Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM

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

Conditions

• Tuberculosis Meningitis
• HIV-1-infection

Interventions

DRUG

Linezolid

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

DRUG

High dose rifampicin

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

DRUG

Aspirin

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

DRUG

Standard of Care anti-tuberculous therapy

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

DRUG

Dexamethasone

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.

Sponsors & Collaborators

• University of Cape Town

  lead OTHER

Principal Investigators

• Robert J Wilkinson, PhD · Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

• Sean Wasserman, MMed · Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

• Graeme Meintjes, PhD · Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

• John Black, MBChB · Department of Medicine, University of Cape Town and Walter Sisal University

• 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 Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2019-06-12

Primary Completion

2021-03-30

Completion

2021-03-31

Countries

• South Africa

Study Locations