J, Szymanski P, Vallie Y, Moosa MS, Wiesner L, Black J, Meintjes G, Maartens G, Wilkinson RJ. Plasma Pharmacokinetics of High-Dose Oral versus Intravenous Rifampicin in Patients with Tuberculous Meningitis: a Randomized Controlled Trial. Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0014021. doi: 10.1128/AAC.00140-21. Epub 2021 Jul 16.
PubMed 33972248
Study at a glance
From the registry record, last updated by the sponsor on 28 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase IIA Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid With or Without Aspirin, for HIV-associated Tuberculous Meningitis
- ClinicalTrials.gov ID
- NCT03927313
- Acronym / sponsor ID
- LASER-TBM / LASER-TBM
- Conditions
- Tuberculosis Meningitis, HIV-1-infection
- Keywords
- TB meningitis, HIV
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- University of Cape TownUniversity, hospital or other
- Study start
- 12 Jun 2019 (actual)
- Primary completion
- 30 Mar 2021 (actual)
- Study completion
- 31 Mar 2021 (actual)
- First posted
- 25 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
LASER-TBM is a parallel group, randomized, multi-arm phase IIa trial evaluating the safety of increased dose rifampicin (RIF) plus linezolid (LZD), with or without aspirin (ASA), for the treatment of HIV-infected adults with tuberculous meningitis (TBM). The study will recruit 100 HIV-infected adults with TBM across four sites in South Africa.
The primary endpoint is the occurrence of solicited treatment-related adverse events.
Secondary endpoints include death and disability (including neurocognitive impairment), radiological outcomes, and the occurrence of immune reconstitution inflammatory syndrome (IRIS).
A nested pharmacokinetic (PK) substudy aims to:
- Describe the plasma and cerebrospinal fluid (CSF) PK of LZD and high dose RIF.
- Evaluate the relationship between drug exposures, toxicity and efficacy.
- Compare exposures between intravenous and oral RIF administration.
- Investigate the impact of high dose RIF on LZD and dolutegravir (DTG).
Detailed description
HIV-1 infected adults with newly-diagnosed TBM (n = 100) will be recruited from four public-sector hospitals in Cape Town and Port Elizebeth, South Africa. Participants will be randomised across two experimental (n = 30 each) and one standard of care (n = 40) arms. Treatment will be provided in all arms for 56 days, after which participants will be referred back to public sector facilities to complete standard therapy for HIV-associated TBM.
The primary objective of the study is to investigate the safety of enhanced antimicrobial therapy including increased dose RIF and LZD with or without adjunctive aspirin added to standard therapy for TBM in HIV-1 infected adults.
Secondary objectives are;
- To determine cerebrospinal fluid M.tb culture positivity and Gene Xpert® Ultra positivity at baseline and at 3 and 28 days post treatment by allocation.
- To evaluate the effect of aspirin and enhanced tuberculosis treatment on the incidence of immune reconstitution syndrome in participants starting antiretroviral therapy.
- To evaluate the effect of high dose rifampicin and linezolid, with and without aspirin on the transcriptional signature derived from whole blood and cerebrospinal fluid RNA sequencing, as well as the metabolomic and proteomic profiles, in tuberculous meningitis.
- To evaluate the effect of high dose rifampicin and linezolid with and without aspirin on central nervous system imaging in conjunction with clinical, immunological and transcriptional profiling.
- To store biological samples for future analysis of potential biomarkers of treatment efficacy and/or novel diagnostic assays.
- To determine i) whether host genotype, including LTA4H genotype, influences therapeutic effect of aspirin in HIV-TBM and ii) the pharmacogenetic influence on rifampicin and linezolid exposures and toxicity.
All participants will receive antitubercular chemotherapy and corticosteroids as standard of care as per national South African guidelines. Participants allocated to experimental arms 2 and 3 will receive additional rifampicin (total oral dose 35 mg/kg/day) plus oral linezolid 1200mg daily for the first 28 days, reduced to 600 mg daily for the next 28 days. Those randomized to experimental arm 3 will also receive oral aspirin 1000 mg daily.
All consenting LASER-TBM participants in experimental arms (n = 60) will undergo a second randomisation to receive either oral (35mg/kg) or IV (20mg/kg) rifampicin at the time of study entry. This sub-study is powered to demonstrate bioequivalence at day 3 of administration, after which all participants will be continued on oral rifampicin dosed at 35mg/kg.
Trial participation will be for 180 days post-randomization: primary safety endpoints and secondary efficacy endpoints will be evaluated at day 56; additional secondary endpoints will be evaluated at day 180.
There are seven scheduled study visits. The first six of thee will occur within the first 56 days, with an additional structured interview at 6 months. All visits will involve a clinical assessment including specified clinical outcome measures to assess functional and cognitive disability. Phlebotomy will be performed at study visits within the first 56 days to monitor for pre-specified parameters of drug safety (haematology, biochemistry) as well as to collect blood for downstream transcriptomic, proteomic and metabolomic analysis. Lumbar puncture will take place at day 3 and day 28. Cerebrospinal fluid will be analysed for Mycobacterium tuberculosis culture and Gene Xpert® Ultra cycle threshold values. Cerebrospinal fluid (CSF) will be stored for downstream transcriptomic, proteomic and metabolomic analysis. Baseline and day 56 brain imaging will be performed in all study participants.
All enrolled participants will undergo sparse plasma PK sampling at the Day 28 and Day 56 visits.
Cerebrospinal fluid (CSF) will be collected from all participants for determination of linezolid and rifampicin concentrations on Days 3 and 28. The timing of the Day 3 lumbar puncture will be randomised to intervals of 1 - 3, 3 - 6, 6 - 10, and 24 hours after observed antitubercular drug dosing in order to construct a concentration-time profile for the population. A single sample will be collected at each time interval. A second lumbar puncture will take place at the Day 28 visit, to coincide with the 4-hour plasma PK sample.
All participants (n=100) will be offered participation in the intensive sampling component of the PK sub-study at the time of randomization to the main study. Intensive plasma sampling will take place at the Day 3 study visit. Serial venous blood samples will be collected through a peripheral intravenous catheter pre-dose, and at 0.5, 1, 2, 3, 6, 8 - 10, and 24 hours after witnessed drug intake and an overnight fast. Sparse sampling will be performed at Day 3 for participants who decline intensive sampling or in whom this fails.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Phase IIA, randomized, active-controlled, open label, parallel-group trial
| Arm | Type | Receives |
|---|---|---|
| Standard of care anti-tubercular therapy | Active comparator | Drug: Standard of Care anti-tuberculous therapy, Drug: DexamethasoneStandard of care anti-TB treatment. (10 mg/kg oral rifampicin, 5 mg/kg oral isoniazid, 15 mg/kg oral ethambutol and 25 mg/kg oral pyrazinamide daily for 2 months as fixed dose combination tablets (followed by 10 mg/kg oral rifampicin and 5 mg/kg isoniazid daily for 4-7 months in routine care after study completed)). |
| Intensified anti-tubercular therapy | Experimental | Drug: Linezolid, Drug: High dose rifampicin, Drug: Standard of Care anti-tuberculous therapy, Drug: DexamethasoneStandard of care anti-TB therapy as described in Arm 1, Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days). |
| Intensified anti-tubercular therapy plus aspirin | Experimental | Drug: Linezolid, Drug: High dose rifampicin, Drug: Aspirin, Drug: Standard of Care anti-tuberculous therapy, Drug: DexamethasoneStandard of care anti-TB therapy as described in Arm 1, Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days), Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- HIV-1 seropositivity by rapid test, confirmed by enzyme-linked immunosorbent assay (regardless of Antiretroviral Therapy (ART) status);
- Age 18 years or older;
- Tuberculous meningitis defined as 'possible', 'probable' or 'definite' as per published case definitions
Key exclusion criteria (19 listed)
- Rifampicin-resistant M. tb detected in any microbiological specimen;
- History of allergy or hypersensitivity to H, E, R and Z, LZD or ASA;
- Received more than 5 days of antitubercular therapy in the 30 days prior to screening;
- Received a dose of ASA or any other NSAID within 2 weeks of screening;
- CSF unobtainable by lumbar puncture or another procedure;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LinezolidFor both experimental arms: 1.2g linezolid 28 days, followed by 600mg linezolid for 28 days | Drug | Intensified anti-tubercular therapy, Intensified anti-tubercular therapy plus aspirin |
| High dose rifampicinFor both experimental arms: additional 25mg/kg (making a total of 35mg/kg) rifampicin, for the first 56 days of treatment | Drug | Intensified anti-tubercular therapy, Intensified anti-tubercular therapy plus aspirin |
| AspirinFor only one of the experimental arms: 1000mg of aspirin daily for 56 days. | Drug | Intensified anti-tubercular therapy plus aspirin |
| Standard of Care anti-tuberculous therapy10mg/kg oral rifampicin, 5mg/kg oral isoniazid, 15mg/kg oral ethambutol, 25mg/kg oral pyrazinamide daily for 56 days. | Drug | Intensified anti-tubercular therapy, Intensified anti-tubercular therapy plus aspirin, Standard of care anti-tubercular therapy |
| DexamethasoneDexamethasone according to doses of Thwaites criteria for the first 8 weeks of anti-tuberculous treatment. Doses differ according to participants Medical Research Council (MRC) grade. Given orally if participant can swallow and intravenously if they cannot. | Drug | Intensified anti-tubercular therapy, Intensified anti-tubercular therapy plus aspirin, Standard of care anti-tubercular therapy |
Primary outcome
Number of participants in each arm who develop treatment related adverse events (AEs).
Time frame: 56 days
The amount of participants who develop any of the following treatment related adverse events by the time they have been on treatment for 56 days will be counted: Peripheral neuropathy, optic neuropathy, anaemia, neutropaenia, thrombocytopaenia, upper gastro-intestinal haemorrhage, intracerebral haemorrhage, drug-induced liver injury.
10 secondary outcomes
Death and disability after 56 days on treatment.
Time frame: 56 days
Death at day 56 and day 180.
Time frame: 180 days
Number of participants who are disabled.
Time frame: 180 days
Number of participants who develop Grade 3 or Grade 4 adverse events (AEs).
Time frame: 56 days
Number of participants in whom experimental drugs had to be stopped.
Time frame: 56 days
Linezolid toxicity
Time frame: 56 days
Major bleeding events.
Time frame: 180 days
Cerebrospinal fluid culture conversion.
Time frame: Day 28 and day 56
The occurrence of TBM-immune reconstitution inflammatory syndrome
Time frame: 56 days
Changes on brain imaging
Time frame: Day 56
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Sep 2021.
- Derived from this study: PubMed 37740554Abdelgawad N, Wasserman S, Abdelwahab MT, Davis A, Stek C, Wiesner L, Black J, Meintjes G, Wilkinson RJ, Denti P. Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis. J Infect Dis. 2024 Apr 12;229(4):1200-1208. doi: 10.1093/infdis/jiad413.
- Derived from this study: PubMed 36482216Davis AG, Wasserman S, Stek C, Maxebengula M, Jason Liang C, Stegmann S, Koekemoer S, Jackson A, Kadernani Y, Bremer M, Daroowala R, Aziz S, Goliath R, Lai Sai L, Sihoyiya T, Denti P, Lai RPJ, Crede T, Naude J, Szymanski P, Vallie Y, Banderker IA, Moosa MS, Raubenheimer P, Candy S, Offiah C, Wahl G, Vorster I, Maartens G, Black J, Meintjes G, Wilkinson RJ. A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial. Clin Infect Dis. 2023 Apr 17;76(8):1412-1422. doi: 10.1093/cid/ciac932.
- Derived from this study: PubMed 34286103Davis AG, Wasserman S, Maxebengula M, Stek C, Bremer M, Daroowala R, Aziz S, Goliath R, Stegmann S, Koekemoer S, Jackson A, Lai Sai L, Kadernani Y, Sihoyiya T, Liang CJ, Dodd L, Denti P, Crede T, Naude J, Szymanski P, Vallie Y, Banderker I, Moosa S, Raubenheimer P, Lai RPJ, Joska J, Nightingale S, Dreyer A, Wahl G, Offiah C, Vorster I, Candy S, Robertson F, Meintjes E, Maartens G, Black J, Meintjes G, Wilkinson RJ. Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM]. Wellcome Open Res. 2021 Jun 1;6:136. doi: 10.12688/wellcomeopenres.16783.1. eCollection 2021.
- Derived from this study: PubMed 33972248Wasserman S, Davis A, Stek C, Chirehwa M, Botha S, Daroowala R, Bremer M, Maxebengula M, Koekemoer S, Goliath R, Jackson A, Crede T, Naude J, Szymanski P, Vallie Y, Moosa MS, Wiesner L, Black J, Meintjes G, Maartens G, Wilkinson RJ. Plasma Pharmacokinetics of High-Dose Oral versus Intravenous Rifampicin in Patients with Tuberculous Meningitis: a Randomized Controlled Trial. Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0014021. doi: 10.1128/AAC.00140-21. Epub 2021 Jul 16.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert J Wilkinson, PhD principal investigator
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town
Sean Wasserman, MMed principal investigator
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town
Graeme Meintjes, PhD principal investigator
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Linezolid, High dose rifampicin and Aspirin in people with Tuberculosis Meningitis and HIV-1-infection, run by University of Cape Town at 4 sites in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants in each arm who develop treatment related adverse events (AEs). (time frame: 56 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03927313, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2021.