Intravenous Iron in the Management of Drug-resistant Restless Legs syndromeI (IRON-RLS)

Intravenous Iron in the Management of Drug-resistant Restless Legs Syndrome: a Randomized Controlled Delayed-start Trial. IRON-RLS

The pathophysiology of restless legs syndrome (RLS) is not well understood: it is thought to involve intracerebral iron deficiency and dopaminergic dysregulation.

This study aims to evaluate the use of intravenous ferric carboxymaltose in patients with restless legs syndrome (RLS).

This study plans to include individuals with RLS, who will be divided into two groups:

• One group will receive intravenous iron immediately after the baseline polysomnography
• The second group will receive intravenous iron 3 months after randomization. In total, participants will be followed for 6 months, during which time they will be required to complete questionnaires regularly, undergo blood draws, and have two polysomnography tests.

Study Overview

• Status: Not yet recruiting
• Conditions: Restless Legs Syndrome (RLS)
• Intervention / Treatment: Drug: Ferric Carboxymaltose Injection [Ferinject]; Drug: Ferric Carboxymaltose Injection [Ferinject]; Other: Randomization; Other: Questionnaire and Physical Exam; Procedure: lumbar puncture; Procedure: urine pregnancy test

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yves DAUVILLIERS, MD - PhD; Phone Number: 0033 467 3374 78; Email: y-dauvilliers@chu-montpellier.fr

Study Locations

• France
  • Montpellier, France
    • CHU de Montpellier
    • Contact: Yves DAUVILLIERS, MD PhD; Phone Number: 033 4 6733 7478; Email: y-dauvilliers@chu-montpellier.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years;
• Weight ≥ 50 kg;
• Drug-resistant RLS;
• Severe to very severe RLS (IRLSSG-Q score > 20), persistent or recurrent for more than one month;
• Treatment with dopamine agonists without exceeding the recommended doses (ropinirole ≤ 2 mg/day, pramipexole ≤ 0.54 mg/day, rotigotine ≤ 3 mg/day);
• Treatment with dopamine agonists and/or α2δ ligands and/or opioids that has been stable for at least 3 months;
• In cases of sleep apnea syndrome, treatment with continuous positive airway pressure (CPAP);
• Participants were required to be fluent in spoken and written French, be enrolled in a health insurance plan, agree to the automated processing of anonymized confidential data, and have provided written, informed consent for the study.

Exclusion Criteria:

• Iron supplementation (oral or intravenous) within 3 months prior to enrollment and throughout the study period
• Serum ferritin < 50 µg/L or > 300 µg/L;
• Transferrin saturation < 20% or > 45%;
• Hemochromatosis;
• RLS augmentation syndrome ;
• Treatment with neuroleptics or antidepressants;
• Allergy to iron;
• Severe infectious or inflammatory disease within the past 3 months;
• RLS associated with chronic kidney disease, pregnancy, or a clinically significant neurological or psychiatric disorder;
• Severe sleep apnea syndrome (AHI > 30/h) that is untreated, or in cases where treatment is refused or has failed;
• Known allergy, inflammatory, or immune disorder;
• History of severe asthma, eczema, or any other atopic allergy;
• Pregnancy or breastfeeding;
• Also excluded are patients participating in another research study, those deprived of their liberty by judicial or administrative order, those living in a medical facility, those subject to a legal protection order, or those from whom consent could not be obtained.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Immediate treatment; The treatment will be administered at at baseline (V1), immediately after the baseline polysomnography	Drug: Ferric Carboxymaltose Injection [Ferinject]; administration of 1 g of CMF for 2 hours under medical monitoring; Drug: Ferric Carboxymaltose Injection [Ferinject]; Administration of 1 g of CMF for 2 hours under medical monitoring; Other: Randomization; Randomization in the arm "Immediate treatment" or "Delayed-onset treatment"; Other: Questionnaire and Physical Exam; Completion of questionnaires and scales: European Quality of Life 5 Dimensions (EQ-5D), Epworth Sleepiness Scale (ESS), Clinical Global Impression (CGI), Patient Global Impression (PGI), Beck Depression Inventory-II (BDI-II), Augmentation Severity Rating Scale (ASRS), International Restless Legs Study Group Severity Rating Scale (IRLSSG-Q), International Restless Legs Syndrome (IRLS), Insomnia Severity Index (ISI); Procedure: lumbar puncture; Lumbar puncture performed according to standard practice; Procedure: urine pregnancy test; During inclusion visit (Day 0) only for women of childbearing age
Active Comparator: Delayed-onset treatment; The treatment will be administered at 12 weeks	Drug: Ferric Carboxymaltose Injection [Ferinject]; administration of 1 g of CMF for 2 hours under medical monitoring; Drug: Ferric Carboxymaltose Injection [Ferinject]; Administration of 1 g of CMF for 2 hours under medical monitoring; Other: Randomization; Randomization in the arm "Immediate treatment" or "Delayed-onset treatment"; Other: Questionnaire and Physical Exam; Completion of questionnaires and scales: European Quality of Life 5 Dimensions (EQ-5D), Epworth Sleepiness Scale (ESS), Clinical Global Impression (CGI), Patient Global Impression (PGI), Beck Depression Inventory-II (BDI-II), Augmentation Severity Rating Scale (ASRS), International Restless Legs Study Group Severity Rating Scale (IRLSSG-Q), International Restless Legs Syndrome (IRLS), Insomnia Severity Index (ISI); Procedure: lumbar puncture; Lumbar puncture performed according to standard practice; Procedure: urine pregnancy test; During inclusion visit (Day 0) only for women of childbearing age

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IRLSSG-Q score	IRLSSG-Q : International Restless Legs Study Group Severity Rating Scale allows for the quantification of the severity of restless legs syndrome	From Day 0 to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Periodic Limb Movements during Sleep (PLMS) index	The PLMS Index measures the average number of involuntary leg movements per hour of sleeping during polysomnography. 15 or more per hour: Considered abnormal for adults and may suggest a condition called Periodic Limb Movement Disorder (PLMD) if it disrupts your sleep.	From V1 (Day 0) to V5 (week 24)
Total sleep time	Total sleep time measured in minutes during polysomnography.	From day 0 to week 24
Sleep latency	Length of time in minutes it takes to transition from full wakefulness to the lightest stage of sleep after the lights are turned off.	From Day 0 to week 24
Sleep time at stage 1-2 during polysomnography	Time spent in stage 1-2 sleep measured in hours and minutes during polysomnography	From Day 0 to week 24
Sleep time at stage 3 during polysomnography	Time spent in stage 3 sleep measured in hours and minutes during polysomnography	From Day 0 to week 24
Micro-awakenings index (MAI)	The Micro-awakenings index measures the number of brief awakenings that the person does not notice per hour of sleep.	From Day 0 to week 24
Apnea-hypopnea index (AHI)	The apnea-hypopnea index (AHI) measures the average number of interruptions or reductions in breathing per hour of sleep to assess the severity of sleep apnea.	From Day 0 to week 24
Average arterial oxygen saturation (SaO2)	The unit of measurement for SaO2 is the percentage (%).	From Day 0 to Week 24
Oxygen desaturation index (IDO)	The oxygen desaturation index (IDO) measures the number of significant drops in blood oxygen levels per hour of sleep.	From Day 0 to week 24
Serum ferritin		From Day 0 to week 24
Transferrin saturation coefficient		From Day 0 to Week 24
Epworth Sleepiness Scale (ESS)	A measure of excessive daytime sleepiness that quantifies the impact of the condition on alertness throughout the day. Eight everyday situations are rated (for example, watching television, riding as a passenger in a car, sitting quietly in a public place). Each situation is scored from 0 to 3 based on the likelihood of falling asleep. Total score 0-24; a score of ≥10 suggests excessive sleepiness	From Day 0 to Week 24
European Quality of Life 5 Dimensions (EQ-5D)	EQ-5D: this self-administered questionnaire assesses five dimensions (mobility, daily activities, self-care, pain/discomfort, anxiety/depression) as well as overall health status on a visual scale from 0 to 100	From Day 0 to Week 24
Clinical Global Impression (CGI)	The clinician's overall assessment of the illness, including CGI-S (severity) and CGI-I (change). 7-point scale: CGI-S 1 = normal, 7 = extremely ill; CGI-I 1 = markedly improved, 7 = markedly worsened	From Day 0 to Week 24
Patient Global Impression (PGI)	Patient's overall perception of the severity of their illness or change; a simple 7-point scale, self-reported. A high score is associated with patients perceiving their symptoms as severe	From Day 0 to Week 24
Beck Depression Inventory-II (BDI-II)	BDI-II: a self-administered questionnaire consisting of 21 items that assess the severity of depressive symptoms over the past two weeks; score range: 0-63; thresholds: 0-13 (mild), 14-19 (moderate), 20-28 (severe), ≥29 (severe)	From Day 0 to Week 24
Augmentation Severity Rating Scale (ASRS)	A 7-item self-administered questionnaire used to quantify the severity of the augmentation syndrome in patients treated with dopamine agonists. It assesses the worsening or early onset of RLS symptoms and their impact on sleep and daily activities	From Day 0 to Week 24
Insomnia Severity Index (ISI)	To assess the severity of the patient's insomnia, taking into account both the quantity and quality of sleep, as well as its impact on daily functioning (fatigue, concentration, mood). A 7-item self-report questionnaire scored from 0 to 4, with a total score of 0-28; 0-7 indicates no insomnia, 8-14 mild, 15-21 moderate, and 22-28 severe insomnia	From Day 0 to week 24

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): October 1, 2030

Study Registration Dates

• First Submitted: August 28, 2026
• First Submitted That Met QC Criteria: September 11, 2026
• First Posted (Actual): September 16, 2026

Study Record Updates

• Last Update Posted (Actual): September 16, 2026
• Last Update Submitted That Met QC Criteria: September 11, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Ferric carboxymaltose; periodic legs movements; intractable restless legs
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Parasomnias; Restless Legs Syndrome; Health Care Quality, Access, and Evaluation; Investigative Techniques; Epidemiologic Research Design; Epidemiologic Methods; Research Design; Methods; Therapeutics; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Biopsy; Data Collection; Health Care Evaluation Mechanisms; Quality of Health Care; Public Health; Environment and Public Health; Behavior Control; Immobilization; Diagnostic Techniques, Neurological; Surveys and Questionnaires; Restraint, Physical; Spinal Puncture; Random Allocation; ferric carboxymaltose
• Other Study ID Numbers: RECHMPL25_0557; 2026-525613-31-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No