The Efficacy and Safety of Crisugabalin (HSK16149) in Fibromyalgia Patients: Protocol for a Prospective Randomized Open Blinded-Endpoint (PROBE) Study.

Background: Fibromyalgia (FM) is a chronic condition, imposing a substantial burden on patients. Pregabalin, a first-line treatment, offers incomplete efficacy for many and is associated with dose-limiting central nervous system adverse effects. Crisugabalin is a novel α2δ ligand with 23-fold higher binding affinity than pregabalin and has shown potentially fewer central nervous system adverse effects in animal models. While crisugabalin has shown efficacy in other neuropathic pain conditions, its efficacy in FM, particularly in a direct comparison with pregabalin, remains unclear. Methods and Analysis: This multicenter, prospective, randomized, pregabalin-controlled, open-label, blinded-endpoint study will be conducted at 10 hospitals in China. A total of 1116 adult patients with FM and a baseline average daily pain intensity of ≥4 on an 11-point numerical rating scale will be enrolled. Participants will be randomly assigned (1:1) to receive either crisugabalin or pregabalin for 12 weeks using a standardized, flexible-titration protocol. While participants and treating physicians will be aware of the treatment allocation, outcome assessors and data analysts will remain blinded. The primary outcome is the proportion of patients achieving at least a 50% reduction in average pain intensity from baseline at week 12. Secondary outcomes include pain intensity measures, study drug dosing and rescue analgesic utilization, Revised FM Impact Questionnaire, Brief Pain Inventory severity and interfere subscales, short-form 36 Health Survey, Patient Global Impression of Change Scale, Medical Outcomes Study Sleep Scale, Beck Depression Inventory-II, and incidence of adverse events. Analyses will be performed on the modified intention-to-treat and per-protocol populations. Ethics and Dissemination: This study, approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (KY2025-217-03), will be conducted in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants, and findings will be disseminated through peer-reviewed publications and scientific conferences. Trial Registration: Clinical Trials.gov identifier: NCT07196657. Registered on September 29, 2025 (https://www.clinicaltrials.gov/search?term=NCT07196657).