Background and rationale {6a}
anaemia, TB, death, cheese syndrome, neutropenia, neuropathy, toxicity, toxicities, infections, ZeNix, XDR-TB, hypertensive, peripheral and optic neuropathy
ANAEMIA, NEUTROPENIA, NEUROPATHY, ADVERSE EVENTS, THROMBOCYTOPENIA, INFECTIONS, TUBERCULOSIS (TB), DRUG-DRUG INTERACTION
Tuberculosis (TB) is the thirteenth leading cause of death worldwide and, before the advent of COVID-19, was the leading cause from a single infectious agent, ranking above human immunodeficiency virus (HIV)/AIDS [Linezolid (LZD), an oxazolidinone, approved by the US Food and Drug Administration (FDA) since 2000 for the treatment of Gram+ infections, acts to inhibit protein synthesis by binding the 23S ribosomal RNA (rRNA) portion of the bacterial 50S subunit.LZD has shown good efficacy in randomized controlled trials (RCTs) and cohort studies, mostly conducted in XDR-TB patients. In a landmark study conducted by Lee et al., LZD was added to failing treatment in participants with extensive resistance; a strategy which is otherwise not advised since the absence of active combination partner drugs predisposes towards new resistance against the drug that is added [In the NiX-TB trial, a novel regimen composed of LZD, bedaquiline (BDQ) and pretomanid (PTM) achieved cure in 90% of participants with XDR-TB or failing MDR-TB treatment [LZD has a challenging safety profile, and its use is limited by adverse events (AEs) due to its inhibition of mitochondrial protein synthesis. Given long-term toxicities related to LZD treatment are anaemia, neutropenia, thrombocytopenia, peripheral and optic neuropathy. In addition, the inhibition of monoamine oxidase A (MAO A) by LZD may result in hypertensive responses after dietary intake of tyramine (tyramine pressor response, “cheese syndrome”) [In NiX-TB, only 15% of participants completed the 6-month course of LZD without interruptions or dose reductions due to toxicity. The Global TB Alliance then set up a ZeNix trial to evaluate whether shorter dosing of LZD or dosing at a lower dose would achieve an acceptable toxicity while maintaining efficacy. This approach was partially successful, but still at the lowest dose tested for the shortest duration (600mg for 9 weeks), 6/45 (13.3%) of participants developed neuropathy (M.Olugbosi, presented at InterTB Meeting 2021); illustrating the need for safer novel oxazolidinones.The Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA; The new oxazolidinones are combined with Delamanid (DLM), a nitroimidazole, and will be used in combination with BDQ and Moxifloxacin (MXF). Safety data suggests that these drugs may have a more favourable safety profile compared to their counterparts LZD and PTM. DLM is approved for use in Europe, Japan, and several other countries. DZD is a new, investigational oxazolidinone that is anticipated to have similar or better efficacy, compared to LZD and may cause less toxicity than LZD. Nonclinical studies demonstrated that DZD is not metabolized by major cytochrome P450 enzymes nor does it inhibit any of them. Also, DZD is neither perpetrator nor victim of drug-drug interactions based on major transporters. Prior to the study, DZD had been studied in 161 healthy participants in Phase 1 studies with the longest treatment being 21 days. 45 subjects were treated for 14 days in an early bactericidal activity (EBA) monotherapy study, but no reliable dose-response was identified for efficacy or toxicity. To assess the safety and efficacy of different doses of DZD, a trial design needs to be chosen that permits longer exposure to an oxazolidinone as most toxicities occur after an exposure of 14 days. Therefore, we developed a trial design that permits longer exposure through combination therapy with established anti-tuberculosis agents. Data from this study will inform the selection of a DZD dose for further assessment in the following studies.