Randomized Delayed‑Start Trial of Intravenous Ferric Carboxymaltose in Pharmacoresistant Restless Legs Syndrome

The primary objective is to determine the efficacy of a single 1000 mg intravenous dose of ferric carboxymaltose, administered according to AASM guidelines, compared with conventional management per SFRMS recommendations, on the change in International Restless Legs Syndrome Study Group Rating Scale (IRLSSG‑Q) score from baseline (V1) to the 3‑month visit (V3) in patients with pharmacoresistant Restless legs syndrome; this outcome addresses the clinical need for effective symptom reduction in a population unresponsive to standard pharmacotherapy. Secondary objectives include: evaluation of the impact of the treatment on the periodic limb movement during sleep (PLMS) index in both immediate‑ and delayed‑treatment groups; assessment of additional polysomnographic parameters as confirmatory measures; analysis of IRLSSG‑Q score changes in relation to baseline peripheral (serum) and central (CSF) iron‑metabolism biomarkers; measurement of alterations in serum iron‑related biological parameters; identification of clinical, biological, and polysomnographic factors predictive of a favorable response; and comparison of treatment effects on associated symptoms (daytime sleepiness, insomnia, depression) and overall quality of life between the immediate‑ and delayed‑treatment cohorts.

The trial enrolled adult individuals (≥ 18 years) of both sexes who were diagnosed with pharmacoresistant Restless legs syndrome and exhibited severe to very severe symptomatology (IRLSSG‑Q score > 20) persisting for more than one month. Participants were required to have a body weight of at least 50 kg, be affiliated with a health‑insurance system, and provide written informed consent. All subjects were on stable regimens of dopamine agonists (ropinirole ≤ 2 mg/day, pramipexole ≤ 0.54 mg/day, rotigotine ≤ 3 mg/day) and/or α2δ ligands or opioids for a minimum of three months; those with coexisting sleep‑apnea syndrome were required to be treated with continuous positive airway pressure. Eligibility also required fluency in French and agreement to the automated processing of anonymized data. No specific dietary, physical‑activity, or habit restrictions were stipulated beyond the medication stability criteria. The sponsor did not provide the total number of participants recruited for the study.

The study is a randomized, controlled delayed-start trial evaluating intravenous ferric carboxymaltose 1000 mg versus conventional management in patients with pharmacoresistant restless legs syndrome. After a screening visit to confirm eligibility, participants undergo a baseline assessment (V1) including the International Restless Legs Syndrome Study Group rating scale (IRLSSG‑Q) and polysomnography. The immediate‑treatment arm receives the iron infusion at V1, while the delayed arm receives standard care and is offered the infusion at the 3‑month visit (V3). Follow‑up visits are scheduled at 3 months (V3) for primary efficacy assessment and at 5 months (V5) for the delayed‑treatment group, with additional safety and laboratory evaluations at each visit. The overall participant involvement spans approximately five months, and the trial recruitment period is projected from April 2026 to October 2028. Primary outcome is the change in IRLSSG‑Q score between V1 and V3; secondary outcomes include alterations in periodic limb movements, sleep architecture, serum ferritin, transferrin saturation, cerebrospinal fluid iron parameters, and several patient‑reported questionnaires.

The investigational product is ferric carboxymaltose, supplied as a sterile solution for intravenous infusion. Each dose contains 1000 mg of elemental iron and is administered by infusion into a peripheral vein. The infusion is given once at the baseline visit in accordance with the American Academy of Sleep Medicine (AASM) dosing guidelines.

All participants receive standard-of-care management for pharmacoresistant restless‑legs syndrome as recommended by the Sleep Medicine Society (SFRMS). Conventional therapy may include dopaminergic agents, α2‑δ ligands, or other symptomatic treatments prescribed by the treating physician.

Study staff record the exact time, duration, and total volume of each infusion to verify adherence. Compliance with the non‑experimental regimen is assessed through medication diaries and pill counts at each scheduled visit. Safety monitoring includes observation for infusion‑related reactions and routine laboratory assessments.

Efficacy will be assessed primarily by the change in the International Restless Legs Syndrome Study Group Rating Scale (IRLSSG‑Q) score from the baseline visit (V1) to the 3‑month follow‑up visit (V3). The scale will be administered by trained study personnel at each visit, and the difference between scores will be calculated for each participant.

Secondary efficacy parameters include:

• Change in the periodic limb movement in sleep (PLMS) index between V1 and V3 for the immediate‑treatment group and between V3 and V5 for the delayed‑treatment group, measured using overnight polysomnography.
• Changes in additional polysomnographic parameters (total sleep time, wake after sleep onset, percentage of slow‑wave sleep, and rapid eye movement sleep) evaluated at the same time points as the PLMS index.
• Alterations in serum biological markers—specifically ferritin and transferrin saturation—between V1 and V3 for the immediate‑treatment group and between V3 and V5 for the delayed‑treatment group, assessed by standard laboratory assays.
• Cerebrospinal fluid (CSF) levels of ferritin and transferrin saturation obtained at V1 for the immediate‑treatment group and at V3 for the delayed‑treatment group.
• Clinical response defined as a decrease of ≥3 points in the IRLSSG‑Q score between V1 and V3.
• Changes in patient‑reported outcome measures—including the Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), Beck Depression Inventory (BDI), Adult ADHD Self‑Report Scale (ASRS), and EQ‑5D health questionnaire—evaluated between V1 and V3 for the immediate‑treatment group and between V3 and V5 for the delayed‑treatment group.

All assessments will be performed according to validated protocols at the designated study visits. Data will be analyzed using appropriate statistical methods to compare changes from baseline within and between treatment arms.