Vitamin D for Acute Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is the most deadly and debilitating form of stroke. To date, effective treatment that could improve the functional outcome of ICH remains elusive. In ICH, the hematoma causes primary mass effect and neuronal damage, and inflammatory responses and elevated intracranial pressure drive secondary brain injuries. Though hematoma removal may alleviate brain injury, surgical evacuation is not indicated for most ICH patients due to significant complications and lack of functional benefit. An alternative approach is to exploit the endogenous mechanism of hematoma clearance, which provides a druggable target in treating ICH. Given the overwhelming burden of ICH in our aging population, a safe and accessible drug that could improve ICH outcomes is in dire need.

Long prescribed to maintain calcium balance and bone health, Vitamin D (VitD) supplement has also shown beneficial effects in preclinical models of brain diseases, including ischemic stroke and subarachnoid hemorrhage. Recently, we reported that a supraphysiological dose of VitD treatment improved neurobehavioral performance in young and middle-aged mice after ICH. In our study, VitD treatment significantly reduced hematoma volume by 41% on day three compared to the vehicle group while reducing perihematomal edema by 47%. We also demonstrated that VitD increased the macrophage number and elevated levels of CD36 and PPAR-γ in the brain, facilitating hematoma clearance. VitD also accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. This study is the first to address the therapeutic effects of VitD in an animal model after ICH.

Currently, data from clinical trials applying post-ICH VitD treatment and involving hematoma volume as primary outcomes are lacking. Based on the promising findings from our preclinical study, we plan to launch VICToHR trial to investigate whether VitD would confer therapeutic benefits in ICH patients. A supraphysiological VitD dose of 4000 IU/day per oral (PO) will be utilized as it is demonstrated to be safe and well tolerated. In this pilot study, we aim to examine the safety and feasibility of VitD treatment for ICH in human subjects.

VICTHoR trial will have 2 phases. The first phase of the study is a single-arm pilot intervention trial involving the recruitment of 10 patients who will be prescribed high doses of VitD. The aim of this phase is to evaluate the safety of VitD before moving on to the second phase of the trial. The second phase will be an open-label, parallel randomized controlled trial.

Consecutive ICH patients aged ≥ 18 years, admitted to Queen Mary Hospital (QMH), Hong Kong, and who fulfill the inclusion criteria (table 1), will be screened for recruitment. Eligible patients will be screened by experienced stroke neurologists (KCT and GKKL) or neurosurgeon (GKL).

During the first phase, written informed consent will be obtained from all study subjects. Ten consecutive patients recruited into VICToHR will be prescribed VitD. During the second phase, written informed consent will be obtained from all study subjects or next-of-kin. For patients with cognitive impairment who are deemed mentally incompetent, informed consent will be obtained from their next-of-kin (spouse, parent, or child) or legal guardian. Randomization will be according to a computer-generated sequence (https://www.sealedenvelope.com) in a 1:1 ratio to VitD or non-VitD (control) group. In VitD group, Daily 4000 IU of VitD will be given orally or via nasogastric tube for two weeks. Subjects are later maintained on a standard daily dose of 1000 IU of VitD for 24 weeks as the incidence of VitD deficiency is reported to be around 60% in stroke survivors. In control group, Subjects will be managed according to the stroke protocol of Queen Mary Hospital.

Study subjects will have clinical assessments, blood checking, and CT brain scan according to the schedule on Day 3, Day 7, Day 14, Day21 and Week 12, Week 26. Three interval CT scans of the brain will be performed for all patients. CT will be assessed for ICH location, volume, and perihematomal edema.

Inclusion criteria

• Spontaneous ICH diagnosis
• Age ≥ 18 years
• Within 96 hours of ICH
• Premorbid Modified Rankin Scale of ≤2
• Supratentorial ICH
• ICH volume ≥2 mL

Exclusion criteria

• Expected life expectancy of <1 year
• Glasgow Coma Scale <9
• Anticipated surgical evacuation of hematoma
• Inability to participate in follow-up activity
• Hypercalcemia
• Hyperphosphatemia
• History of kidney stones
• Bleeding tendency
• Severe renal impairment
• Severe liver impairment
• Known contraindication or allergy to vitamin D