Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM

NCT03927313 | Completed Phase 2 DMC

• 1 other identifier: LASER-TBM
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 4

Brief 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). 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:

1. 1.Describe the plasma and cerebrospinal fluid (CSF) PK of LZD and high dose RIF.
2. 2.Evaluate the relationship between drug exposures, toxicity and efficacy.
3. 3.Compare exposures between intravenous and oral RIF administration.
4. 4.Investigate the impact of high dose RIF on LZD and dolutegravir (DTG).

Conditions

Tuberculosis Meningitis; HIV-1-infection

Keywords

TB meningitis, HIV

Outcome Measures

Primary Outcomes (1)

• 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.

  56 days

Secondary Outcomes (10)

• Death and disability after 56 days on treatment.

  56 days

• Death at day 56 and day 180.

  180 days

• Number of participants who are disabled.

  180 days

• Number of participants who develop Grade 3 or Grade 4 adverse events (AEs).

  56 days

• Number of participants in whom experimental drugs had to be stopped.

  56 days

Study Arms (3)

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)).

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).

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)

Drug: Linezolid; Drug: High dose rifampicin; Drug: Aspirin; Drug: Standard of Care anti-tuberculous therapy; Drug: Dexamethasone

Interventions

Linezolid DRUG

For both experimental arms: 1.2g linezolid 28 days, followed by 600mg linezolid for 28 days

Intensified anti-tubercular therapy; Intensified anti-tubercular therapy plus aspirin

High dose rifampicin DRUG

For both experimental arms: additional 25mg/kg (making a total of 35mg/kg) rifampicin, for the first 56 days of treatment

Intensified anti-tubercular therapy; Intensified anti-tubercular therapy plus aspirin

Aspirin DRUG

For only one of the experimental arms: 1000mg of aspirin daily for 56 days.

Intensified anti-tubercular therapy plus aspirin

Standard of Care anti-tuberculous therapy DRUG

10mg/kg oral rifampicin, 5mg/kg oral isoniazid, 15mg/kg oral ethambutol, 25mg/kg oral pyrazinamide daily for 56 days.

Intensified anti-tubercular therapy; Intensified anti-tubercular therapy plus aspirin; Standard of care anti-tubercular therapy

Dexamethasone DRUG

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.

Intensified anti-tubercular therapy; Intensified anti-tubercular therapy plus aspirin; Standard of care anti-tubercular therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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;
• 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

Sponsors & Collaborators

• University of Cape Town: lead

Study Sites (4)

Livingstone Hospital

Port Elizabeth, Eastern Cape, 6020, South Africa

Location

Mitchells Plain Hospital

Cape Town, Western Cape, 7786, South Africa

Location

Groote Schuur Hospital

Cape Town, Western Cape, 7925, South Africa

Location

New Somerset Hospital

Cape Town, Western Cape, 8001, South Africa

Location

Related Publications (4)

• 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.

  PMID: 37740554 DERIVED

• Davis 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.

  PMID: 36482216 DERIVED

• Davis 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.

  PMID: 34286103 DERIVED

• Wasserman 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.

  PMID: 33972248 DERIVED

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Linezolid; Rifampin; Aspirin; Dexamethasone

Condition Hierarchy (Ancestors)

Meningitis, Bacterial; Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated

Study Officials

• Robert J Wilkinson, PhD

  Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

  PRINCIPAL INVESTIGATOR

• Sean Wasserman, MMed

  Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

  PRINCIPAL INVESTIGATOR

• Graeme Meintjes, PhD

  Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

  PRINCIPAL INVESTIGATOR

• John Black, MBChB

  Department of Medicine, University of Cape Town and Walter Sisal University

  PRINCIPAL INVESTIGATOR

• Angharad G Davis, Dr

  1. Faculty of Life Sciences, University College London, UK 2. Department of Medicine, University of Cape Town, Observatory 7925, Republic of South Africa

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: National Principal Investigator

Model Details: Phase IIA, randomized, active-controlled, open label, parallel-group trial

Study Record Dates

• First Submitted: March 26, 2019
• First Posted: April 25, 2019
• Study Start: June 12, 2019
• Primary Completion: March 30, 2021
• Study Completion: March 31, 2021
• Last Updated: September 28, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE

Locations

ZA (4)