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]

Abstract

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).

Keywords: Aspirin; HIV; Linezolid; Rifampicin; Tuberculous meningitis.

Conflict of interest statement

No competing interests were disclosed.

Copyright: © 2021 Davis AG et al.

Figures

Figure 1.. Study design schematic describing randomisation to study arms, treatment intervention per am, visit schedule, overview of clinical procedures and timepoints relating to primary and secondary endpoint data collection.

RHZE: Rifampicin, Isoniazid, Pyrazinamide, Ethambutol; R 10: Rifampicin 10mg/kg/day; R 35: Rifampicin 35mg/kg/day; LZD: Linezolid; ASA; Aspirin.

Figure 2.. Schematic to describe second randomisation to intravenous rifampicin (IV RIF).

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) RIF, together with linezolid (LZD) (with or without aspirin), at the time of study entry. The second randomisation will take place at the time of study entry, prior to receipt of study drug. Randomisation will be done in a 1:1 ratio using an electronic randomization tool, and fully integrated with main trial procedures). Due to the nature of the intervention, and because the outcome measure is a pharmacokinetic (PK) endpoint, allocation of IV versus oral RIF will be unblinded. Study drug will be stored at site pharmacies and administered as an infusion, in accordance with instructions in the package insert and trial standard operating procedures (SOP), by nursing staff of the trial.

Figure 3.. Schematic to summarise intensive pharmacokinetic (PK) sampling schedule.

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.