Deferiprone for Ruptured Brain Aneurysm
Deferiprone for Ruptured Brain Aneurysm
Ruptured cerebral aneurysms lead to subarachnoid hemorrhage (SAH),that has a high morbidity
 and mortality rate, the severity of which is predicted by the "Hunt-Hess grade" (HHG).

 SAH leads to iron (Fe) and hemoglobin (Hb) accumulation in the brain, which is toxic for
 neurons. Ferritin (iron reported in the brian) and iron overload leads to brain atrophy,
 specifically in the mesial temporal lobe (hippocampus, impairing patients' cognition. It is
 estimated that 50% of survivors have cognitive deficits.

 Most of the survivors of SAH could not return to work. Iron chelation therapy has been
 recently gaining ground as a therapeutic intervention in intraparenchymal hemorrhage and in
 SAH. However, there has not been any study that assess the iron deposition in the brain and
 the level of ferritin in the cerebrospinal fluid of SAH patients. The investigators propose
 to conduct a randomized trial using Deferiprone (oral chelating agent, "De") + standard of
 care vs standard of care in patient with SAH to:

 1. assess the level of ferritin (Ft) in CSF (CSF withdrawn from ventriculostomy tube),

 2. assess functional outcomes measured by the Montreal Cognitive Assessment (MoCA) score, a
 score used to assess the level of dementia, mainly in Alzheimer disease patients.

 3. quantify the the total iron deposition in the brain based on MRI
I) SIGNIFICANCE

 1) Significance and Incidence and Burden of the disease Intracranial aneurysm is a prevalent
 disease estimated around 2-5% of the population. Aneurysm rupture leads to aneurysmal
 subarachnoid hemorrhage , which have a tremendous impact on the patient's health, and a high
 mortality rate (~60%), with a large proportion of the survivors becoming functionally
 dependent. It accounts for 27% of all stroke-related years of life lost before age 65, and it
 has a predilection for a relatively younger age. Survivors have long term cognitive deficits
 and memory impairment in their productive years with major responsibilities with respect to
 work and family. Despite that, only one-third have neurological deficits. Most of the
 survivors could not return to work. Poor functional outcomes are related to iron and heme
 toxicity with resultant delayed cerebral ischemia , early brain injury , hydrocephalus and
 cerebral edema. As of today, there has not been any intervention that improves neurocognitive
 outcomes in these patients. The investigators postulate that iron chelation therapy can
 decrease the amount of Iron (Fe) deposition in the brain, reduce ferritin (Ft) in patients'
 cerebrospinal fluid (CSF) and potentially improve functional outcome.

 Our group was the first in the world to detect and quantify Fe concentration at the interface
 of brain aneurysms' wall and brain tissue using QSM-MRI sequence. This technique allowed us
 to detect microbleeds associated with sentinel headache in subjects with IAs and negative
 non-contrast head CT and negative lumbar puncture. In this proposal, the investigators will
 also use high-resolution MRI sequence to assess difference in volumes of amygdala and
 hippocampus and correlate that with CSF-ferritin.

 This will make our proposal the first go/no-go randomized double-blind placebo vs.
 deferiprone trial that attempts to establish Ft (a reporter of total Fe in the brain and CSF)
 as a biomarker of neurocognitive decline specifically in subarachnoid hemorrhage subjects and
 test the effect of deferiprone in decreasing the levels of Ft and therefore ameliorate the
 neurocognitive decline associated with this disease. If our hypothesis is validated, then
 this would set the stage for a phase 3 clinical trial and test our hypothesis in larger
 cohort of subjects.

 III) PRELIMINARY DATA (obtained with collaboration with our colleagues in Europe):

 To provide proof-of-concept of the effect of deferiprone on the levels of Ft in the CSF of
 subjects with aneurysmal subarachnoid hemorrhage (aSAH), Tthe investigators conducted a pilot
 study to analyze the concentration Ft in the CSF of subjects with aSAH and Hunt and Hess
 grade 1-3. Fourteen subjects were included (7 with only cisternal SAH but no intraventricular
 hemorrhage (IVH), and 7 subjects with cisternal aSAH and IVH). Their CSF (2-3 cc) were drawn
 daily (from day 0 to day14) and analyzed with Fe-ELISA kit. Then 4 subjects (2 with aSAH
 without IVH and 2 with SAH and IVH) were treated with 1000 mg of deferiprone twice orally for
 14 days. The mean Ft level in subjects with aSAH without IVH was 900ng/ml vs. 420 ng/ml for
 those receiving deferiprone. The mean Ft level of patients with SAH and IVH was 1500ng/ml
 compared to 690 ng/ml in the deferiprone group. This small pilot study provided
 proof-of-concept that 1) aSAH increases the CSF-Ft in human, and this effect can be reduced
 significantly with deferiprone, and 2) aSAH associated with IVH increases furthermore CSF-Ft,
 which is also reduced significantly by deferiprone.
Subjects should be at least 18 years of age, presents with aneurysmal SAH, that requires
 the placement of a ventriculostomy (EVD) and coiling or stent assisted coiling of the
 aneurysm.

 Inclusion criteria:

 1. Age greater or equal to 18

 2. Historical modified Rankin Scale Score (mRS) 0-1 (pre-subarachnoid hemorrhage onset)

 3. World Federation of Neurosurgical Societies SAH Scale (WFNS) grade lesser or equal to
 3, due to a spontaneous SAH attributed to a ruptured cerebral aneurysm.

 • Initial WFNS grade may be determined at admission or enrollment, preferably after
 the patient's mental status has been optimized by resuscitation and interval treatment
 of hydrocephalus (i.e., placement of intraventricular catheter [EVD]) or
 reversal/wearing-off of sedating medications used commonly during patient transfers
 and transport or procedure related anesthesia.

 4. Admission head CT showing modified Fisher grade 1-4 due to aSAH primarily in the
 supratentorial space. The Modified Fisher CT rating scale is: Grade 1 (minimal or
 diffuse thing SAH without intraventricular hemorrhage); Grade 2 (minimal or thin SAH
 with intraventricular hemorrhage), Grade 3 (thick cisternal clot without
 intraventricular hemorrhage), Grade 4 (thick cisternal clot with intraventricular
 hemorrhage)

 5. Location and pattern of the SAH must have the majority of the SAH in the
 supratentorial space caused by either an intradural anterior circulation aneurysm or a
 basilar apex/posterior circulation aneurysm with primarily supratentorial hemorrhage
 extension. Angiographic location of the aneurysm will be confirmed by catheter digital
 subtraction angiography usually obtained during the coil embolization procedure.

 6. Onset of symptoms of aSAH (ictus) occurred < 24 hours prior to presentation at the
 treating facility.

 7. Initiation of aneurysm securement procedure occurred < 48 hours from the ictus and
 less than 12 hours from admission to the treating facility.

 8. All aneurysm(s) suspected to be responsible for the hemorrhage or potentially
 responsible for the hemorrhage must be secured in the following manner prior to
 enrollment: endovascular Coil Embolization with a post-embolization Raymond-Roy Score
 of 1 (Complete) or 2 (Residual Neck)

 9. Ability to screen the patient and obtain head CT and CT perfusion on admission and
 follow after recovering from anesthesia following the aneurysm coiling procedure, the
 patient must remain a WFNS SAH grade less or equal to 3 without evidence of a
 significant new focal neurological deficit including monoparesis / monoplegia,
 hemiparesis / hemiplegia, or receptive, expressive or global aphasia. New minor
 cranial nerve defect without any other new findings is permissible. If a national
 institute of health stroke scale (NIHSS) score was obtained prior to the aneurysm
 coiling procedure, a post-coiling (pre-enrollment) NIHSS score must not have increased
 by 4 points or more and Glasgow coma score must not be decreased by 2 points or less.
 The clinician should use their best clinical judgment as to whether a significant
 neurological decline has occurred due to the coiling procedure.

 10. Ability to obtain MRI for ischemic changes evaluation, measurement of iron deposition
 and volume of and hippocampus.

 11. Subject's Legally Authorized Representative (LAR) has provided written informed
 consent

 Exclusion Criteria:

 1. Angio-negative SAH

 2. A likely hemorrhage event within several days prior to admission related hemorrhage
 ictus due to the increased risk of early vasospasm.

 3. Prior sentinel headache with negative CT or prior sentinel headache where the patient
 did not seek medical attention does not exclude the patient.

 4. Surgical clipping of the ruptured aneurysm or any non-ruptured aneurysm on the same
 admission prior to enrollment.

 5. SAH not caused by aneurysm rupture or aneurysm is identified to be traumatic, mycotic,
 blister or fusiform type by catheter DSA.

 6. Any intracranial stent placement or non-coil intra-aneurysmal device (i.e., stent-
 assisted coiling with Neuroform, Enterprise, LVIS, LVIS Jr, Barrel Stent, Pulse Rider,
 WEB, LUNA, Medina or a similar device) where the stent device is implanted to treat
 the ruptured aneurysm and / or antiplatelet therapy is needed.

 7. Subject has remaining aneurysm(s) that are untreated and could reasonably be
 considered a possible alternate cause of the aSAH based on the observed bleeding
 pattern. Adequate treatment of these aneurysms by coiling embolization would result in
 the aneurysms no longer causing an exclusion. MRI may be used in some situations to
 determine that the associated aneurysms did not rupture based on lack of blood seen
 adjacent to the additional aneurysms.

 8. Diagnosis of sepsis or current documented active bacterial or viral infection prior to
 enrollment. A minor uncomplicated community-acquired urinary tract infection would not
 be an exclusion but should be treated promptly.

 9. New parenchymal hemorrhage or new infarction larger the 15cc in volume, or significant
 increased mass effect as seen on the post coiling pre-enrollment head CT when compared
 to baseline admission head CT. New hyperdensity on CT scan related to contrast
 staining is not an exclusion.

 10. Subject developed SAH-induced cardiac stunning prior to enrollment, with an ejection
 fraction< 40%, or requiring intravenous medications for blood pressure maintenance.

 11. Concurrent significant intracranial pathology identified prior to enrollment,
 including but not limited to, Moyamoya disease, high suspicion or documented CNS
 vasculitis, severe fibromuscular dysplasia, arteriovenous malformation, arteriovenous
 fistula, significant cervical or intracranial atherosclerotic stenotic disease
 (greater or equal to 70%), or malignant brain tumor.

 12. Known seizure or epilepsy disorder (diagnosed prior to this aSAH diagnosis) where
 anti-epileptic medication was previously taken by the patient or have been recommended
 to be taken by the patient. Childhood seizures that have resolved and no longer
 require treatment are not part of this exclusion criteria

 13. Serious co-morbidities that could confound study results including but not limited to:
 Multiple Sclerosis, dementia, severe major depression, cancer likely to cause death in
 2 years, multi-system organ failure, or any other conditions that could cause any
 degree of cognitive impairment.

 14. Immunosuppression therapy including chronic corticosteroid usage.

 15. Remote history of previous ruptured cerebral aneurysm.

 16. History of gastrointestinal hemorrhage or major systemic hemorrhage within 30 days,
 hemoglobin less than 8 g/dL, international normalized ratio greater or equal1.5,
 severe liver impairment, creatinine > 2.0 mg/dL, or estimated glomerular filtration
 rate < 60 ml/min.

 17. Major surgery (including open femoral, aortic, or carotid surgery) within previous 30
 days.

 18. Currently pregnant.

 19. Contraindication for MRI

 20. No hydrocephalus requiring EVD

 21. Known hypersensitivity to De or to any of the excipients in the formulation.

 22. Past medical history of agranulocytosis.

 23. Past medical history of any hematologic conditions requiring transfusion of red blood
 cells or platelets

 24. Active or chronic liver disease.

 25. If endovascular treatment of their aneurysm requires adjunctive antiplatelet treatment
 26 Subjects with SAH-induced cardiac stunning prior to enrollment, with an ejection
 fraction< 30%