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)

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 (The LASER-TBM Trial)

“…Details of further analysis can be found in the full statistical analysis plan published alongside the study protocol 23 .…”

“…Dosing was calculated by weight bands as published in the study protocol 23 . After 56 days participants were referred to government TB facilities to receive continuation therapy (rifampicin 10mg/kg/day and isoniazid 5mg/kg/day) for 7 months as per national South African guidelines 25 .…”

“…Interim analysis for safety was performed by an independent data safety monitoring board (DSMB) board after every 15 participants enrolled. A full version of the study protocol is published elsewhere 23 .…”

“…• Arm 1 (standard of care): rifampicin 10 mg/kg, isoniazid (H) 5 mg/kg, ethambutol (E) 15 mg/kg, and pyrazinamide (Z) 25 mg/kg daily for 56 days • Arm 2: as per arm 1 plus adjunctive 25mg/kg rifampicin (total dose 35mg/kg) and linezolid (1200mg for 28 days, reducing to 600mg for 28 days) daily for 56 days • Arm 3: as per arm 2 plus adjunctive aspirin (1000mg) daily for 56 days Dosing was calculated by weight bands as published in the study protocol 23 . After 56 days participants were referred to government TB facilities to receive continuation therapy (rifampicin 10mg/kg/day and isoniazid 5mg/kg/day) for 7 months as per national South African guidelines 25 .…”

“…Assessment for AESI was also made at each study visit up to and including day 56 involving; a clinical history to assess symptoms of bleeding (GI or intracerebral), BPNS and modified total neuropathy score to assess for peripheral neuropathy, a LogMAR or tumbling E charts to assess for optic neuropathy, a full blood count to assess for haematological abnormalities and liver function tests to assess for a transaminitis. A full list of clinical outcome measures and assessments performed at each study visit are listed in the published protocol 23 .…”