RESULTS
hemiplegia, death, seizures, lower motor neuron VII, cranial nerve palsy, tuberculosis, tuberculous meningitis, worst-grade, Death, lower limb weakness, disability, TBM
ADVERSE EVENT, IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME, ADVERSE EVENTS, CRANIAL NERVE PALSY, EVENT, RECRUITMENT, TUBERCULOSIS, TUBERCULOUS MENINGITIS, EVENTS, MYELOPATHY, MRS
A total of 98 patients were screened and 52 were randomized between June 2019 and January 2021 (Consolidated Standards of Reporting Trials diagram describing recruitment and arm allocation. One participant was randomized but excluded prior to any study investigational product (IP) being dispensed due to emergence of an exclusion criterion (estimated glomerular filtration rate <20) on a hospital blood test performed prior to randomization. Another participant was excluded from the modified intention-to-treat analysis as they died prior to receiving any dose of study drug. Six participants discontinued the study prior to day 56, and an additional 4 participants discontinued between day 56 and day 180 (Baseline CharacteristicsAbbreviations: ART, antiretroviral therapy; CSF, cerebrospinal fluid; IQR, interquartile range.Previous ART refers to participants who at the time of enrollment were not taking ART due to defaulting treatment.The primary end point analysis was performed in the modified intention-to-treat population (n = 50: arm 1, 20; arm 2, 14; arm 3, 16). The composite primary end point of AESI or death occurred in 6 of 20 participants in arm 1, 4 of 14 in arm 2, and 10 of 16 in arm 3 (Adverse Events of Special Interest by Treatment ArmArm 3 vs arm 1.Individuals with an event.Details of Adverse Events of Special Interest by EventAbbreviations: LogMAR, logarithm of the minimum angle of resolution; MRI, magnetic resonance imaging; PI, principal investigator.Timing and Cause of Death Prior to Day 56Abbreviation: TBM, tuberculous meningitis.Death prior to receiving study investigational product and therefore excluded from modified intention-to-treat population analysis.The cumulative incidence of the composite end point of worst grade AESI or death at day 56 demonstrated worse outcomes when comparing arm 3 vs arm 1 (Time to worst-grade adverse events of special interest (AESI) or death. Kaplan–Meier analysis of time to worst grade AESI or death, comparing arms 1, 2, and 3 (Time to death. Kaplan–Meier analysis of time to death, comparing arms 1, 2, and 3 (Time to adverse events of special interest (AESI). Kaplan–Meier analysis of time to AESI, comparing arms 1, 2, and 3 (The frequency of grade 5 MRS (severe disability) or death was 4 (arm 1) vs 3 (arm 2) vs 5 (arm 3); Functional outcome at day 56 as defined by modified Rankin scale (MRS). Neurological SequalaeFew IRIS events occurred (arm 1, 2; arm 2, 2; arm 3, 3), of which 4 of 7 were defined as neurological IRIS. Within the first 56 days of treatment, 4 participants developed new-onset lower limb weakness (tuberculosis myelopathy, 2; tuberculosis radiculomyelopathy/arachnoiditis, 1; other [no cause found prior to death], 1); 3 participants developed new-onset hemiplegia; 1 patient developed new-onset isolated cranial nerve palsy (lower motor neuron VII). Thirteen participants presented with new-onset seizures at tuberculous meningitis diagnosis. An additional 9 participants had new-onset seizures within the first 2 months of follow-up (arm 1, 5; arm 2; 2; arm 3, 2; Abbreviation: IRIS, immune reconstitution inflammatory syndrome.No cause found prior to death.Spaghetti plot analysis of longitudinal CSF parameters over time demonstrated a downward trend of parameters across all 3 treatment arms (Change in cerebrospinal fluid (CSF) parameters over time. Spaghetti plots for CSF parameters, lymphocyte count (