Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM

• Status: Completed
• Trial end date: 2021-03-31
• Target enrollment: 0
• Participant gender: All

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).

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Cape Town
• Treatments: Aspirin; BB 1101; Dexamethasone; Dexamethasone acetate; Linezolid; Rifampin

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

• 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.