Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis

Study Overview
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Brief Summary
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Superficial siderosis is a progressive neurological disease caused by iron deposition in the central nervous system (CNS) from chronic subarachnoid bleeding. Until 2011, there has been no effective treatment for this progressive condition that leads to hearing loss, spasticity, weakness, loss of bowel/bladder function, incoordination, dementia and ultimately death. Last year, the investigators demonstrated that a lipid soluble iron chelator, deferiprone, can reduce hemosiderin deposition in patients with superficial siderosis by MRI in as little as 3 months. As the only therapy that can improve this condition, chelation with deferiprone is the standard of care for treatment of superficial siderosis. Now that the FDA has approved deferiprone in the United States for thalassemia, the investigators propose documenting the clinical effect of deferiprone over 2 years in superficial siderosis patients. The investigators' goal is to understand how the clinical course of this disease is altered using standard of care chelation therapy with deferiprone. Patients with superficial siderosis who are taking deferiprone for chelation therapy at doses consistent with the standard of care will be offered enrollment into this observational study. Patients will be treated and monitored locally by participating neurologists who have agreed to help the investigators collect information for this study. The investigators are interested in documenting the clinical effect of deferiprone on hearing, ataxia and myelopathy using standardized scales performed and documenting the effect of deferiprone on hemosiderin deposition in the CNS by MRI, all performed according to standard of care.

Detailed Description
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First described over 100 years ago, superficial siderosis is a rare neurodegenerative disease caused by iron toxicity in the CNS due to chronic subarachnoid bleeding. Iron from red blood cells in the subarachnoid space is preferentially taken up by the Bergmann glia in the cerebellum, brainstem, spinal cord, eighth cranial nerve and the cerebral cortex; the iron is stored as ferritin within the glial cells. With continued subarachnoid bleeding, the glia are overwhelmed by the ferritin load and die. Glial cell loss exposes neurons to free iron which is toxic to cells because it catalyzes the breakdown of hydrogen peroxide to superoxide, a reactive oxygen species that can cause lipid peroxidation, membrane dysfunction, and neuronal cell death. Neurological consequences of iron overload depend on the area of the brain exposed to free iron. With chronic subarachnoid bleeding, the blood tends to pool around the brainstem, cerebellum and spinal cord thus leading to the classic triad of hearing loss, ataxia and myelopathy that is seen in more than 50% of patients with superficial siderosis. The eighth cranial nerve courses through the subarachnoid space until it reaches the inner ear exposing it to the toxic blood; in contrast, the other cranial nerves are protected by the peripheral Schwann cells within 1 mm of exiting the brainstem. Compared to the other CNS structures affected in superficial siderosis, the eighth cranial nerve is the most susceptible because it exposes the most surface area to volume. Thus, the most common and often the first symptom patients get is sensorineural hearing loss. This is followed by ataxia due to dysfunction of both the vestibular component of the eighth cranial nerve and neurodegeneration of the cerebellum. Myelopathy develops when the brainstem and spinal cord are involved. With continued bleeding, other areas of the brain can degenerate leading to a myriad of other symptoms seen in superficial siderosis including urinary problems headaches, anosmia, diplopia, bowel problems, ageusia, cranial nerve palsies, and dementia. The etiologies of chronic subarachnoid bleeding are (in order of incidence): Idiopathic, Head/back trauma, A/V malformations, Current CNS tumor, Previously resected CNS tumor, CNS post-surgical (non-tumor), Amyloid angiopathy, Brachial plexus/root injury. Currently, there are fewer than 50 patients world-wide with the diagnosis of superficial siderosis. In the United States, there are an estimated 50-60 patients. Iron chelators, other than deferiprone, used in other iron-overload disorders such as hemochromatosis are not expected to be effective in superficial siderosis because iron chelators do not cross the blood brain barrier. Copper chelators used in Wilson's disease can permeate the brain-blood barrier, but are unfortunately not effective in superficial siderosis, as copper chelators do not bind iron. Surgical intervention is thought to be key to slowing the disease by stanching the leak of blood into the subarachnoid space. However, once the neurodegenerative process has begun, surgical intervention does not prevent the neurodegenerative disease from progressing. Recently, the investigators have demonstrated that deferiprone, a lipid-soluble iron chelator, at a dose of 30 mg/kg/day administered over 90 days is safe in a population of 10 superficial siderosis patients. Although not designed to assess efficacy, the investigators also found that 4 of 10 patients showed reduced hemosiderin deposition in the CNS after the trial, which is very different from the natural course of disease in which hemosiderin deposition either remains the same over 3 months or increases over time. This suggests that deferiprone may be effective in chelating hemosiderin in patients with superficial siderosis.

Official Title
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Phase IV Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis

Conditions
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Superficial Siderosis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of superficial siderosis by MRI. Must be receiving deferiprone according to standard of care under the supervision of the treating physician. Must be able to understand and sign the informed consent form. Exclusion Criteria: 1. If the patient is unwilling or unable to comply with the requirements of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Deferiprone<br>All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Show Stability, Improvement or Decline in Self Reported Hearing | Number of participants who show stability, improvement or decline in self reported hearing. | At the end of the 2-year period | 
| Number of Participants Who Show Stability, Improvement or Decline in Self Reported Coordination | Number of participants who show stability, improvement or decline in self reported coordination. | At the end of the 2-year period | 
| Number of Participants Who Show Stability, Improvement or Decline in Self Reported Walking | Number of participants who show stability, improvement or decline in self reported walking. | At the end of the 2-year period | 
| Number of Participants Who Show Stability, Improvement or Decline in Self Reported Fine Motor Function | Number of participants who show stability, improvement or decline in self reported fine motor function. | At the end of the 2-year period | 
| Number of Participants Who Show Stability, Improvement or Decline in Self Reported Bowel/Bladder Function | Number of participants who show stability, improvement or decline in self reported bowel/bladder function. | At the end of the 2-year period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With MRI of the Brain and Spinal Cord Showing Changes in Hemosiderin Deposition | MRI of the brain and spinal cord without contrast to monitor for changes in hemosiderin deposition in terms of worsening or improvement. | Baseline, At the end of the 2-year period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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superficial siderosis