Long COVID can produce prolonged neurological manifestations, most commonly cognitive impairment described as “brain fog,” and disturbances of sleep. The pathophysiology implicated in these persistent symptoms includes ongoing neuroinflammation driven by several potential mechanisms: persistence of a viral reservoir, activation or reactivation of other viruses, enduring macrophagic inflammatory memory, or continued presence of viral Spike protein that stimulates proinflammatory cytokine production via toll-like receptor (TLR) signalling. These hypothesised drivers provide a mechanistic rationale for testing anti-inflammatory agents that penetrate the central nervous system.
Bezisterim (NE3107) is an oral, blood–brain barrier–permeable dehydroepiandrosterone derivative with anti-inflammatory and insulin-sensitising properties. It is reported to inhibit TLR-driven neuroinflammation, a pathway thought to contribute to cognitive decline in neurodegenerative disorders and potentially to persistent cognitive symptoms in long COVID. On this mechanistic basis, bezisterim is being assessed for its capacity to reduce neuroinflammation and improve cognitive and related symptoms in people with long COVID.
ADDRESS-LC (ClinicalTrials.gov identifier NCT06847191) is a phase 2, triple-blind, randomised, placebo-controlled, multicentre proof-of-concept study. The primary aim is to evaluate the efficacy and safety of bezisterim in adults with long COVID who report fatigue and neurocognitive impairment persisting for at least 3 months after an index SARS-CoV-2 infection. The protocol defines participant randomisation, treatment duration, and planned outcome assessments to establish proof of concept for symptomatic and functional benefit.
The study will enrol 208 adults aged 18 to 69 years who have experienced fatigue and neurocognitive impairment for a minimum of 3 months following documented or presumptive SARS-CoV-2 infection. Eligible individuals who meet all inclusion and exclusion criteria will be randomised to active treatment or placebo. The trial is being conducted at multiple clinical research sites across the USA; a current list of participating sites is available via the study’s ClinicalTrials.gov registration record.
Participants who meet eligibility criteria will be randomised in a 1:1 ratio to receive either bezisterim (NE3107) 20 mg or matching placebo, administered orally twice daily for 12 weeks. The study is described as triple-blind, indicating that participants, investigators, and those assessing outcomes are blinded to treatment allocation.
The trial will evaluate a range of symptom domains and functional outcomes. Cognitive function will be assessed using a bespoke Cogstate Cognition Battery in addition to the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function Short Form (SF)-8a. Fatigue will be measured with the PROMIS Fatigue SF-13a. Other assessed domains include sleep, post-exertional malaise, overall burden of symptoms, quality of life, and patient global impression measures such as the Patient's Global Impression of Severity. These instruments together aim to capture both objective and patient-reported changes in cognition, fatigue, and related symptoms over the 12-week treatment period.
Safety and tolerability will be assessed as part of the trial conduct, consistent with standard phase 2 study procedures. Authorised representatives of the sponsor, regulatory authorities, and ethics committees are permitted to access study-related records for monitoring, auditing, and regulatory review in accordance with participants’ informed consent. The protocol describes compliance with applicable regulations and Good Clinical Practice guidelines.
The study protocol received central institutional review board approval (Advarra #Pro00081088) before initiation. Participating sites obtained necessary local approvals and agreements required for study conduct and data access. The protocol indicates that conduct adheres to institutional review board oversight and regulatory requirements; specific details of local approvals and consenting procedures were handled by each site in line with the central approval and applicable regulations.
The study intends to disseminate findings through academic publications and presentations at scientific conferences. Trial registration is documented on ClinicalTrials.gov under identifier NCT06847191, where a current list of participating sites and the public trial record are maintained.