ClinicalTrials.gov
ClinicalTrials.gov Menu

Deferiprone for Ruptured Brain Aneurysm

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03754725
Recruitment Status : Not yet recruiting
First Posted : November 27, 2018
Last Update Posted : November 27, 2018
Sponsor:
Information provided by (Responsible Party):
David Hasan, University of Iowa

Brief Summary:

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") + stadndard 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 assess the level of ferritin (Ft) in CSF (CSF withdrawn from ventriculostomy tube),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

Condition or disease Intervention/treatment Phase
SAH Dementia Drug: Deferiprone pill Drug: placebo Phase 2

Detailed Description:

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 diease. 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Deferiprone Trial for Subarachnoid Hemorrhage (SAH) Patients
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : July 1, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Deferiprone

Arm Intervention/treatment
Experimental: Deferiprone
This is the drug arm (deferiprone). Patients will receive oral deferiprone
Drug: Deferiprone pill
500 mg of deferiprone (oral)

Placebo Comparator: Control
this group will only receive the placebo (sugar pill)
Drug: placebo
patients will receive sugar pills orally




Primary Outcome Measures :
  1. Ferritin levels in cerebrospinal fluid [ Time Frame: Day 10 from enrollment ]
    concentration of ferritin in the cerebrospinal fluid


Secondary Outcome Measures :
  1. change in cognition [ Time Frame: 12 month from enrollment ]
    Score to detect impaired cognition by using Montreal Cognitive Assessment Score (0-30). Lower score means more cognitive impairment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Subjects should be aged 18-70, 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 and less or equal to 70 years
  2. Historical modified Rankin Scale Score (mRS) 0-1 (pre-subarachnoid hemorrhage onset)
  3. World Federation of Neurosurgical Societies SAH Scale (WFNS) 50 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. In subjects where the exact time of the ictus is uncertain, an estimated time of ictus may be assigned and that time will be used for the inclusion criteria above assuming the estimation is deemed to be reasonably reliable [i.e., actual time is highly likely to be within 6 hours of estimated time].
  9. 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) 52
  10. 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.
  11. Ability to obtain MRI for ischemic changes evaluation, measurement of iron deposition and volume of and hippocampus.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03754725


Contacts
Contact: David Hasan, MD 319-384-8669 david-hasna@uiowa.edu

Locations
United States, Iowa
Univesity of Iowa Hospital and Clinics Not yet recruiting
Iowa City, Iowa, United States, 52242
Contact: David Hasan, MD    319-384-8669    david-hasan@uiowa.edu   
Sponsors and Collaborators
David Hasan
Investigators
Principal Investigator: David Hasan, MD University of Iowa

Responsible Party: David Hasan, Principal Investigator, University of Iowa
ClinicalTrials.gov Identifier: NCT03754725     History of Changes
Other Study ID Numbers: Pending IRB
First Posted: November 27, 2018    Key Record Dates
Last Update Posted: November 27, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by David Hasan, University of Iowa:
Deferiprone

Additional relevant MeSH terms:
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Deferiprone
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action