ADDRESS-LC: study protocol for a phase 2, triple-blind, randomised, placebo-controlled trial to evaluate the efficacy and safety of bezisterim (NE3107) in adults with long COVID.

introductionLong COVID is a debilitating condition consisting of prolonged neurological symptoms such as cognitive impairment ('brain fog') and sleep disturbance. Symptoms may be associated with ongoing neuroinflammation from the persistence of a viral reservoir, activation of other viruses, protracted macrophagic inflammatory memory or enduring viral Spike protein that stimulates proinflammatory cytokines via toll-like receptor (TLR) signalling. Bezisterim (NE3107) is an oral, blood-brain barrier-permeable, anti-inflammatory, insulin-sensitising dehydroepiandrosterone derivative that inhibits TLR-driven neuroinflammation and is being developed for neurodegenerative diseases in which TLR-driven inflammation contributes to cognitive decline. METHODS AND ANALYSIS: ADDRESS-LC (NCT06847191) is a phase 2, triple-blind, placebo-controlled, randomised proof-of-concept study to evaluate the efficacy and safety of bezisterim in adults with long COVID. This multicentre study will recruit 208 adults (aged 18-69 years) with symptoms of fatigue and neurocognitive impairment for at least 3 months following an index SARS-CoV-2 infection. Individuals who meet all eligibility criteria will be randomised 1:1 to receive bezisterim 20 mg or placebo two times per day for 12 weeks. Cognition, fatigue, sleep, post-exertional malaise, quality of life and burdensome symptoms will be evaluated via several assessments, including a bespoke Cogstate Cognition Battery, Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function Short Form (SF)-8a, PROMIS Fatigue SF-13a and Patient's Global Impression of Severity, among others. ETHICS AND DISSEMINATION: The protocol has been approved by an institutional review board prior to study initiation. The study is being conducted at multiple clinical research sites across the USA. A current list of participating study sites is publicly available through the ClinicalTrials.gov registration record (NCT06847191). The study protocol has received central institutional review board approval (Advarra #Pro00081088), and participating sites obtained the necessary approvals and agreements required for study conduct and data access in accordance with applicable regulations and Good Clinical Practice guidelines. Authorised representatives of the sponsor, regulatory authorities and ethics committees may access study-related records for monitoring, auditing and regulatory purposes consistent with participant informed consent. The study will disseminate results through academic publication and conference presentations. TRIAL REGISTRATION NUMBER: NCT06847191.