Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Authorised, recruitment pending
Participants planned
140
Countries
1
Sites
1
restless leg syndrome
Main objective of this study is to investigate the effect of iron supplementation or placebo (in combination or not with dopaminergic therapy) on clinical RLS symptoms measured by the IRLS.
Key facts
- Sponsor
- Medizinische Universitaet Innsbruck
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Not possible to specify
- Decision date (initial)
- 2024-10-14
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- No
External identifiers
- EU CT number
- 2024-512117-40-00
- EudraCT number
- 2019-004583-22
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy
Main objective of this study is to investigate the effect of iron supplementation or placebo (in combination or not with dopaminergic therapy) on clinical RLS symptoms measured by the IRLS.
Secondary objectives 1
- Secondary objectives are to investigate the effect of iron supplementation a. on clinical RLS symptoms measured by other validated scales, b. on the mitochondrial respiration and serological biomarkers, and c. on iron content in the substantia nigra.
Conditions and MedDRA coding
restless leg syndrome
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 21.1 | LLT | 10038741 | Restless leg syndrome | 10029205 |
Study design 4 periods
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Screening The following study screening assessments are to be completed prior to study entry:
• Screening for inclusion and exclusion criteria
• Signed and dated informed consent
• Demographic data: date of birth, sex
• Physical examination including vital signs
• RLS clinical data (age at onset of RLS, family history of RLS, current/previous augmentation, RLS medication)
• Medical history: All active conditions and any condition diagnosed within lifetime considered to be clinically significant by the investigator (disease specific history excluded)
• Concomitant medication (no changes allowed between screening visit and baseline visit)
• International Restless Legs Severity Scale (IRLS), Restless Legs Syndrome-6 Scale (RLS-6), Clinical Global Impression Severity Scale (CGI-S), self-administered International Restless Legs Severity Scale (sIRLS)
• Blood samples for analyses of the following parameters: blood count, iron, Tf, TSAT, ferritin, sTfR, hepcidin-25, creatinine (GFR), GPT, GOT, LDH, electrolytes (Na, K, P, Ca), PTH, dopamine, 1,25-(OH)2 vitamin D, 25-OH vitamin D
• Pregnancy test
• Iron content in the substantia nigra detected by an MRI in a subgroup of patients (40 patients with dopaminergic treatment and 40 patients without RLS treatment)
|
Not Applicable | None | [{"id":81366,"code":1,"name":"Subject"},{"id":81367,"code":2,"name":"Investigator"}] | |
| 2 | Baseline Visit Baseline visit corresponds to the day of intravenous iron isomaltoside 1000 or placebo administration over 60 minutes.
• Blood samples will be drawn before study drug infusion for analyses of the following parameters: EPO, ERFE, PBGF-BB, LCN2 and metabolites (ATP, NADH/NAD, Lactate, Succinate, Citrate, Pyruvate, free fatty acids). Infusion of the study drug will be applied once the results relevant for inclusion/exclusion criteria are available. eGFR values will be calculated with the MDRD-IDMS formula.
• CRP test
• Peripheral monocytes will be analyzed for the expression of cytoplasmic and mitochondrial iron genes as well as metabolic mitochondrial genes (Krebs cycle) by RT-PCR.
• Mitochondrial respiration of selected and randomly assigned patients (N=60) will be assessed with high-resolution respirometry (Oxygraph-2k).
• AEs will be recorded.
|
Randomised Controlled | Double | [{"id":81370,"code":2,"name":"Investigator"},{"id":81369,"code":1,"name":"Subject"}] | |
| 3 | Follow-Up Visit 1 During the follow-up visit 1 on day 30 ± 7 the following procedures will be performed:
• Physical examination (incl. vital sings)
• International Restless Legs Severity Scale (IRLS), Restless Legs Syndrome-6 Scale (RLS-6), Clinical Global Impression Severity scale (CGI-S), Clinical Global Impression Improvement scale (CGI-I) and self-administered International Restless Legs Severity Scale (sIRLS) will be determined.
• Blood samples will be drawn for analyses of the following parameters: blood count, iron, Tf, TSAT, ferritin, sTfR, hepcidin-25, creatinine (GFR), GPT, GOT, LDH, CRP, electrolytes (Na, K, P, Ca), PTH, dopamine, 1,25-(OH)2 vitamin D, 25-OH vitamin D, EPO, ERFE, PBGF-BB, LCN2 and metabolites (ATP, NADH/NAD, Lactate, Succinate, Citrate, Pyruvate, free fatty acids).
Peripheral monocytes will be analyzed for the expression of cytoplasmic and mitochondrial iron genes as well as metabolic mitochondrial genes (Krebs cycle) by RT-PCR.
• Pregnancy test
• Mitochondrial respiration of the patients selected and randomly assigned at the baseline visit will be assessed with high-resolution respirometry (Oxygraph-2k).
• AEs and concomitant medications will be recorded.
|
Randomised Controlled | Double | [{"id":81373,"code":1,"name":"Subject"},{"id":81372,"code":2,"name":"Investigator"}] | |
| 4 | Follow-Up Visit 2 During the follow-up visit 2 on day 30 ± 7 the following procedures will be performed:
• Physical examination (incl. vital sings)
• International Restless Legs Severity Scale (IRLS), Restless Legs Syndrome-6 Scale (RLS-6), Clinical Global Impression Severity scale (CGI-S), Clinical Global Impression Improvement scale (CGI-I) and self-administered International Restless Legs Severity Scale (sIRLS) will be determined.
• Blood samples will be drawn for analyses of the following parameters: blood count, iron, Tf, TSAT, ferritin, sTfR, hepcidin-25, creatinine (GFR), GPT, GOT, LDH, CRP, electrolytes (Na, K, P, Ca), PTH, dopamine, 1,25-(OH)2 vitamin D, 25-OH vitamin D, EPO, ERFE, PBGF-BB, LCN2 and metabolites (ATP, NADH/NAD, Lactate, Succinate, Citrate, Pyruvate, free fatty acids).
Peripheral monocytes will be analyzed for the expression of cytoplasmic and mitochondrial iron genes as well as metabolic mitochondrial genes (Krebs cycle) by RT-PCR.
• Pregnancy test
• Mitochondrial respiration of the patients selected and randomly assigned at the baseline visit will be assessed with high-resolution respirometry (Oxygraph-2k).
• AEs and concomitant medications will be recorded.
Iron content in the substantia nigra detected by an MRI in the subgroup of patients, which had an MRI at the screening visit.
|
Randomised Controlled | Double | [{"id":81375,"code":2,"name":"Investigator"},{"id":81376,"code":1,"name":"Subject"}] |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 6
- RLS diagnosed according to the current IRLSSG criteria Essential diagnostic criteria (all must be met): a) An urge to move the legs usually but not always accompanied by, or felt to be caused by, uncomfortable and unpleasant sensation in the legs. b) The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting c) The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. d) The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day. d) The occurence of the above features is not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g. myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping).
- Female and male participants aged ≥ 18 years
- Negative urine/serum pregnancy test in women of childbearing potential (WOCBP). WOCBP who are sexually active, agree to use highly effective means of contraception during the study and for at least 1 month post-study treatment. Allowed are accepted and effective hormonal/non-hormonal methods of contraception and sexual abstinence or vasectomised partners (> 3 months previously). Vasectomy has to be confirmed by two negative semen analyses.
- IRLS score >=15
- For the DA group, DA dosage not exceeding the max recommended dosage for RLS (PMID 27448465): Pramipexole 0.75 mg/day, Ropinirole 4mg/day, Rotigotine 3 mg/day
- Written, signed and dated informed consent
Exclusion criteria 14
- Secondary RLS
- Sporadic RLS
- Dialysis-dependent renal failure (eGFR<20mL/min/1.73m² calculated by MDRD formula)
- Moderate or severe heart failure (NYHA III - IV)
- Malignancies
- Pregnancy/brestfeeding
- Known thalassaemia minima/minor, hemochromatosis, polycythemia vera, hemolytic anemia
- Current intake of opiates
- Iron substitution, erythropoietin therapy or blood transfusion in the previous 6 months
- Ferritin > 200 mg/dL or Transferrin Saturation over 45%
- Phosphate levels below the lower limit normal before study drug initiation
- Contraindications for performing a MRI (for example claustrophobia, pacemakers, metal implants)
- Body weight < 50 kg
- Known Hypersensitivity to the active substance or any of its excipients (Sodium hydroxide/Hydrochloric acid
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Changes in RLS severity as detected by the IRLS
Secondary endpoints 5
- Changes in RLS severity as detected by the sIRLS, RLS-6 and CGI
- Changes in blood count, iron, Tf, TSAT, ferritin, sTfR, hepcidin-25, creatinine (GFR), GPT, GOT, LDH, CRP, electrolytes (Na, K, P, Ca), PTH, LCN2, dopamine, 1,25-(OH)2 vitamin D, 25-OH vitamin D, EPO, ERFE, PDGF-BB, LCN2 and metabolites (ATP, NADH/NAD, Lactate, Succinate, Citrate, Pyruvate, free fatty acids)
- Changes in mitochondrial iron and Krebs cycle metabolism gene expression in monocytes detected by RT-PCR
- Changes in mitochondrial respiration of selected and randomly assigned patients measured with OROBOROS respirometry
- Changes in iron content in the substantia nigra detected by an MRI in a subgroup of 80 patients (20 dopaminergic therapy/iron, 20 dopaminergic therapy/placebo, 20 no previous treatment/iron and 20 no previous treatment/placebo)
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 1
MonoFer 100 mg/ml Lösung zur Injektion/Infusion
PRD538657 · Product
- Active substance
- Ferric Derisomaltose
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INTRAVENOUS INFUSION
- Max daily dose
- 20 mg/kg milligram(s)/kilogram
- Max total dose
- 20 mg/Kg milligram(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- B03AC — IRON TRIVALENT, PARENTERAL PREPARATIONS
- Marketing authorisation
- 75060.00.00
- MA holder
- PHARMACOSMOS A/S
- MA country
- Germany
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Placebo 1
Kochsalz ”Braun” 0,9% - Infusionslösung
PRD564003 · Product
- Active substance
- Sodium Chloride
- Substance synonyms
- SODIUM CHLORID
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INFUSION
- Max daily dose
- 40 millilitre(s)/kilogram
- Max total dose
- 40 millilitre(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- B05BB01 — ELECTROLYTES
- Marketing authorisation
- 16468
- MA holder
- B.BRAUN MELSUNGEN AG
- MA country
- Austria
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Medizinische Universitaet Innsbruck
- Sponsor organisation
- Medizinische Universitaet Innsbruck
- Address
- Innrain 52
- City
- Innsbruck
- Postcode
- 6020
- Country
- Austria
Scientific contact point
- Organisation
- Medizinische Universitaet Innsbruck
- Contact name
- University Hospital for Neurology
Public contact point
- Organisation
- Medizinische Universitaet Innsbruck
- Contact name
- University Hospital for Neurology
Locations
1 EU/EEA country · 1 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Austria | Authorised, recruitment pending | 140 | 1 |
| Rest of world | — | 0 | — |
Investigational sites
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 4 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2024-512117-40 | 2.2 |
| Recruitment arrangements (for publication) | K1_Assessment_under_CTD_available | 1 |
| Subject information and informed consent form (for publication) | L1_ICF IDRLS | 3.2 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SmPC Monofer | 1 |
Application history
1 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-09-06 | Austria | Acceptable 2024-10-09
|
2024-10-14 |