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

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01284127
• Collaborator: (none)
• Enrollment: 38
• Location: 1
• Duration (Months): 79.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Superficial Siderosis

Detailed Description

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.

Study Design

• Study Type: Observational
• Actual Enrollment: 38 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Phase IV Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Jan 8, 2018
• Actual Study Completion Date: Oct 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
Deferiprone All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.

Outcome Measures

Primary Outcome Measures

1. 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 hearing.

2. 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 coordination.

3. 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 walking.

4. 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 fine motor function.

5. Number of Participants Who Show Stability, Improvement or Decline in Self Reported Bowel/Bladder Function [At the end of the 2-year period]

   Number of participants who show stability, improvement or decline in self reported bowel/bladder function.

Secondary Outcome Measures

1. Number of Participants With MRI of the Brain and Spinal Cord Showing Changes in Hemosiderin Deposition [Baseline, At the end of the 2-year period]

   MRI of the brain and spinal cord without contrast to monitor for changes in hemosiderin deposition in terms of worsening or improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Confirmed diagnosis of superficial siderosis by MRI.

2. Must be receiving deferiprone according to standard of care under the supervision of the treating physician.

3. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University

Investigators

• Principal Investigator: Michael Levy, MD, PhD, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 1, 2012

More Information

Publications

• Levy M, Llinas RH. Deferiprone reduces hemosiderin deposits in the brain of a patient with superficial siderosis. AJNR Am J Neuroradiol. 2011 Jan;32(1):E1-2. doi: 10.3174/ajnr.A2331. Epub 2010 Nov 4.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01284127
• Other Study ID Numbers: NA_00067749
• First Posted: Jan 26, 2011
• Last Update Posted: Sep 23, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Johns Hopkins University: superficial siderosis
• Additional relevant MeSH terms: Siderosis

Study Results

Participant Flow

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Period Title: Overall Study
STARTED	38
COMPLETED	31
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Overall Participants	38
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	18 47.4%
Male	20 52.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.6%
White	36 94.7%
More than one race	0 0%
Unknown or Not Reported	1 2.6%
Region of Enrollment (Count of Participants)
United States	38 100%
Cause of Bleed (Count of Participants)
Dural Tear	11 28.9%
Prior Neurosurgical Procedure	8 21.1%
Central Nervous System (CNS) Tumor/Cyst	4 10.5%
Undetermined	15 39.5%
Duration of Clinical Disease (years) [Median (Full Range) ]
Median (Full Range) [years]	7
Participants with Repair of Bleed (Count of Participants)
Count of Participants [Participants]	7 18.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Show Stability, Improvement or Decline in Self Reported Hearing
Description	Number of participants who show stability, improvement or decline in self reported hearing.
Time Frame	At the end of the 2-year period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Measure Participants	31
Stable	13 34.2%
Worse	18 47.4%
Improved	0 0%

2. Primary Outcome

Title	Number of Participants Who Show Stability, Improvement or Decline in Self Reported Coordination
Description	Number of participants who show stability, improvement or decline in self reported coordination.
Time Frame	At the end of the 2-year period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Measure Participants	31
Stable	8 21.1%
Worse	21 55.3%
Improved	2 5.3%

3. Primary Outcome

Title	Number of Participants Who Show Stability, Improvement or Decline in Self Reported Walking
Description	Number of participants who show stability, improvement or decline in self reported walking.
Time Frame	At the end of the 2-year period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Measure Participants	31
Stable	9 23.7%
Worse	21 55.3%
Improved	1 2.6%

4. Primary Outcome

Title	Number of Participants Who Show Stability, Improvement or Decline in Self Reported Fine Motor Function
Description	Number of participants who show stability, improvement or decline in self reported fine motor function.
Time Frame	At the end of the 2-year period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Measure Participants	31
Stable	9 23.7%
Worse	22 57.9%
Improved	0 0%

5. Primary Outcome

Title	Number of Participants Who Show Stability, Improvement or Decline in Self Reported Bowel/Bladder Function
Description	Number of participants who show stability, improvement or decline in self reported bowel/bladder function.
Time Frame	At the end of the 2-year period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Measure Participants	31
Stable	12 31.6%
Worse	18 47.4%
Improved	1 2.6%

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants with follow up MRIs (16) were evaluated.

Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
Measure Participants	16
Worse	8 21.1%
Improved	8 21.1%

Adverse Events

Time Frame	2 years
Arm/Group Title	Deferiprone
Arm/Group Description	All patients must have MRI evidence of superficial siderosis and be treated with deferiprone according to standard of care guidelines.
All Cause Mortality
	Deferiprone
	Affected / at Risk (%)	# Events
Total	0/38 (0%)
Serious Adverse Events
	Deferiprone
	Affected / at Risk (%)	# Events
Total	0/38 (0%)
Other (Not Including Serious) Adverse Events
	Deferiprone
	Affected / at Risk (%)	# Events
Total	10/38 (26.3%)
Musculoskeletal and connective tissue disorders
Joint Pain	2/38 (5.3%)
Nervous system disorders
Fatigue	10/38 (26.3%)
Skin and subcutaneous tissue disorders
Mouth sores	2/38 (5.3%)

Limitations/Caveats

The major limitations of this study relate to the observational design.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.