Iron chelation therapy for cognitive deficits after subarachnoid hemorrhage

A Phase 1/2a Exploratory Clinical Trial to Evaluate the Safety of Oral Deferiprone (14 Days) Including Its Effect on Decreasing the Content of Iron in Subjects With Aneurysmal Subarachnoid Hemorrhage (aSAH) sIRB

This study is testing if a medication called Deferiprone can help improve thinking and memory in people who have had a brain bleed from a ruptured aneurysm.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 66 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Duke University (other)
• Locations: 2 sites (Iowa City, Iowa and 1 other locations)
• Trial ID: NCT03754725 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effects of Deferiprone, an oral iron chelator, on cognitive outcomes in patients who have suffered from subarachnoid hemorrhage (SAH) due to ruptured cerebral aneurysms. The study aims to assess the levels of ferritin and iron deposition in the brain and cerebrospinal fluid, which are believed to contribute to cognitive impairments in SAH survivors. Participants will be randomized to receive either Deferiprone plus standard care or standard care alone, with cognitive assessments conducted to evaluate the efficacy of the intervention. The trial seeks to establish a potential therapeutic approach to improve neurocognitive outcomes in this patient population.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 to 75 who have experienced a spontaneous SAH with a modified Rankin Scale score of 0-1 prior to the event.

Not a fit: Patients with severe neurological deficits or those with a WFNS grade greater than 4 may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved cognitive function and quality of life for survivors of subarachnoid hemorrhage.

How similar studies have performed: While iron chelation therapy has shown promise in other contexts, this specific approach for SAH is novel and has not been previously tested.

Eligibility criteria

Inclusion criteria:

1. Age greater than or equal to 18 and less than or equal to 75 years.
2. Historical modified Rankin Scale Score (mRS) 0-1 (pre-subarachnoid hemorrhage onset).
3. World Federation of Neurosurgical Societies SAH Scale (WFNS) grade less than or equal to 4, 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 or lumbar puncture \[LP\]) 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 aneurysmal subarachnoid hemorrhage (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. Less than 72 hours from rupture of aneurysm. In patients 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).
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 than or equal to 4 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.
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 Digital Subtraction Angiography (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, 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 (systemic inflammatory response syndrome \[SIRS\] criteria plus the presence of known or suspected infection) or current documented active bacterial or viral infection prior to enrollment (Example: significant upper respiratory infection (URI), community-acquired pneumonia). A minor non-complicated community-acquired urinary tract infection (UTI) would not be an exclusion but should be treated promptly.
9. New parenchymal hemorrhage or new infarction larger the 15 milliliters 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 than or equal to1.5, severe liver impairment (Aspartate Aminotransferase or Transaminase \[AST\], Alanine Aminotransferase or Transaminase \[ALT\], Alkaline Phosphatase \[AP\] 2 times normal or cirrhosis).
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 or LP.
21. Known hypersensitivity to Deferiprone or to any of the excipients in the formulation.
22. If endovascular treatment of their aneurysm requires adjunctive antiplatelet treatment.

Where this trial is running

Iowa City, Iowa and 1 other locations

• Univesity of Iowa Hospital and Clinics — Iowa City, Iowa, United States (ACTIVE_NOT_RECRUITING)
• Duke University Health System — Durham, North Carolina, United States (RECRUITING)

Study contacts

• Principal investigator: David Hasan, MD — Duke University
• Study coordinator: David Hasan, MD

Conditions: SAH, Dementia, Deferiprone