Axsome has dosed the first patient in FORWARD, a Phase 3 randomized withdrawal trial of AXS-14 (esreboxetine) for fibromyalgia. The study uses a 12-week open-label run-in with once-daily AXS-14 at 8 mg to identify responders, who will then be randomized 1:1 to continue drug or switch to placebo for up to 12 weeks. The primary endpoint is time from randomization to loss of therapeutic response, making the readout event-driven and centered on maintenance of effect rather than mean change in pain scores.
The move signals a deliberate pivot to a maintenance-efficacy strategy in a crowded but underperforming category where discontinuation and placebo response have repeatedly blunted signal detection. A randomized withdrawal design reduces noise by enriching for initial responders and can generate a compelling durability dataset that often resonates with FDA for chronic, centrally mediated pain conditions. It also positions Axsome to produce a confirmatory-quality study that could complement legacy data on esreboxetine and strengthen the overall evidence package for an eventual filing.
Operationally, this design shifts key risks and levers to the open-label period. Screen-to-randomization conversion rates, time to reach steady-state benefit, and early tolerability will determine both sample size efficiency and the risk of underpowered post-randomization comparisons. Sites will need tight control of concomitant analgesics, consistent ePRO capture for pain and functional endpoints, and proactive management of typical NRI tolerability issues such as insomnia, tachycardia, or blood pressure elevations that can drive attrition. Because the endpoint is time to loss of response, near real-time monitoring of potential “events” and standardized criteria for relapse will be critical for CROs to avoid misclassification and preserve statistical power.
For sponsors and sites, the design may prove more recruitment-friendly than parallel-placebo models by limiting placebo exposure and offering a guaranteed active run-in, a useful lever in a population with high prior-treatment failure. For payers and guideline bodies, a clean maintenance signal could differentiate AXS-14 from SNRIs and gabapentinoids that suffer from early dropout and waning benefit, though comparative data will still be an unmet need. Regulators have accepted withdrawal designs to demonstrate durability, but for initial approval the totality of evidence will matter, including consistency across patient-reported outcomes and function, not just pain.
The watch items are clear: responder enrichment rates during the open-label phase, the event accrual curve once randomized, and whether the separation on time-to-loss persists across subgroups with high comorbidity burdens. If enrollment and event capture track as planned, Axsome could move quickly toward a registrational package; if responders don’t relapse at the expected rate, the study could drag, complicating timelines and powering assumptions. Expect close scrutiny of safety and sleep-related outcomes, and signals on whether Axsome is building this as the pivotal or as the confirmatory leg of a two-trial strategy.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
