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 Research

article

Angharad G. Davis¹  Sean Wasserman³  Mpumi Maxebengula³  Cari Stek³  Marise Bremer³  Remy Daroowala³  Saalikha Aziz³  Rene Goliath³  Stephani Stegmann³  Sonya Koekemoer³  Amanda Jackson³  Louise Lai Sai³  Yakub Kadernani³  Thandi Sihoyiya³  C.Jason Liang⁶  Lori Dodd⁶  Paolo Denti⁷  Thomas Crede⁸  Jonathan Naude⁸  Patryk Szymanski⁸  Yakoob Vallie⁹  Ismail Banderker⁹  Shiraz Moosa⁹  Peter Raubenheimer⁴  Rachel P.J. Lai¹  John Joska^1,10  Sam Nightingale^1,10  Anna Dreyer^1,10  Gerda Wahl^1,11  Curtis Offiah^1,12  Isak Vorster^1,13  Sally Candy^1,13  Frances Robertson^1,14  Ernesta Meintjes^1,14  Gary Maartens⁷  John Black^1,11  Graeme Meintjes³  Robert J. Wilkinson¹ 

[1] The Francis Crick Institute;Faculty of Life Sciences, University College London;Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town;Department of Medicine, University of Cape Town;Department of Infectious Diseases, Imperial College London;Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town;Mitchells Plain Hospital;New Somerset Hospital;Department of Psychiatry and Mental Health, HIV Mental Health Research Unit, Neuroscience Institute, University of Cape Town;Department of Medicine, Water Sisulu University;Department of Neuroradiology, Imaging Department, Royal London Hospital, Barts Health NHS Trust;Division of Diagnostic Radiology, University of Cape Town, Groote Schuur Hospital;MRC/UCT Medical Imaging Research Unit Department of Human Biology, Faculty of Health Sciences, University of Cape Town

关键词: Tuberculous meningitis;    HIV;    Rifampicin;    Aspirin;    Linezolid;   

DOI  :  10.12688/wellcomeopenres.16783.1

学科分类：内科医学

来源: Wellcome

【 摘 要 】

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.

【 授权许可】

CC BY