Clinical trial NCT04088630
Conditions: Intracerebral Hemorrhage Cerebral Edema Stroke Hemorrhagic Intracerebral Hemorrhage, Hypertensive Intracerebral Hemorrhage Intraparenchymal
Keywords: Fingolimod Neurologic Deficits Brain Injury Stroke Intracerebral hemorrhage Neuroimmunomodulation
Sponsor: Wake Forest University Health Sciences
Start date: 2020-08-07; Completion date: 2024-06-05
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the safety and effectiveness of a single dose of fingolimod in patients with primary spontaneous intracerebral hemorrhage (ICH).

Detailed description:
This is a double-blinded, placebo-controlled pilot trial of fingolimod in patients with primary spontaneous intracerebral hemorrhage. Eligible participants will be allocated to study groups using fixed allocation randomization and a computer-based random number-generating allocation. For those patients who meet all inclusion criteria without exclusion criteria subjects will receive oral or nasogastric tube (NGT) or Dobhoff feeding tube administration of fingolimod versus placebo. Participants will be monitored at time of enrollment and days 1, 3 5, 7, and 14 (discharge dependent) by 2 blinded assessors (neuroscience subspecialists) and will receive standard of care for the duration of the study. After discharge from the hospital, participants will enter a follow up phase of 12 months, with clinic visits at 30±14 days, 90±14 days, 180±14 days, and 365±14 days. They will receive a standard of care neuroimaging at these follow up time-points and will be assessed with the pre-selected outcome assessments established by the NINDS Common Data Elements for Stroke.

Arms: arm 1: In addition to Standard of care treatment, those participants randomized to the fingolimod group will receive a single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset. arm 2: In addition to Standard of care treatment, those participants randomized to the control group will receive a single dose placebo pill within 24 hours of symptom onset arm 3: In addition to standard of care treatment,10 subjects who are unable to be administered oral medication will be assigned to the open-label group who will receive a single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset to assess feasibility of administration through NGT or Dobhoff tube.
Interventions: intervention 1: Fingolimod intervention 2: Placebo intervention 3: Open-label Fingolimod
Intervention descriptions: intervention 1: A single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset intervention 2: A single oral placebo pill within 24 hours of symptom onset intervention 3: A single dose of 0.5 mg fingolimod through an NGT or Dobhoff tube within 24 hours of symptom onset

Protocol documents:
Prot_SAP_001.pdf: 
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Study Title: Fingolimod as a Treatment for Cerebral Edema after Intracerebral Hemorrhage 
 
Principal Investigator:  Stacey Q. Wolfe, MD  
Co-Investigators:; Cheryl Bushnell, MD; Pamela W. Duncan, PhD; Aarti Sarwal, MD; Dr. Tim Howard, 
PhD; Dr. Greg Hawkins, PhD; Dr. Carl Langefeld, PhD; Martha Alexander-Miller, PhD; Carol Kittel 
Funding source: Wake Forest School of Medicine CTSI grant 
Study Coordinators: Wendy Jenkins, BSN RN, CCRC; Kim Hawley, BSN RN 
Background/Rationale and Context: 
1.1 Overview 
Spontaneous intracerebral hemorrhage (ICH) is a catastrophic illness representing a global public 
healthcare problem. Unfortunately, there currently exists no specific treatment outside of supportive 
medical care. Of the 15 million strokes reported worldwide per annum, ICH accounts for approximately 
10-15% of all stroke cases in the US, Europe and Australia; and approximately 20-30% of strokes in Asia.1 
This is associated with a 40% 30-day mortality rate2, and those who survive have major neurologic deficits, 
with only around 20% of patients reaching functional independence at 6 months.3 Although there has been 
a significant reduction in overall age-adjusted incidence of stroke, the incidence of ICH has remained 
unchanged in the past 40 years.2 In the US alone, the annual healthcare costs of ICH is estimated at $12.7 
billion.4  
 
Hospitalizations for ICH have increased by 18% in the last decade5, most likely due to the aging population 
and the increasing use of anticoagulants, thrombolytics, and antiplatelet agents. The most important risk 
factor is age. With each advance in decade after the age of 50, there is a 2-fold increase in ICH incidence.6 
ICH due to hypertension (HTN) accounts for approximately 65% of all spontaneous ICH7 and 50-70% of 
patients are hypertensive at the time of hemorrhage.8 ICH in the setting of HTN commonly occurs in the 
deep cerebral locations (basal ganglia, thalamus), followed by cerebral lobes, cerebellum, and brainstem 
(predominantly pons).6 ICH occurring in the setting of cerebral amyloid angiopathy almost always present 
in a lobar location. Other causes of ICH include neoplasms, aneurysms, arteriovenous malformations 
(AVM), cerebral cavernous malformations, arteriovenous fistulae (AVF), and venous thrombosis.7  
 
1.2 Primary Brain Injury 
Primary brain injury from ICH typically occurs within the first few hours of ictus and is due to hematoma 
formation, leading to mechanical damage of the adjacent tissues from dissection and compression.  The 
subsequent brain injury that occurs after an ICH typically involves both grey and white matter.7 
Hemorrhagic volume is an important factor in determining ICH outcome, with hemorrhage volumes > 
100mL associated with poor prognosis.9 The mass of the hemorrhage can increase intracranial pressure, 
leading to further compression of brain structures, which can potentially impact cerebral blood flow and 
lead to brain herniation. Because of the consequences due to mass effect, recent clinical trials have focused 
on examining the effects of early clot removal. New approaches to limit surgical morbidity are underway 
with promising results.10-14 Location of the ICH is important for outcome, and it should be noted that 
guidelines support the evacuation of cerebellar clots as potentially life and function saving, whereas 
thalamic hemorrhage has a notoriously poor outcome despite treatment.15 Although evacuation of the 
hematoma addresses the issue of physical disruption and mass effect, it does not address the sequelae of 
secondary brain injury from the body/tissue response to the hematoma. 
 
 
1.3. Secondary Brain Injury 


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Secondary injury plays a significant role in the neurologic decline of ICH patients.16 This is triggered by 
the presence of intraparenchymal blood, which activates cytotoxic, excitotoxic, oxidative, and 
inflammatory pathways17, and is characterized by the mobilization and activation of inflammatory cells. It 
is believed that the microglia and astrocytes are the earliest of the inflammatory cells to respond to 
extravasated blood.18 The activation of microglia leads to infiltration of various circulating inflammatory 
cells, most notably leukocytes, macrophages, and T-cells. This subsequently leads to the release of 
inflammatory cytokines (e.g. IL-1β, TNF-α, INF-γ) chemokines, free radicals, various adhesion molecules, 
cell surface receptors, and inflammatory enzymes (e.g. iNOS, COX-2, PLA2) coordinated via the 
transcription factor nuclear factor kappa B (NF- κB).19, 20 These chemicals, coupled with cell death products, 
further activate intrinsic and migrating lymphocytes, leading to increased infiltration of lymphocytes and a 
continued cycle of inflammatory response. There is increasing evidence that this inflammatory response 
contributes to the formation of edema around the hematoma, which exacerbates mass effect, augments the 
cell death process through secondary ischemia, and produces further inflammatory insults to the 
surrounding brain tissue.21 This pro-inflammatory state begins immediately and augments breakdown of 
the hematoma, with phagocytosis and increased blood brain barrier permeability.  This gives way to a more 
anti-inflammatory phenotype around day 3 to begin the healing and rebuilding process.  
 
Table 1. Different components of inflammation 
Pro-inflammatory components 
Anti-inflammatory components 
M1 microglia 
M2 microglia  
Th1 cells 
Th2 cells 
Th17 cells 
Treg cells 
IL-1β 
IL-4 
IL-6 
IL-10 
IFN-γ 
TGF-β 
TNF-α 
 
 
1.3a Microglia (Table 2) 
Microglia are the resident macrophages of the central nervous system and play an important role in the 
inflammatory and recovery phases as a result of injury to the CNS. They are vital in the maintenance of the 
overall homeostasis of the CNS, including clearance of pathogens and pathologic neurons, and remodeling 
of the extracellular matrix and synapses.22 They account for approximately 5-20% of the total CNS glial 
population.23 Under normal conditions, microglia reside in their ramified state, performing surveillance of 
the CNS. They contain short and fine processes, allowing for constant monitoring for any potential changes 
to the local brain milieu or pathogen/injury.24 Once activated, they become morphologically 
indistinguishable from the infiltrating macrophages, becoming more amoeboid in shape with stout 
processes to allow for the phagocytosis process.  
 
Microglia/macrophages are activated very early following ICH, occurring as early as 1 hour after ictus. In 
the murine model, once microglia have been activated, IL-1β can be detected as early as 6 hours, and may 
persist up to 24 hours.25 By 72 hours, microglia/macrophages have reached their peak, and by day 7, the 
numbers begin to decrease. By 21 days, the microglia/macrophages have returned to their baseline 
numbers.26 Once tissue damage occurs, microglia can be activated within minutes via neurotoxic substances 
released into the extracellular space by necrotic neurons.27  
 
Based on ischemic injury and TBI models, two microglia phenotypes have been identified.  The M1 
phenotype is considered pro-inflammatory/damage-inducing and is known to produce inflammatory 
cytokines (IL-1β, IL-12, IL-23, and TNF-α), chemokines, nitric oxide (NO), and reactive oxygen species 


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(ROS), which initiates the breakdown process and the opening of the blood brain barrier (BBB).26, 28 The 
M2 phenotype is considered to be anti-inflammatory and is generally involved in phagocytosis, release of 
trophic factors, and the overall regeneration and resolution of inflammation.29 The presence of anti-
inflammatory cytokine IL-4 can prime the polarization to M2 phenotype, leading to the production of IL-
10 and upregulation of M2 specific surface phenotype markers. 29  
 
In the setting of spontaneous ICH, murine models demonstrated the acute increase in M1 microglia within 
6 hours of ictus that decreased over the course of 14 days, whereas the M2 phenotype was noted at day 1 
and increased over the course of 14 days.30, 31 Most models indicate that a M1 to M2 phenotype switch 
occurs within the first 7 days of hemorrhage, but the exact timing and driving force of the phenotype switch 
remain unclear.29 With the various roles they play during CNS development, injury, aging and associated 
neurodegenerative diseases, the microglia are not static and have a great deal of plasticity, allowing 
alterations to either phenotype based on cues from the microenvironment.32, 33 
 
Table 2. Microglia phenotype and functions 
Phenotype 
Molecule 
Type 
Role 
M1 
IFN-γ 
Cytokine 
Pro-inflammatory, induces M1 phenotype 
 
IL-1β, IL-6, IL-
23, TNF-α 
Cytokine 
Pro-inflammatory 
 
IL-12 
Cytokine 
Involved in the differentiation to Th1 cells 
 
IL-17  
Cytokine 
Pro-inflammatory, modulating factor of cytokine 
production 
 
ROS, iNOS 
Metabolic 
enzyme 
Oxidative damage 
 
CD11b, CD16, 
CD32 
Surface 
receptors 
Phagocytosis, chemotaxis 
 
CD68 
Surface receptor 
Scavenger receptor 
 
CD86 
Surface receptor 
Surface receptor, otherwise called B5-2, interacts 
with CD28 
 
MHC-II 
Surface receptor 
Presentation of extracellular proteins 
 
NF-κB 
Transcription 
factor 
Participate in modifying the detrimental M1 
phenotype 
 
STAT1, STAT3 
Transcription 
factor 
Elevate the expression of NF-κB/p65 
M2 
IL-4 
Cytokine 
Anti-inflammatory, induces M2 phenotype 
 
IL-10 
Cytokine 
Anti-inflammatory, human cytokine synthesis 
inhibitory factor 
 
TGF-β 
Cytokine 
Regulation of lymphocyte proliferation, 
differentiation, and survival; regeneration; 
upregulate Bcl-2 and Bcl-x1 
 
YM-1 
Protein 
Binds heparin/heparin sulfate, proposed to prevent 
degradation of extracellular components 
 
Arginase 1(Arg1) 
Protein 
Downregulation of nitric oxide synthesis. Induces 
fibrosis and tissue regeneration 
 
FIZZ1 
Protein 
Associated with reconstruction of extracellular 
matrix 


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CD36 
Surface receptor 
Scavenger receptor, involved in hematoma 
resorption in setting of upregulation of PPAR-γ 
 
CD163 
Surface receptor 
Scavenger receptor for haptoglobin-hemoglobin 
complex 
 
CD206 
Surface receptor 
Antigen internalization and processing/mannose 
receptor type 1 
 
PPAR-γ 
Transcription 
factor 
Induce M2 phenotype 
 
STAT6 
Transcription 
factor 
Inhibit the activation of NF-κB 
 
SOCS3 
Signaling 
modulator 
Cytokine-inducible negative regulators of 
cytokine signaling 
 
1.3b T lymphocytes (Table 3) 
T lymphocyte functions have been well-characterized in ischemic stroke models34, but their role in ICH is 
less defined. Much of the T lymphocyte descriptions in ICH are extrapolations from pre-clinical ischemic 
models. In the healthy brain, there are very low numbers of T cells functioning as CNS surveillance35 and 
appear to enter through the cerebrospinal fluid either through choroid plexus veins or meningeal blood 
vessels to monitor the subarachnoid space, allowing for the ability to initiate a local immune response or 
return to secondary lymphoid organs.36 Following a stroke, immunohistochemistry has identified different 
T cell subtypes invading the infarcted region. It is theorized that T-cells can cross the BBB once a T-cell 
response is activated by a CNS autoantigen without antigen specificity.37 In the stroke model, CD4+ and 
CD8+ T cells have been reported to have a detrimental role in perpetuating ischemic tissue injury by 
contributing to the microvascular dysfunction caused by cerebral ischemia/reperfusion (I/R) injury.38 This 
was confirmed by models of CD4+ or CD8+ deficiencies resulting in decreased stroke volume and improved 
neurologic performance.17, 39 On the other hand, there has been an abundance of evidence that regulatory T 
cells have a neuroprotective effect in stroke and promote recovery via their immunomodulating properties.40, 
41 
It has been reported that there is an increase in CD4+ T helper (Th) cells starting on day 1 and peaking 
around day 3-4 days after a hemorrhagic event.41, 42 Guo et al. confirms the presence of Th cells in the 
perihematomal region in surgical specimens of patients with ICH.43 Another study showed infiltrating 
lymphocytes peaking around day 3. This T cell population was noted to have an equal number of T- and B-
lymphocytes, with a predominance of T-helper cells at that time point.44 Regulatory T (Treg) cells have 
shown a similar pattern in timing, but the peak was sustained up to 7 days after ICH.41 It has also been 
documented in pre-clinical stroke models that the T cells persist as late as 7 weeks post-stroke, but their 
function in this post-acute phase remains unclear.45  
T helper cell differentiation and their role in CNS injury and neuroregeneration have undergone extensive 
research. In the 1980’s, two subtypes of CD4+ T cells were described based on their cytokine secretion 
patterns: Th1 and Th2 cells.35 Th1 cells are programmed to fight intracellular pathogens via cell-mediated 
response. Th1 cell differentiation is initiated by IL-12 and INF-γ, known to perpetuate pro-inflammatory 
reactions. Although the presence of Th1 cells have been confirmed at the site of lesion (ischemic infarct or 
intracerebral hemorrhage), their role in the pathogenesis of secondary brain injury yet remains to be defined. 
A possible mechanism is that these cells may, in part, induce apoptosis of neurons via production of 
inflammatory cytokines. In the case of ischemic stroke, Th1 cells may contribute its pathogenesis by 
accumulating within the microcirculation and impairing perfusion, thereby aggravating the hypoxic strain.37 


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Alternatively, Th2 cells function to fight extracellular pathogens via the humoral response. Their 
differentiation is typically initiated by IL-4 and IL-2, and they secrete IL-4, IL-5, IL-6, IL-9, IL-10, and IL-
13, which are involved in various anti-inflammatory functions. It is presumed that Th2 cells act by 
producing the above cytokines with downregulation, and in some cases, direct suppression of Th1 cells.37 
In an effort to better characterize the subsets and functions of Th1 and Th2 cells in ischemic stroke, a pre-
clinical study found that Th1 deficiency dramatically inhibited infarct size, whereas Th2 deficiency 
worsened infarct size and neurologic outcomes.46 There is further evidence to suggest that inhibiting the 
proliferation of Th1 improves neurologic outcomes, while the inhibition of Th2 worsens brain injury in the 
setting of cerebral ischemia.47  
There is increased infiltration of regulatory T (Treg) cells in the setting of both ischemic infarct and 
intracerebral hemorrhage. These cells are known for their anti-inflammatory function by mediating immune 
tolerance to self-antigens. Treg cells have been shown to decrease ICH-induced inflammatory injury.41 In 
a rat ICH model, Treg transfusion resulted in the inhibition of IL-1β, TNF-α, and MMP-2 in the 
perihematomal tissue and increased presence of anti-inflammatory cytokines IL-4, IL-10, and TGF-β.48 
Treg cells have also been known to decrease perihematomal edema and BBB permeability after ICH, 
leading to improved short-term and long-term neurologic function in the animal model.49  
Table 3. T lymphocyte phenotype and functions 
Phenotype 
Molecule 
Type 
Role 
Th1 
IL-12, TNF-α 
Cytokine 
Activate macrophages and are responsible for cell-
mediated immunity and phagocyte-dependent 
protective responses  
 
T-bet 
Transcription 
factor 
Induce Th1 phenotype, enhances production of 
IFN-γ and mediates repression of IL-4 expression 
 
STAT1 
Transcription 
factor 
Primarily regulates T-bet and mediates IL-4 
repression to mediate Th1 cell commitment 
Th2 
IL-4, IL-5, IL-10, 
IL-13 
Cytokines 
Responsible for strong antibody production, 
eosinophil activation, and inhibition of several 
macrophage functions, providing phagocyte-
independent protective responses 
 
GATA3 
Transcription 
factor 
Key for Th2 cytokine production; inhibition of 
Th1 responses 
 
STAT3 
Transcription 
factor 
Required by STAT6 for interaction with 
appropriate gene loci 
 
STAT5 
Transcription 
factor 
Independent of IL-4 signaling; coordinates with 
GATA3 to induce Th2 phenotype 
 
STAT6 
Transcription 
factor 
Upregulates expression of GATA3 and mediates 
Th2 cell phenotype 
Th17 
IL-17A/F, IL-21, 
IL22, IL-23, TGF-β 
Cytokines 
Creates inflammation and tissue injury in 
autoimmune diseases; unclear of function in ICH 
 
RORγt 
Transcription 
factor 
Master regulator to induce Th17 phenotype via 
STAT3 activation 
 
STAT3 
Transcription 
factor 
Activated by IL-6 and IL-23 to induce expression 
of RORγt 


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Treg 
IL-2, IL-10, TGF-β 
Cytokines 
Essential for the maintenance of peripheral 
tolerance, prevention of autoimmune disease, and 
limiting chronic inflammatory disease 
 
Foxp3 
Transcription 
factor 
Major lineage-specific transcription factor 
involved in Treg differentiation 
 
STAT5 
Transcription 
factor 
Enhances Foxp3 expression to promote Treg 
development 
 
1.4 Sphingosine 1-Phosphate Receptor Modulation 
Fingolimod (FTY720) is an oral immunomodulatory agent approved by the Food and Drug administration 
in 2010 for the treatment of relapsing-remitting multiple sclerosis (MS). It has been shown to reduce the 
number of MS relapses and limits the loss of brain volume via several mechanisms.50-52 FTY720 is a 
functional analogue of phosphorylated sphingosine, a bioactive sphingolipid. In nature, sphingosine is 
phosphorylated by sphingosine kinase 1/2 (Sphk) to sphingosine 1-phosphate (S1P), which then binds to 
G-protein coupled receptors called sphingosine 1-phosphate receptors (S1PRs). There are five known S1PR 
subtypes, S1PR1-5. S1PRs1-3 are broadly expressed in the immune and cardiovascular systems and the CNS. 
S1PR1 is highly expressed on T and B lymphocytes. S1PR4 is generally found in the hematopoietic and 
lymphoid tissues. S1PR5 is predominantly found within the CNS white matter.53 These receptors participate 
in a wide variety of biologic processes, including leukocyte recirculation, cellular proliferation and 
differentiation, morphologic changes, cellular motility, endothelial cell function, vascular regulation, and 
cardiovascular and nervous system development.54 S1P and S1PRs play a key role in the maintenance of 
normal immune function. Once an appropriate activating antigen is encountered in the lymph nodes, naïve 
T cells become activated and enter the circulation to reach the corresponding site of inflammation.  
 
FTY720 is a sphingosine 1-phosphate receptor (S1PR) modulator and functions to regulate various cellular 
responses, including proliferation, apoptosis, and inflammation.53 FTY720 binds with a high affinity to the 
following S1PR subtypes: S1PR1, S1PR3, S1PR4, and S1PR5.53 As noted above, S1PR1 is present on 
lymphocytes to aid in the egress of T cells with the appropriate antigen stimulation. The classic mechanism 
of action of FTY720 is presumed to be hematopoietic. Although structurally similarly to S1P, FTY720 acts 
as a functional antagonist at S1PR1, causing internalization and degradation of this receptor and removing 
the lymphatic S1P gradient necessary for lymphocyte egress. As a result, this inhibits the egress of 
lymphocytes from lymph nodes, thereby reducing the overall number of inflammatory cells migrating to 
the CNS.55   However, based on the high expression of S1PRs in the CNS, a new aspect of FTY720 function 
is emerging, focusing on direct neurologic cellular modulation. FTY720 has been found to easily cross the 
blood-brain barrier in its unphosphorylated form, where it is then phosphorylated by endogenous CNS 
sphingosine kinase 2.53 It is then presumed that FTY720 influences the biology of CNS cells such as 
astrocytes and oligodendrocytes by reducing astrogliosis and demyelination.56  
 
The metabolism and pharmacokinetics of FTY720 have been studied both in animal studies and healthy 
volunteers. It has been found that FTY720 undergoes extensive metabolism, with biotransformation 
occurring mainly through three pathways. The first pathway is the reversible phosphorylation of fingolimod 
phosphate, the active metabolite, predominantly via sphingosine kinase 2, with a lesser contribution by 
sphingosine kinase 1. It is then dephosphorylated by lipid phosphate phosphohydrolases LPP1a and LPP3.57 
The second pathway of metabolism involves hydroxylation and oxidation via the hepatic cytochrome P450 
(CYP) 4F subfamily of enzymes, which produces several inactive carboxylic acid metabolites that are then 
excreted in the urine.58, 59 CYP4 enzymes are primarily known for their role in the metabolism of 
endogenous fatty acids, prostaglandins, and steroids, therefore the low potential for drug-drug 
interactions.58 The third pathway involves the formation of inactive non-polar ceramides.57 In single dose 
studies of both fingolimod and fingolimod phosphate, it has been found that FTY720 has high oral 


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bioavailability, with an absolute oral bioavailability of 93%.60 After oral administration of a single dose, 
blood absolute maximum concentration is reached by 12-16 hours and found to have a long half-life of 6-
9 days that is independent of drug dose.61, 62 Additionally, after oral administration of a single dose of 
fingolimod, there is a decrease in the total lymphocyte count to approximately 60% of baseline within 4-6 
hours of administration and begins to recover within a few days after stopping the drug.60  
 
As mentioned previously, S1PRs are expressed essentially by all neural cell lines in the CNS, and level of 
receptor subtype expression can vary based on the type of cell, and in the case of microglia, based on their 
state of activation.63 In the ramified state, microglia express S1PR1, S1PR2, S1PR3, and S1PR5, with S1PR1 
expression being the dominant receptor type.53 It has been found that S1P and its subsequent pathway is 
essential in key neuron specific functions such as the regulation of transmitter release and the proliferation 
and survival of neurons and glia.64 It has been reported that sphingosine kinase 1 plays a critical part in the 
inflammatory processes mediated by TNF-α in immune cells.65 In vitro, once microglia have been activated, 
S1P has been noted to amplify the release of pro-inflammatory cytokines, and with the suppression of 
Sphk1, there was suppression of TNF-α, IL-1β, and iNOS gene expression.66 This was confirmed in vitro 
with the binding of S1PRs with FTY720, which downregulated the production of pro-inflammatory 
cytokines and promoted the increased expression and release of neurotrophic factors. The effect on gene 
expression was also shown to be dose-dependent.67, 68 In addition to gene expression regulation of 
inflammatory and chemoattractant molecules, functional antagonism of the S1PRs with FTY720 may also 
limit the inflammatory response of activated microglia by affecting the polarization of microglia. In 
ischemic white matter damage murine models, treatment with FTY720 enhanced the protein expression 
and phosphorylation level of STAT3, polarizing microglia to the M2 phenotype, which suggests that S1P 
could be involved in the activation of the JNK/STAT3 cascade that is typically associated with M2 
polarization.69 Alternatively, gene expression profiling has been performed to better understand the 
molecular effects of FTY720. It has been found that FTY720 inhibited the expression of important 
transcription factors, most importantly STAT1, thereby suppressing the activation of microglia (M1 
phenotype).70 The effect of FTY720 on microglial activation was confirmed in vivo on MS patients, where 
serial PET imaging was performed, showing decreased microglial activation at the sites of focal 
inflammatory lesions.71  
 
Based on literature showing FTY720 and its protective effects from ischemia-reperfusion injury in heart, 
liver, and kidney72, 73, several groups hypothesized the potential neuroprotective effect of FTY720 in the 
setting of cerebral ischemia. FTY720 showed a neuroprotective effect after middle cerebral artery occlusion 
in the rat model with significantly diminished infarct volume and improved overall neurologic scores at 24 
and 72 hours74 and fewer activated neutrophils and microglia/macrophages.75 Based on this pre-clinical 
evidence, a small human pilot study was recently performed to evaluate the efficacy and safety of FTY720 
in the treatment of acute ischemic stroke. Their clinical results mirrored the results seen in animal models, 
with reduced infarct size and improved clinical outcomes.76  
 
Beyond ischemic modulation, FTY720 has also been shown to potentially reduce the incidence of 
reperfusion hemorrhage in the setting of delayed tPA administration via enhancement of the BBB 
integrity.77 In light of this evidence, Lu et al studied the effects of FTY720 in the setting of ICH in the rat 
model. It was found that FTY720 significantly reduced perihematomal edema (PHE), apoptosis, and 
associated brain atrophy, but they did not find a difference in the number of inflammatory cells between 
the treated and control groups.78 However, Rolland et al compared single dosing to 3-day dosing and found 
significant reduction in hematogenous and intracerebral lymphocytes compared to control rats for both 
dosing regimens.79 They also found decreased expression of intercellular adhesion molecule-1 (ICAM-1), 
interferon-γ (INF-γ), and interleukin-17 (IL-17) at 72 hours. At 8 and 10 weeks post-ICH, treated rats were 
noted to have significantly reduced spatial and motor learning deficits, brain atrophy, and neuronal cell 


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loss.79 Given the multiple subtypes of S1PRs that are present in the CNS and the multiple target receptors 
of FTY720, efforts have been made to elucidate specific receptors associated with the improved clinical 
outcomes after FTY720 administration. In experimental ICH models, a selective S1PR1 immunomodulator 
was used as a treatment paradigm. In the presence of the S1PR1 immunomodulation, there was significant 
attenuation of neurologic deficits and improved post-ICH survival. Overall lesion volume was reduced. 
There was decreased edema and midline shift noted on MRI, most likely due to the exhibited reduced counts 
of microglia and T cells with associated decreased production of pro-inflammatory cytokines IL-1β and 
TNF-α.80 
 
A small clinical pilot study of 3-day dosing of fingolimod in ICH patients also exhibited radiographic 
evidence of smaller perihematomal edema, significant reduction in neurologic impairment and 
improvement in GCS by day 7. At 3 months, 63% of fingolimod-treated patients achieved full neurologic 
recovery compared to 0% in the control group. There were no differences in adverse event rates between 
the treated and control groups.81  
 
1.5 Data Sharing 
As a member of the International Stroke Genetic Consortium, Wake Forest collaborates to identify medical, 
environmental and genetic risk factors and causes of stroke to better care for our patients. 
The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study originally recruited over 3000 
cases of spontaneous hemorrhage with equal power among white, black and Hispanic cases. ERICH-Gene 
will combine additional ICH cases from around the world to maximize the power of our study to identify 
novel genetic variants across ethnicities. The new goal is to perform centralized genotyping of 5,200 new 
ICH cases under the ERICH-Gene Study with case harmonization of advanced clinical and neuroimaging 
phenotypes.  These data will be de-identified prior to sharing in accordance with NIH dbGap broad data 
sharing regulations.  De-identified data may be shared for future studies according to NIH road data sharing 
requirements. 
Given the devastating nature of ICH and the data provided, a randomized double blinded, placebo-
controlled pilot trial of fingolimod plus best standard of care management versus placebo plus best standard 
of care management in the treatment of ICH is justified. First, given the long half-life of fingolimod, this 
study will assess the safety of single dosing of fingolimod to be given to critically ill patients, considering 
that a large portion of patients with ICH requires a prolonged ICU stay (the rate of nosocomial infections 
in the ICH patient population is approximately 23.1%82, and the incidence of clinically significant 
bradycardia after the first dose has been reported in 0.5%60).  Secondly, we will explore the use of T and B 
cell subsets as biomarkers of drug effect in this critically ill patient population. And finally, we will be 
evaluating for any differences in clinical outcomes during an extended 365 day period and perihematomal 
edema on radiographic imaging.   
Objectives: 
Specific Aim #1: Assess the safety of a single dose of fingolimod in patients who present with ICH. 
 
Hypothesis #1: We hypothesize that there will be no difference in adverse events compared with placebo, 
as defined by a) drug-related adverse events; b) nosocomial infections; and c) neurologic decline.   
 
Specific Aim #2: Evaluate the use of CD4+ T, CD8+ T, and CD19+ B cells as biomarkers of drug effect 
in a critically ill ICH population.  
 
Hypothesis#1: We hypothesize that similar to the effect in multiple sclerosis patients, there will be a 
decrease in inflammatory cells within 24 hours of drug administration, which will persist over 30 days, as 


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measured by the following biomarkers: CBC with differential and flow cytometry to measure levels of 
CD4+ T cells, CD8+ T cells, and CD19+ B cells.  
 
Specific Aim #3: Evaluate for differences in clinical outcomes, including a) mortality and disability at 90 
and 180 days, and b) perihematomal edema on standard of care radiographic imaging.  
 
Hypothesis#1: We hypothesize that clinical improvement, as measured by mortality and global disability 
measures established by the NINDS Common Data Elements for Stroke, will be more evident at 180 days 
than at 90 days, and outcomes will be no worse compared with placebo.  
Hypothesis#2: We hypothesize that the biomarker levels of inflammatory cells will correlate with 
volumetric measurements of perihematomal edema calculated on standard of care neuroimaging modalities 
(MRI and CT).  
 
Specific Aim #4: Perform multi-omics characterization regarding the immune response related to ICH.  We 
will collect and store DNA from peripheral whole blood at all assessment time points, with additional 
samples from CSF, if applicable. Stored blood and CSF samples will be used for DNA methylation and 
metabolomics evaluated with mass spectrometry. 
 
Methods and Measures: 
Study Design: We propose a randomized, double-blinded, placebo-controlled pilot trial of 
fingolimod in patients with primary spontaneous intracerebral hemorrhage. Eligible participants will be 
allocated to study groups using fixed allocation randomization and a computer-based random number-
generating allocation. Allocation will be equal. For those patients who meet all inclusion criteria without 
exclusion criteria subjects will receive oral or nasogastric tube (NGT) or Dobhoff feeding tube 
administration of fingolimod versus placebo. Participants will be monitored at time of enrollment and days 
1, 3 5, 7, and 14 (discharge dependent) by 2 blinded assessors (neuroscience subspecialists) and will receive 
standard of care for the duration of the study. After discharge from the hospital, participants will enter a 
follow up phase of 12 months, with clinic visits at 30±14 days, 90±14 days, 180±14 days, and 365±14 days.  
They will receive a standard of care Neuroimaging at at these follow up time-points day visit and will be 
assessed with the pre-selected outcome assessments established by the NINDS Common Data Elements for 
Stroke. 
 
Laboratory studies: We will perform standard of care CBC with differential and flow cytometry 
to follow numbers of T helper cells, cytotoxic T cells, B cells, and macrophages in peripheral blood to 
assess the viability of these levels as a biomarker of drug effect.  
Cells isolated from the peripheral blood or CSF will be incubated with a panel of antibodies to 
identify the following immune populations: CD4+ T cells: CD4+CD3+ and Tbet (Th1), GATA-3 (Th2), 
ROR T (Th17) FoxP3 (Treg); CD8+ T cells: CD8+CD3+T-bet; CD19+ B cells; M1:CD68+CD163-
CD80+CD64+; M2:CD68+CD163+CD206+TGM2+ 
Additional markers of activation/differentiation tested include P2Y12, S1PR1, S1PR5, PD-1. Cells 
will be washed and analyzed using the BD Fortessa flow cytometric analysis instrument. In some cases, 
populations will be isolated for further analysis by fluorescence-based cell sorting. 
With the use of commercially available assays, quantification of the top 5-10 cytokines that are 
present in the peripheral blood will also be performed.   


Page 10 of 27 
 
Version 2.0, 5.01.2023 
 
We will store all CSF and blood samples to perform future Next-Gen multi-omic analysis of all 
CSF and blood samples including: mRNA-seq, SPLiT-seq, antibody fluorescent, DNA methylation, and 
mass spectroscopy. Future laboratory study procedures as detailed below.  
Blood for RNA analysis will be collected in PAXgene Blood RNA tubes (Qiagen, Inc.) before 
shipping to Wake University. This method requires that a “discard” tube of blood be drawn prior to the 
PAXgene tube, and we will use this tube to perform a CBC (with differentials) that will be used for analysis 
(see below). RNA will be isolated using the PAXgene 96 Blood RNA Kit (Qiagen, Inc.), which is a 96-
well plate-based system for increased efficiency and quality control. RNA concentration, purity and 
integrity of the purified RNA will be assessed using a 2100 Bioanalyzer (Agilent). Samples with an RNA 
integrity number (RIN) <8 will be excluded from analyses. RNA-seq will be performed in the Cancer 
Genomics Core, where Dr. Hawkins (Co-Investigator) is Co-Director. RNA-seq libraries will be 
constructed using the Illumina TruSeq Stranded Total RNA kit with Ribo-Zero. This kit allows total RNA 
(100 ng – 1 ug per sample) to be analyzed after undergoing ribosomal RNA depletion. Only RNA samples 
with RIN > 8.0 will be utilized for highest quality sequencing.  The indexed libraries will be sequenced 
using an Illumina NextSeq 500 platform (high throughput mode) using 1x75 single end (SE) reads. The 
NextSeq 500 has a flexible throughput platform and we have the option of running paired-end (PE) 
sequencing and performing read lengths up to 150 bp (SE) or 150x150 (PE).  Pooling 8-10 libraries per 
flow cell and assuming >80% >Q30 reads, we should be able to generate 30-40 million reads per sample in 
12 hours. This sequencing depth is standard for analysis of differential gene expression.  
DNA will be isolated from the blood and CSF using standard protocols currently performed in Dr. 
Timothy Howard’s laboratory. DNA will be bisulfite-converted using the EZ DNA Methylation Gold kit 
(Zymo, Irvine, CA), as performed routinely in our laboratory.  This kit is designed to work with a wide 
range of DNA amounts, ranging from 500 pg to 2 µg of DNA. Bisulfite treatment of DNA converts all non-
methylated cytosines in the genomic DNA to uracil, whereas methylated cytosines remain unchanged.  To 
determine the proportion of DNA methylation at each site, we will use the Infinium MethylationEPIC 
BeadChip (Illumina, Inc.), which targets approximately 850,000 CpG sites at single-nucleotide resolution, 
and the HiScan Reader (Illumina, Inc.).  This microarray assays CpG sites from RefSeq genes, including 
the promoter, 5' UTR, first exon, gene body, and 3' UTR.  The proportion of methylation for each site is 
based on the ratio of the fluorescence intensity of the methylated versus the combined methylated and 
unmethylated probes (referred to as the beta value), and will be determined with GenomeStudio (Illumina, 
Inc.). A ratio value of 0 equals no methylation of the locus and a ratio of 1 equals total (100%) methylation. 
Setting: The study will occur at Wake Forest Baptist Medical Center during the patient’s 
hospitalization 
through 
admission, 
operation, 
Neurosciences 
Intensive 
Care 
Unit 
stay, 
Neurology/Neurosurgery floor stay, and outpatient follow up in the neurosurgical clinic. The duration of 
the study for each participant will be approximately 12 months.  
  
Subjects selection criteria: 
All adult patients ages 18-80 who present to Wake Forest Baptist Medical Center with the diagnosis of 
spontaneous intracerebral hemorrhage. 
 
• 
Inclusion Criteria 
o Has given written informed consent to participate in the study in accordance with required 
regulations; if a participant is not capable of providing informed consent, written consent 
must be obtained from the participant’s legally authorized representative (LAR). When the 
LAR is not available for consent, Docusign for econsent may be obtained. 


Page 11 of 27 
 
Version 2.0, 5.01.2023 
 
o Stated willingness to comply with all study procedures and availability for the duration of 
the study.  
o Men and non-pregnant women ages 18-80 years old 
o Has a confirmed diagnosis of spontaneous supratentorial ICH. The presence of cerebellar 
ICH is exclusionary. Presence of hydrocephalus due to mass effect and cerebral edema is 
not exclusionary. If the patient has hydrocephalus requiring CSF drainage, an external 
ventricular drain will be placed as standard of care and will not be exclusionary.  
o Symptoms less than 24 hours prior to enrollment if all eligibility criteria are met. An 
unknown time of onset is exclusionary. Use the time the patient was last known to be well 
for patients that awaken from sleep with symptoms.  
o Has a GCS score ≥ 5 on presentation.   
o Has a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 on presentation.  
o Maintenance of SBP < 200 mmHg at the time of enrollment and randomization. 
o Historical Modified Rankin Scale score of 0-2.  
 
 
• 
Exclusion Criteria 
o Men or women < 18 years old 
o Incarcerated patients 
o ICH known as a result of trauma. 
o Primary intraventricular hemorrhage without significant intraparenchymal component. 
o Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, Moyamoya 
disease, hemorrhagic conversion of an ischemic infarct, recurrence of recent (< 1 year) 
hemorrhage, neoplasms diagnosed with radiographic imaging.  
o Patients with unstable mass or evolving intracranial compartment syndrome. 
o Brainstem hemorrhage or irreversible impaired brain stem function (bilateral fixed, dilated 
pupils and extensor motor posturing), GCS ≤ 4.  
o Platelet count < 100,000; INR > 1.4.  
o Any irreversible coagulopathy or known clotting disorder.  
o . 
o Known history of Mobitz Type II second-degree or third-degree atrioventricular (AV) 
block or sick sinus syndrome. 
o Admission within the past 6 months for the following: myocardial infarction, unstable 
angina, stroke, decompensated heart failure requiring hospitalization, or Class III/IV heart 
failure.  
o Baseline QTc interval ≥500 ms. 
o Current treatment with Class Ia or Class III anti-arrhythmic drugs. 
o Implanted cardiac devices that are not compatible with the desired MRI sequences needed 
for the study (non-contrast T1, T2, SWI/GRE, and FLAIR sequences). 
o Abnormal liver function or liver failure. 
o Active acute infection that is deemed by the Principal Investigator to be clinically 
significant.  
o Chronic viral or fungal infection. 
o Active use of antineoplastic, immunosuppressive, or immunomodulating therapies. 
o Leukopenia with a WBC < 2.0 x 109/L. 
o Not expected to survive to the 365 day visit due to co-morbidities or is DNR/DNI status 
prior to randomization.  
o Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements.  


Page 12 of 27 
 
Version 2.0, 5.01.2023 
 
o Concomitant enrollment in another interventional study. 
o Inability or unwillingness of participant or legal guardian/representative to give written 
informed consent.  
 
• 
Sample Size 
o Because this is a pilot study to assess the safety and feasibility of single dosing of an 
immunomodulator in a critically ill population, we estimate that a sample size of 30 total 
subjects, is sufficient to provide safety data that will help inform feasibility and elements 
of design for a future trial. We will include 10 patients to be enrolled in an open-label arm 
to assess the feasibility of administering fingolimod through an NGT or Dobhoff tube. 
Once this is determined to be without complication and drug delivery via the NGT or 
Dobhoff tube is not inhibited, we will include subjects with NGT or Dobhoff tube in the 
randomized portion of the sample. 
o  
Interventions and Interactions: 
I. For all patients presenting with symptoms of stroke, including arm/leg weakness, speech difficulties, 
altered mental status or vision changes: 
• 
Medical history: 
o Obtained at time of admission to include last known well time 
o Should be focused on inclusion/exclusion criteria, as noted previously 
o Review of medications for documentation of any active use of antineoplastic, 
immunosuppressive, or immunomodulating agents 
o Documentation of historical Modified Rankin Scale for inclusion/exclusion criteria 
o Intracerebral hemorrhage score (ICH) will be calculated at this time to document the 
severity of the disease.  
 
• 
NIHSS 
o Obtained at time of admission 
o Code stroke, including formal neurology consult 
 
• 
Vital signs: 
o Obtained at time of admission, important for inclusion/exclusion criteria 
 
• 
Physical exam: 
o Obtained at time of admission 
o Documentation of initial GCS score at time of admission for inclusion/exclusion criteria 
 
• 
EKG: 
o Obtained at time of admission as part of standard of care and important for exclusion 
criteria 
 
• 
Blood samples: 
o Obtained at time of admission for standard of care baseline set of admission labs, to include 
CBC with differential with a baseline lymphocyte subset analysis, basic metabolic panel, 
liver function panel (LFTs) to rule out underlying hepatic dysfunction, and coagulation 
panel to rule out underlying coagulopathy.  
o If they meet all eligibility criteria, prior to the administration of study drug, 5 cc of blood 
will be set aside in storage for future multi-omic analysis.  
 


Page 13 of 27 
 
Version 2.0, 5.01.2023 
 
• 
Pregnancy test: 
o For women of child-bearing age, obtained at time of admission as part of standard of care.  
 
• 
Urinalysis: 
o As part of admission standard of care to rule out UTI as cause of alterations in mental status. 
 
• 
Neuro imaging:  Most appropriate clinically indicated standard of care 
o CT scan of the head to evaluate for ischemic infarct or intracerebral hemorrhage 
o CT angiogram of the head and neck to be obtained as part of standard of care work up to 
exclude vascular etiologies of hemorrhage. If a CTA is contraindicated due to renal 
impairment, an MRA will be performed instead. 
o MRI of the brain to be obtained as part of standard of care work up to exclude neoplasms 
or cavernous malformations as etiology of hemorrhage.  
 
• 
Speech and swallow evaluation to assess for any dysphagia, important for exclusion criteria. This 
procedure occurs as part of standard of care. A bedside swallow evaluation is appropriate.  
 
II. For participants who meet the inclusion criteria, without exclusion criteria, and are enrolled in the study: 
• 
Each participant is to be admitted to the Neuroscience Intensive Care Unit for standard of care close 
neurologic monitoring, vital signs as part of standard of care, intracranial pressure and drain output 
monitoring if an EVD is in place.  
• 
Those participants randomized to the fingolimod plus best standard of care group will receive a 
single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset. Those participants 
randomized to the control group will receive a single dose placebo pill within 24 hours of symptom 
onset that will appear, smell, and taste identical to the fingolimod capsule.  
• 
For participants who are eligible for the open-label arm, they will receive a single dose of 0.5 mg 
fingolimod through an NGT or Dobhoff tube within 24 hours of symptom onset.  
• 
For participants with evidence of clinical or radiographic hydrocephalus, they will undergo 
standard of care placement of an external ventricular drain (EVD). Unless it is emergent and needs 
to be placed in the emergency room as a life-saving procedure, each participant will be admitted to 
the Neuroscience Intensive Care Unit for expeditious placement of the EVD. Once the head is 
secured to the bed, the hair on the right side of the head will be clipped. Kocher’s point will be 
identified, and incision will be marked with a skin marker. The area will be prepped sterilely with 
Chloroprep. The procedure is then completed in the usual sterile manner for twist drill burr hole 
placement and the placement of the EVD. This will then be tunneled subcutaneously under the 
scalp away from the incision and secured. At this time, 5 cc of CSF will be collected and saved for 
future multi-omic analysis. 
• 
All participants enrolled are to be placed on telemetry to monitor for any cardiac events.   
• 
Each participant will receive neurologic assessments by 2 blinded neuroscience subspecialists on 
Day 1, 3, 5, 7, and 14 (discharge dependent).   
• 
Each participant will have their vitals performed and collected as part of standard of care. Vitals 
will be specifically recorded at the time of their neurologic assessment by the blinded assessors.  
• 
Each participant will be getting daily standard of care blood draws, approximately 10 cc worth of 
blood, until time of discharge. The standard of care studies will include CBC with differential, basic 
metabolic panel (BMP), and LFTs. On Day 1, 3, 5-7 (discharge dependent), these standard of care 
blood draws will include 5 cc of blood that will be collected for lymphocyte subset analysis for 
research purposes for biomarker testing. Drug response will be assessed by lymphocyte subset 
levels. Additionally, 10 cc of blood will also be drawn at the 30 day visit for standard of care studies 


Page 14 of 27 
 
Version 2.0, 5.01.2023 
 
(CBC with differential and lymphocyte subset analysis, BMP), in addition to 5 cc set aside in 
storage for future multi-omic analysis. However, there will be no blood draws if the participant is 
experiencing severe anemia. 
• 
If an EVD is present, the drain output will be collected daily as part of standard of care. On Day 1, 
3, 5, 7, 10, and 14 after placement, 5 cc at each time point will be collected and 4 cc to be sent off 
for standard of care infectious surveillance and 1 cc to be saved for future multi-omic analysis. The 
EVD will be removed in a standard fashion based on the clinical and radiographic determination 
that the participant no longer has hydrocephalus. If a patient undergoes EVD removal if clinically 
indicated prior to the Day 10 or 14 collection time points, they will not undergo these final CSF 
draws.   
• 
Each participant will undergo a standard of care Neuroimaging of the brain 24 hrs and 5-7 days, 90 
days, 180 days and 365 days after drug administration to assess the stability and resolution of the 
hemorrhage, follow the perihematomal edema, evaluate for evidence of hydrocephalus, and the 
development of subsequent brain atrophy that occurs after ICH. There will be a standard of care 
Neuroimaging on day 14 if the participant is still hospitalized or clinically indicated.  
• 
72 hours after admission, each participant will undergo a standard of care non-contrast 
Neuroimaging of the brain to assess the extent of perihematomal edema after drug administration. 
There will also be a standard of care Neuroimaging at the 30 day follow up to follow the resolution 
of hematoma and perihematomal edema. All radiographic data will be used to calculate volumetric 
measurements via RAPID protocol to measure hematoma and perihematomal edema volume.   
• 
Each participant will undergo standard of care speech, cognitive, physical, and occupational 
therapy to be initiated upon admission. At time of discharge, post-ICH reference outcome measures 
established by the NINDS Common Data Elements for Stroke are to be performed and recorded. 
These will include interviewer-administered modified Rankin Scale (mRS), patient-reported 
PROMIS 10, Montreal Cognitive Assessment (MoCA), and the Western Aphasia Battery-Revised. 
These outcome measures will assess for various aspects of recovery, including physical, emotional, 
and neurocognitive. These clinical assessments will also be performed and recorded at the time of 
discharge, and at the 30, 90, 180, and 365 day visits. We will also be collecting each participant’s 
disposition at time of discharge, 30, 90, 180, and 365 days.  
 
III. Adverse events: 
• 
All adverse events to be monitored from admission until day of discharge and at all follow up visits. 
These will include a) clinically significant cardiac events, b) nosocomial infections, and c) 
neurologic decline.  
o Clinically significant cardiac events: All subjects will be placed on telemetry for 72 hours 
after administration of drug and changes in heart rate or rhythm will be recorded. Maximal 
decrease in heart rate occurs within 6 hours of drug administration and recovers, with only 
0.5% of patients experiencing clinically symptomatic bradycardia.60 
o Nosocomial infections: All UTI, sepsis, and pneumonia events will be recorded and 
compared to published ICH nosocomial infection rates (23%).82 
o Neurologic decline: Throughout hospitalization, all subjects will be monitored for 
neurologic decline, which has been reported to occur in up to 33% of patients within the 
first 48-72 hours.83 Each subject will be assigned a GCS score and NIHSS score at time of 
enrollment, Day 1, 3, 5, 7, and 14 (discharge dependent). As per ischemia stroke criteria, a 
change ≥ 4 in the NIHSS will be considered a neurologic change and will be followed over 
time.  
o Additionally, during hospitalization and at all follow up visits, we will monitor for all drug 
related and other adverse events, not limited to hepatic function, in-hospital mortality, 30-
day mortality, 90-day mortality, and all-cause mortality.  


Page 15 of 27 
 
Version 2.0, 5.01.2023 
 
 
IV. Outpatient follow-up: 
Follow-Up Visit 1 (30 ± 14 days after admission) 
Standard of care in-person follow up visit to assess neurologic status and functional recovery based on the 
outcome measures above. At this time, a standard of care Neuroimaging of the brain will be done to follow 
the resolution of perihematomal edema and to assess for delayed hydrocephalus. 10 cc of blood will also 
be drawn for standard of care studies (CBC with differential and lymphocyte subset analysis, CMP), in 
addition to 5 cc set aside in storage for future multi-omic analysis. Any potential long-term drug adverse 
effects are to be followed at this time.  
 
Follow-Up Visit 2 (90 ± 14 days after admission) 
Standard of care in-person follow up visit to assess neurologic status and functional recovery based on the 
outcome measures above. At this time, there will be a standard of care Neuroimaging of the brain to follow 
the resolution of both the hematoma and perihematomal edema. Any potential long-term drug adverse 
effects will be followed at this time.  
 
Follow-Up Visit 3 (180 ± 14 days after admission)  
In-person follow up visit to assess neurologic status and functional recovery based on the outcome measures 
above. Any potential long-term drug adverse effects will be followed at this time.  At this time, there will 
be a Neuroimaging of the brain to follow the resolution of both the hematoma and perihematomal edema. 
Any potential long-term drug adverse effects will be followed at this time 
 
Follow-Up Visit 4 (365 ± 14 days after admission) 
In-person follow up visit to assess neurologic status and functional recovery based on the outcome measures 
above. Standard of care Neuroimaging will be performed to assess brain injury and atrophy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
24 
hrs 
post
-
72 
hrs 
post -
ictus 
5-7 days 
10-
14 
days 
Discharge 
30±1
4 
days 
90±14 
days 
180±14 
days 
365±1
4 days 


Page 16 of 27 
 
Version 2.0, 5.01.2023 
 
ictus 
+ 
Neuroimaging 
Diagnostic 
CT,CTA,MRA 
or MRI 
X 
X 
X 
X 
X‡ 
 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
ICH score 
X 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
Speech and 
swallow 
evaluation 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Single drug dose 
(fingolimod or 
placebo) 
X 
 
 
 
 
 
 
 
 
 
CSF* 
X* 
X* 
X* 
X* 
X* 
 
 
 
 
 
Peripheral whole 
blood (CBC, 
CMP, lymphocyte 
subsets) 
 
X 
 
X 
 
X 
 
X 
 
X‡ 
 
 
X 
 
 
 
 
 
Telemetry 
X 
X 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Neuro exam 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
NIHSS 
X 
X 
X 
X† 
X† 
X 
X 
X 
X 
X 
mRS 
Historic 
 
 
X† 
X† 
X 
X 
X 
X 
X 
PROMIS 10 
 
 
 
X† 
X† 
X 
X 
X 
X 
X 
MoCA 
 
 
 
X† 
X† 
X 
X 
X 
X 
X 
WAB-R 
 
 
 
X† 
X† 
X 
X 
X 
X 
X 
* If the participant requires EVD placement.  
†Or at time of discharge 
‡ If still hospitalized or clinically indicated 
+ At least 6 hours after medication given 
 
 
 
 
 
 
 
 
 
 
 
 
Outcome Measures: 
Primary outcome measure: 


Page 17 of 27 
 
Version 2.0, 5.01.2023 
 
• 
Safety of a single-dose administration of fingolimod to critically ill patients. We will be assessing 
rates of the following adverse events: 
o Clinically significant cardiac events at 30 days  
o Nosocomial infections (UTI, sepsis, and pneumonia) at 90 days  
o Neurologic decline, considered a change ≥ 4 points of the NIHSS at 30 days 
 
Secondary outcome measures: 
• 
Feasibility of administering fingolimod through an NGT or Dobhoff tube.  
• 
Changes seen in the lymphocyte subpopulations at 30 days. The lymphocyte subsets of CD4+ T, 
CD8+ T, and CD19+ B cells will be compared among the three groups and the trends will be 
followed over time in all participants.  
• 
All radiographic imaging performed (CT and MRI) will undergo volumetric measurement 
calculations of hematoma and perihematomal volumes via RAPID protocol. These volumes will be 
correlated with biomarker levels of inflammatory cells and clinical outcome assessments. 
• 
NIHSS at 365 days post-ictus. 
• 
Interviewer-administered modified Rankin Scale score at 365 days post-ictus. 
• 
Patient-Reported Outcomes Measurement Information System 10 at 365 days (patient report of 
physical and neurobehavioral function). As referenced in the ICF, all these outcomes measures will 
be done in the context of a standard of care visit. If any participant endorses symptoms consistent 
with depression or are at risk of causing harm to self and others, we will follow the institutional 
policy regarding making the appropriate referral to their primary physician to address these 
concerns or appropriate psychiatric referral.  
• 
Montreal Cognitive Assessment (MoCA) at 365 days post-ictus.  
• 
Western Aphasia Battery – Revised (WAB-R) at 365 days post-ictus. 
• 
Mortality at 30 days 
• 
Mortality at 90 days 
• 
All cause mortality within the study period 
• 
Patient disposition: number of home days over 365 days 
• 
Multi-omic analysis of inflammatory phenotypes related to ICH 
 
Analytical Plan: 
Randomization: 
Randomization of the study participants should occur after the participant has undergone eligibility 
screening and has been consented if all criteria have been met. Consented participants will be allocated to 
study groups using fixed allocation randomization and a computer-based random number-generating 
allocation. Allocation will be equal. The study pharmacist will be the only unblinded member of the study 
and will provide the appropriate study agent based on the statistician’s randomization schema. Enrollment 
into the open-label arm of fingolimod will not be randomized.   
 
Statistical Analysis: 
• 
Aim 1. Safety of a single dose of fingolimod in ICH patients. The purpose of the primary analyses 
will be to measure safety and feasibility of the intervention (rates of drug-related adverse events, 
nosocomial infections, and neurologic decline), and to measure these in the comparison group to 
help inform feasibility and elements of design for a future trial. In general, we will estimate 
composite outcome rates (95% CIs) in our study groups, for example of UTI, sepsis, and hospital-
acquired pneumonia events, and we will compare these rates to historical rates, when available. 
This will help ensure the rates of adverse events are not elevated, and are comparable or lower than 
those in previous reports. Baseline demographic and clinical characteristics will be described and 


Page 18 of 27 
 
Version 2.0, 5.01.2023 
 
compared between medical management groups, and differences may be used to help explain 
heterogeneity in the safety outcomes.  
• 
Aim 2. Evaluate CD4+ T, CD8+ T, and CD19+ B cells as biomarkers of drug effect in a 
critically ill ICH population. To provide initial assessments of ‘clinical activity,” we will compare 
inflammation-related biomarkers between the fingolimod and placebo groups over time. In general, 
we will calculate individual-level changes in the biomarkers from baseline to the later biomarker 
collections. For example, changes in CD4+ and CD8+ T cells and CD19+ B cells at 24 hr, 72 hr, 
5-7 days, and 30 days will be useful to evaluate if levels of inflammation are lower with fingolimod. 
Prior to analysis, summary statistics and graphic approaches will be used to examine data 
distributions, both overall, and by study group. Changes will then be compared between the groups 
using the two-sample t test or Wilcoxon rank sum test and alpha level = 0.05 (two-sided). These 
initial assessments will be interpreted cautiously, given the small sample sizes and possible missing 
data.  
• 
Aim 3. Evaluate differences in mortality and disability between placebo and treatment groups. 
Analyses will provide 1) initial percentages of patients who benefit from intervention, specifically 
focusing on clinical improvements as measured by items from the NINDS Common Data Elements 
for Stroke, and will provide 2) estimates of variability and correlations in our sample over time. 
Additional analyses will explore correlations between biomarkers, or their changes over time, 
including with the perihematomal edema volume. Though the sample sizes in this pilot trial are 
quite small, these outcome measures have been used extensively in other studies, and our estimates 
will be helpful to assess comparability in this context, thus informing sample size calculations for 
a future trial.  
• 
Aim 4. Perform future multi-omics characterization regarding the immune response related 
to ICH. RNAseq Data Analysis: Alignment of reads will be performed using the STAR sequence 
aligner,84 and gene counts determined using feature Counts software.85 Differential gene expression 
(DEG) will be analyzed using DESeq2 software.86 All experimental conditions will be prepared in 
the same experiment, so that the paired-sample analysis can be calculated to detect DEGs at each 
time point using DESeq2 as described.87 Although the primary purpose is to estimate parameters 
for subsequent power analysis, current analysis will consider Benjamini-Hochberg false discovery 
rate (FDR) adjusted p<0.05 as significant.88 DEGs will be analyzed for significant enrichment of 
biological pathways and signaling networks using Ingenuity Pathway Analysis (IPA), Causal 
Network Analysis and Upstream Regulator Tools89 and the DAVID software as described.90  A 
parallel analysis to the detection of DEG will be computed on the percent methylation (i.e., 
estimation of parameters for future power calculations and study design, FDR-adjusted p-values). 
Further statistical analyses will necessarily rely on data descriptions, and the formal statistical 
inference (hypothesis testing) will be limited due to the small sample size (n=10).  
 
Human Subjects Protection: 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 Code of Federal Regulations [CFR] Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR 312, and/or the International Council on Harmonisation E6.  
 
The appropriate IRB/EC must approve the protocol and informed consent documents, agree to monitor the 
conduct of the study, and agree to review the study progress periodically, at intervals of no more than 1 
year. 
 
The study provides an opportunity to “bank” tissue samples from willing participants for future innovative 
ICH research, namely Next-Gen multi-omic analysis of the inflammatory process surrounding ICH. 


Page 19 of 27 
 
Version 2.0, 5.01.2023 
 
Therefore, we plan to collect additional tissue samples (CSF) to be stored and analyzed in the future. For 
participants meeting eligibility criteria, peripheral whole blood will be collected prior to the dose of drug, 
and at 24 hr, 72 hr, 7 days, and 30 days after drug administration. If the participant requires CSF diversion 
for hydrocephalus, prior to the administration of the study agent, we will also collect CSF that would 
otherwise be discarded as medical waste. If an external ventricular drain is present, CSF will also be 
collected at 24 hr, 72 hrs, and 7 days after drug administration. Participants’ participation in this tissue 
banking repository will be optional; they do not have to participate in the repository sub-study in order to 
participate initially or to continue their participation in the main study. All samples will be stripped of 
identifiers and assigned a unique code number. The key linking code numbers and identifying information 
will be kept in a secure location accessible only to the PI of the study or his or her designee, on a password-
protected network drive. All samples will be stored at -80o F low temperature, locked, and frozen until the 
multi-omic analysis can be performed. The samples will be stored indefinitely or until no more remains for 
research that can be performed at future dates.  
 
Subject Recruitment Methods: 
Adult patients coming the Emergency Department or direct admitted to the Neurosciences Intensive Care 
Unit with the diagnosis of spontaneous ICH will be identified as potentially eligible participants and 
screened by interview.   
 
For patients meeting inclusion criteria without exclusion criteria, the participant or the participant’s health 
power of attorney will be approached for consent for participating in the study. The study will be discussed 
with the participant and their surrogate as soon as approachable and available during the participant’s care 
in the hospital.  If the participant or health care power of attorney does not want to be included in the study, 
there will be no examinations or data collected.   
Equal access by women and minorities will be ensured as inclusion criteria will apply to all patients 
presenting to Wake Forest Baptist Hospital, regardless of gender or race. 
Privacy will be protected by using secured computers for data gathering and storage, and by following strict 
HIPAA protocol.  
Informed Consent: 
Consent forms describing in detail the study agent, study procedures, and benefits/risks are given to the 
participant, and signed, IRB-approved informed consent must be obtained from each participant before 
starting intervention/administering study product. The ICF will conform to applicable regulations, 
including the FDA regulation in 21 CFR Part 50, and to institutional requirements for informed consent.  
 
Consent may be obtained by one of the study investigators or research coordinators once it has been 
determined that the participant is an appropriate candidate for the study. The study team will attempt to 
obtain the informed consent in person either in the emergency department, the neurology/neurosurgery 
floor, or the neurosciences ICU setting.  
 
When the LAR is not available in person, the consent options to be utilized will be: 
1. 
The study team can communicate via phone or webex with a family member of legal 
representative and explain the study and answer questions.  If the person is present at the medical center 
or will be coming in within the allowed window, then a wet signature could be obtained, and the patient 
enrolled on study. 
2.  
If the legal representative is not available for a wet signature within the allowed window, then the 
institution has recently obtained a validated and compliant version of DocuSign that may be available in 
this situation.  The study team would still communicate the consent process over the phone or webex, but 


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instead of obtaining a wet signature, they would send an email with a link to DocuSign and obtain an 
electronic signature. 
 
The ICF will be reviewed with the prospective participant (or participant’s LAR), by the 
investigator/qualified designee, and they will answer any questions. Once completed satisfactorily, the 
participant (or LAR) and the investigator/qualified designee will sign and date the ICF. The participant will 
receive a copy of the signed ICF and the original signed and dated ICF will be kept in the site’s files. 
Documentation of the participant’s informed consent for, and participation in, this trial will be noted in the 
participant’s medical record.  
 
If a prospective participant is not capable of providing informed consent because of neurologic injury, 
consent will be sought from the participant’s LAR. Diminished capacity does not limit a participant’s right 
to refuse participation. If the prospective participant refuses participation, the refusal stands. Furthermore, 
if an LAR consents on behalf of a participant and the participant regains cognitive ability, the participant’s 
consent must be sought directly, and the participant has the right to withdraw consent given by an LAR. 
Periodic assessment by site study staff will be made to evaluate the ability of a participant to give direct 
consent. Additionally, the subject’s assent must also be obtained if he or she is able to understand the nature, 
significance, and risks associated with the study. A portion of the consent will also describe the possibility 
of storing blood for potential multi-omic testing that will be performed, and it will be clarified that the 
information collected from the stored blood or CSF samples is for research purposes only and does not 
serve a therapeutic purpose.  
 
If the participant or LAR is not capable of reading the ICF, an impartial witness is required to be present as 
the consent is read aloud and while questions are answered or any discussion of consent takes place. 
Afterward, the participant or LAR should be asked to sign and date the ICF for the verbal consent process. 
The impartial witness and the individual who read the consent document and answered questions should 
also sign and date the verbal consent document. In every case, the participant should receive a copy of the 
full text of the ICF.   
 
The participant (or participant’s LAR) will be informed as soon as possible if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the trial. The 
communication of this information to the participant will be documented.  
 
Confidentiality and Privacy: 
Participant information collected in this study will comply with the standards for protection of privacy of 
individually identifiable health information as promulgated in HIPAA and as mandated in Title 45 CFR, 
Parts 160 and 164. All records will be kept confidential, and the participant’s name will not be released at 
any time. Participant records will not be released to anyone other than responsible regulatory authorities, 
when requested. In all cases, caution will be exercised to assure the data are treated confidentially and that 
the participant’s privacy is guaranteed.  
An authorization for use and disclosure of protected health information under the HIPAA Privacy Rule will 
be obtained from every trial participant before, or at the time of, enrollment. It will be presented to, and 
signed by, the participant at the same time as the study consent. The investigator is responsible for obtaining 
participants’ (or their legal representatives’) authorizations and signature and for explaining the elements 
of the HIPAA authorization form if necessary. 
Data and Safety Monitoring: 


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The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants. The principal investigator will be assisted by other members of the study staff. Routine safety 
data in the review include SAEs, AEs, discontinuation due to AEs, clinically significant post-drug 
worsening of neurologic status, EKGs, vital signs, and laboratory assessments.   
 
Reporting of Unanticipated Problems, Adverse Events, or Deviations: 
Any unanticipated problems, serious and unexpected adverse events, deviations, or protocol changes will 
be promptly reported by the principal investigator or designated member of the research team to the IRB 
and sponsor or appropriate government agency if appropriate.  
 
Adverse event reporting: 
All AEs occurring between the times informed consent is obtained and the last study-related procedure is 
completed as part of the day 365 follow up will be recorded on the appropriate eCRF form. Adverse events 
may be volunteered by subjects and or solicited at each assessment by the investigator or designee.  
 
Recording should be done in a concise manner using standard, acceptable medical terms. The investigator 
should make every effort to establish a diagnosis of the event based on the presenting signs, symptoms, 
and/or clinical information. In such cases, the diagnosis should be documented as the AE/SAE.  
 
Diseases, signs, symptoms, or laboratory abnormalities already existing at enrollment are not considered 
AEs unless they worsen (i.e. increase in intensity or frequency). Surgical procedures themselves are not 
AEs – they are therapeutic measures for conditions that require surgery. The condition for which the surgery 
is required may be an AE. Surgical procedures planned before enrollment and the conditions leading to 
these measures are not AEs.  
 
If, in the investigator’s judgment, a clinically significant worsening from baseline is observed in any 
laboratory or other testing parameter (e.g. EKG, CBC, BMP), physical examination finding, or vital sign, 
a corresponding clinical AE should be recorded on the AE pages of the eCRF. If the cause is not known, 
the abnormal test or finding should be recorded as an AE, using appropriate medical terminology. Actual 
numeric values of test results should not be reported.  
 
Serious adverse event reporting: 
All SAEs occurring between the times informed consent is obtained and the last study-related procedure is 
completed as part of the day 365 follow up, whether or not deemed drug-related or expected, must be 
reported by the investigator or qualified designee within 1 working day of first becoming aware of the event. 
The investigator/qualified designee will enter the required information regarding the SAE into the 
appropriate module of the eCRF, which will automatically result in distribution of the information to DCRI 
Safety Surveillance. If the eCRF system is temporarily unavailable, the event, including the investigator-
determined causality to study drug, should be reported via a paper back-up SAE form to DCRI Safety 
Surveillance. Upon return of the availability of the EDF system, the SAE information must be entered into 
the eCRF.  
 
The investigator is responsible for reporting AE/SAEs to their IRB/ethics committee (EDC) according to 
local guidelines and/or requirements.  
 
All SAEs will be reviewed for expectedness per the Investigator. Events determined to be related to the 
investigational drug and unexpected per the investigator will be reported in the expedited manner to the 
regulatory authorities and participating sites. For SAEs resulting in death or considered life threatening, 


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reporting should occur no later than 7 days after the event; for unexpected, non-life threatening SAEs, 
reporting should occur no later than 15 days after the event.  
 
Unanticipated problems reporting: 
It is the site investigator’s responsibility to report UPs to their IRB/EC and to the data coordinating center. 
The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB/EC project 
number. 
• 
Detail description of the vent, incident, experience, or outcome.  
• 
Explanation of the basis for determining that the event, incident, experience, or outcomes represents 
a UP.  
• 
Description of any deviations from protocol or other corrective actions that have been taken or are 
proposed in response to the UP.  
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
• 
UPs that are SAEs will be reported as per the instructions for SAE reporting outlined above.  
• 
Any other UP will be reported to the IRB/EC and to the DCC as per the IRB/EC’s reporting 
requirements, but no later than 30 days of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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82. 
Murthy SB, Moradiya Y, Shah J, Merkler AE, Mangat HS, Iadacola C, et al. Nosocomial 
Infections and Outcomes after Intracerebral Hemorrhage: A Population-Based Study. 2016;25(2):178-84. 
83. 
Lord AS, Gilmore E, Choi HA, Mayer SA, Collaboration V-I. Time course and predictors of 
neurological deterioration after intracerebral hemorrhage. Stroke. 2015;46(3):647-52. 
84. 
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal 
RNA-seq aligner. Bioinformatics. 2013;29(1):15-21. 
85. 
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning 
sequence reads to genomic features. Bioinformatics. 2014;30(7):923-30. 
86. 
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq 
data with DESeq2. Genome biology. 2014;15(12):550. 
87. 
Ching T, Huang S, Garmire LX. Power analysis and sample size estimation for RNA-Seq 
differential expression. Rna. 2014;20(11):1684-96. 
88. 
Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful 
Approach to Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological). 
1995;57(1):289-300. 
89. 
Kramer A, Green J, Pollard J, Jr., Tugendreich S. Causal analysis approaches in Ingenuity 
Pathway Analysis. Bioinformatics. 2014;30(4):523-30. 
90. 
Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, et al. DAVID Bioinformatics 
Resources: expanded annotation database and novel algorithms to better extract biology from large gene 
lists. Nucleic acids research. 2007;35(Web Server issue):W169-75. 
 
 

ICF_000.pdf: 
FITCH trial
IRB00060619 
NCT04088630
IRB Approval Date:  08.18.2022


Page 1 of 14
Adult Consent Form
02.05.2021
Department of Neurosurgery
SELECTIVE IMMUNOMODULATION IN THE TREATMENT OF CEREBRAL EDEMA 
AFTER INTRACEREBRAL HEMORRHAGE
Informed Consent Form to Participate in Research
Stacey Quintero Wolfe, MD, Principal Investigator
SUMMARY
You are invited to participate in a research study. Research studies are designed to gain scientific 
knowledge that can be used in the future to help other people. The purpose of this research study 
is to assess the safety of a medication, fingolimod, to treat brain swelling because of bleeding in 
the brain, also called intracerebral hemorrhage or ICH. You are invited to be in this study 
because you have experienced an intracerebral hemorrhage, or ICH. Your participation in this 
research will involve the same care and follow-up appointments that all patients with 
intracerebral hemorrhage undergo.  This involves your hospital stay and 4 follow up visits – one 
at 30 days, 3 months, 6 months and the final visit at 12 months after your hospitalization.  
This study is designed to find out if it is safe to give a medication, fingolimod, to treat 
inflammation, or swelling, that occurs due to the bleeding you experienced in the brain.  
Participation in this study will involve all standard of care management of your blood clot in 
addition to a single dose of study medication. Standard therapy for blood clots in the brain may 
involve standard ICU care, standard medical therapies, and/or if needed, a standard of care 
placement of a drain (external ventricular drain – EVD) for enlargement of the fluid-filled spaces 
(ventricles) in the brain, known as hydrocephalus, to drain cerebrospinal fluid (body fluid found 
in the brain and spinal cord) with the goal to decrease pressure in your brain.
Regarding the dose of medication, there is a risk of side effects, all of which occur in < 1% of 
people who take the medication on a regular everyday basis, including: temporary slowing of the 
heart rate, increase in risk of infections, macular edema (swelling of the part of the eye 
responsible for detailed vision) which is reversible, liver problems, headache, diarrhea, cough, 
sinus inflammation, back pain, abdominal pain, or pain in arms and legs. There is a 0.5% chance 
of a serious side effect, including progressive multifocal leukoencephalopathy (very rare brain 
infection), posterior reversible encephalopathy syndrome (swelling and narrowing of the blood 
vessels in the brain that can lead to stroke). Because this study is evaluating the safety of a 
medication that could treat the inflammation that occurs because of bleeding in the brain, you 
may benefit from participation in this study. 
Your participation in this study is voluntary. You do not have to participate in this study if you 
do not want to. There may be other choices available to you to treat your brain bleeding. Other 
choices may include standard medical management without receiving this medication or surgical 
removal of the blood clot if it is considered necessary. You will not lose any services, benefits, or 
rights you would normally have if you choose not to participate. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


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Adult Consent Form
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The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is Dr. Stacey Wolfe. If you have questions, suggestions, 
or concerns regarding this study or you want to withdraw from the study her contact information 
is: 
Dr. Stacey Wolfe
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
 or the Research Subject 
Advocate at Wake Forest at 3
.
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have bleeding in the brain, also called intracerebral hemorrhage or ICH. Your 
participation is voluntary. Please take your time in making your decision as to whether or not 
you wish to participate. Ask your study doctor or the study staff to explain any words or 
information contained in this informed consent document that you do not understand. You may 
also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to test the safety of the medication fingolimod as a potential 
agent to treat the inflammation caused by brain bleeding in combination with standard clinical 
care. The goal is to see what effects (good and bad) it has on you and your condition.
 
The rate of death in patients with ICH despite best medical management remains very high. 
Also, the rate and amount of recovery is variable. Although the ICH itself can cause damage to 
brain structures, the swelling because of an inflammatory response to the blood in the brain can 
cause further significant injury to the brain, leading to worse neurologic problems and less 
recovery in the future. But there have been recent studies that show that if the swelling can be 
reduced after ICH has occurred, the rate and amount of recovery can be improved. 
Fingolimod has been approved by the US Food and Drug Administration (FDA) to treat the 
inflammation that causes multiple sclerosis, but it has not been approved for use in the treatment 
of inflammation due to ICH. In this study, fingolimod will be compared to a placebo. A placebo 
is a substance, like a sugar pill, that is not thought to have any effect on your disease or 
condition. In this study, you will either receive the active study medication, fingolimod, or 
placebo which is not active. Placebos are used in research studies to see if the drug being studied 
really does have an effect. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 3 of 14
Adult Consent Form
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HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
A total of 30 people at 1 research site will take part in this study. All 30 subjects will be from Wake 
Forest Baptist Health. In order to identify the 30 subjects needed, we may need to screen as many 
as 60-70 potential subjects because some people will not qualify to be included in the study. 
WHAT IS INVOLVED IN THE STUDY?
If you take part in this study, you will have the following tests and procedures:
Screening: With your consent, we will review all of the information used to treat your condition 
to find out if you are eligible for this study. 

At the time of your admission to the hospital, a standard of care CT scan will be done to 
confirm the diagnosis of ICH. A CT scan is a test that produces an image of your body 
using a small amount of radiation. The image shows the body tissues and structures in 
three dimensions (“3-D”). These CT scans may already have been done per standard 
clinical care. 

A MRI (magnetic resonance imaging) scan and a MRA (magnetic resonance angiogram) 
or a CTA (computed tomography angiogram) will also be done. These procedures are 
part of the standard clinical care to see if the bleeding is caused by abnormal blood 
vessels, such as an aneurysm (thinning of the wall of an artery), arteriovenous 
malformation (tangle of blood vessels), or tumor. If this is the cause of your bleeding, 
you will not be eligible for this study. 

A pregnancy test will be done if you are a female of childbearing potential. This test is 
part of standard clinical care.  You must not be pregnant to be in this study. 

Standard of care speech and swallow evaluation will be done to test your ability to 
swallow. This can be done at the bedside by a nurse. If you are having trouble 
swallowing, you will get a nasogastric tube or Dobhoff feeding tube as part of standard of 
care. The purpose of these devices is to help deliver medications and nutrition directly to 
your stomach until you recover and are able to safely swallow on your own.  
Randomization:
If you are found to be eligible for this study, you will be randomized into one of the study groups 
below. Randomization means that you are put into a group by chance. It is like flipping a coin. 
You will have an equal chance of being in any group. You will either continue to receive 
standard medical care with a placebo, or you will receive standard medical care with the study 
drug fingolimod. 
Neither you nor the investigator will know which study drug you are receiving. This is done so 
that a fair evaluation of results can be made. This information is available to the researchers if 
needed in an emergency.
Standard medical care plus placebo: if you are randomly assigned to continue to receive 
standard medical care and placebo:
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 4 of 14
Adult Consent Form
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
You will be given a single dose of the placebo, which will look, taste, and smell exactly 
like the study drug. If you are unable to swallow, this will be given through the 
nasogastric tube or Dobhoff feeding tube. 

You will then be taken to the intensive care unit as part of standard clinical care. 

Your vital signs, such as heart rate, blood pressure, temperature, and neurological 
condition will be monitored daily for the next 6 days. This is done as part of standard 
clinical care but will be reviewed for study purposes. 

If you require cerebrospinal fluid drainage as part of your clinical care, this procedure 
will be performed in the Neuroscience Intensive Care Unit. This will involve the 
placement of a catheter that is less than 1 centimeter in diameter through the brain into 
the fluid filled spaces (ventricles) in the brain, and this will allow for constant pressure 
monitoring of your brain, as well as drainage of cerebrospinal fluid. A 5 teaspoon sample 
of this will be store for future testing of the immune cells and the proteins produced after 
ICH on Day 1, 3, 5-7 and 10-14 only while the fluid drain is in place.  If you do not 
require cerebrospinal fluid drainage, cerebrospinal fluid will not be collected and stored.

A standard CT scan will be done on Day 1 after your admission to make sure the 
bleeding has stopped as part of standard of care, but it will also be reviewed for study 
purposes to follow the swelling of the brain.

On Day 3 after your admission, you will also get a standard of care MRI of the brain to 
evaluate the swelling of the brain. This does not involve radiation or contrast, and carries 
minimal risk. 

Standard of care blood samples, about 2 tablespoons worth of blood, will be drawn from 
a vein daily for the first 7 days to monitor natural chemical levels in the blood related to 
the bleeding in your brain. As part of this study participation, on Days 1, 3, and between 
5-7 after taking the medication, a half of the blood that is already drawn (1 tablespoon) 
will be sent off for testing of the different white blood cells that are affected by the 
medication. If you are still hospitalized 10-14 days after taking the medication, we will 
collect another 1 tablespoon worth of blood to send off for testing of the different white 
blood cells. A small amount of the blood collected will be stored for future tests to 
analyze the different immune cells and the proteins that can be made by these cells. In the 
future, research on your specimen may involve whole genome sequencing. However, if 
you have low blood counts, we will not be collecting your blood. 
Standard medical care plus study drug: if you are randomly chosen or assigned to the group 
that will get the study drug: 

You will be given a single dose of the study drug fingolimod, 0.5 mg, by mouth. If you 
are unable to swallow, this will be given through the nasogastric tube or Dobhoff feeding 
tube.

You will then be taken to the intensive care unit as part of standard clinical care. 

Your vital signs, such as heart rate, blood pressure, temperature, and neurological 
condition will be monitored daily for the next 6 days. This is done as part of standard 
clinical care but will be reviewed for study purposes. 

If you require cerebrospinal fluid drainage as part of your clinical care, this procedure 
will be performed in the Neuroscience Intensive Care Unit. This will involve the 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 5 of 14
Adult Consent Form
02.05.2021
placement of a catheter that is less than 1 centimeter in diameter through the brain into 
the fluid filled spaces (ventricles) in the brain, and this will allow for constant pressure 
monitoring of your brain, as well as drainage of cerebrospinal fluid. A 5 teaspoon sample 
of this will be store for future testing of the immune cells and the proteins produced after 
ICH on Day 1, 3, 5-7 and 10-14 only while the fluid drain is in place.  If you do not 
require cerebrospinal fluid drainage, cerebrospinal fluid will not be collected and stored.

A standard CT scan will be done on Day 1 after your admission to make sure the 
bleeding has stopped as part of standard of care, but it will also be reviewed for study 
purposes to follow the swelling of the brain.

On Day 3 after your admission, you will also get a standard of care MRI of the brain to 
evaluate the swelling of the brain. 

Standard of care blood samples, about 2 tablespoons worth of blood, will be drawn from 
a vein daily for the first 7 days to monitor natural chemical levels in the blood related to 
the bleeding in your brain. As part of this study participation, on Days 1, 3, and between 
5-7 after taking the medication, a half of the blood that is already drawn (1 tablespoon) 
will be sent off for testing of the different white blood cells that are affected by the 
medication. If you are still hospitalized 10-14 days after taking the medication, we will 
collect another 1 tablespoon worth of blood to send off for testing of the different white 
blood cells.  A small amount of the blood collected will be stored for future tests to 
analyze the different immune cells and the proteins that can be made by these cells. In the 
future, research on your specimen may involve whole genome sequencing. However, if 
you have low blood counts, we will not be collecting your blood. 
Study follow up visits: Study participants will be followed for 12 months after surgery. 

You will be asked to return to the clinic at 30-45 days, 3 months, 6 months, and 12 
months from today. At these standard of care follow up visits, your neurological 
condition and blood pressure will be checked and you will be asked questions about how 
well you are doing. You will also be asked if you are experiencing any side effects or 
problems from the medication. Standard of care Neuroimagingwill be performed at the 3, 
6v and 12 month visits to check for brain swelling and fluid buildup.  This is a necessary 
part of standard care for this problem.  You may be asked to undergo another blood 
sample for laboratory testing and storage for future analysis at the 30 day visit.

At each of your study follow up visits at 30-45 days, 3 months, 6 months, and 12 months, 
you will undergo a set of assessments to check different aspects of your recovery. We 
will evaluate your ability to take care of yourself at home or if you require assistance at 
home or your facility. We will also test your thinking and memory, and we will be asking 
if there are changes in your mood since your ICH.
We can send copies of your test results to your personal physician. Even if you do not wish to 
have any of your medical information sent to your physician, you can still participate in this 
research study. As part of this study, as mentioned in the next section, we will be asking 
questions regarding your mental health. If you indicate any feelings of depression or desire to 
harm yourself or others, per our institution protocol, we will be sharing this information with 
your physician to appropriately address these concerns. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 6 of 14
Adult Consent Form
02.05.2021
Storage of Biological Tissue
If you agree to participate in this study, we will collect a total of 5 tablespoons of blood, and 
possibly a total of 3 tablespoons of cerebrospinal fluid (if your condition requires a spinal fluid 
drain) to use for future research. These samples will be kept and may be used in future research to 
learn more about other diseases.  Your samples will be obtained by the Department of 
Neurosurgery and Center for Precision Medicine at Wake Forest University Baptist Medical 
Center. The samples will be stored in Dr. Timothy Howard’s laboratory on the third floor of the 
NRC and it will be given only to researchers approved by Stacey Wolfe, MD. An Institutional 
Review Board (IRB) must also approve any future research study using your tissue sample. You 
are not required to provide samples for future research in order to participate in this study.
The research that may be performed with your blood and cerebrospinal samples is not designed 
to help you specifically. There is no personal benefit to you from taking part in this aspect of the 
research study. It might help people who have diseases at some point in the future, but it is not 
known if this will happen. The results of the research performed with your blood and 
cerebrospinal samples will not be given to you or your doctor. The results will not be put in your 
medical record. The research using your blood and cerebrospinal samples will not affect your 
care.
Your blood and cerebrospinal samples will be used only for research and will not be sold. The 
findings from this research may result in the future development of products that are of 
commercial value. There are no plans to share any of the profits with you which may occur as a 
result of the research.
Your cerebrospinal fluid and blood samples will be stored with a unique identifier and will not 
include any identifiable information about you such as your name, address, telephone number, 
social security number, medical record number or any of the identifiers outlined in the HIPAA 
Privacy Rule. The unique identifier will be a randomly assigned number and only the principal 
investigator will have access to the code that links the unique identifier to you. Your name, 
address, social security number, etc., will never be disclosed to future researchers and neither 
will the code that links your identifiers to the sample.
In addition, de-identified information regarding your DNA and clinical information will be sent 
to the National Institute for Health’s or equivalent database of genotypes and phenotypes 
(dbGaP) after genome-wide analysis and will be shared with other investigators for research 
purposes. DNA and information sent to these databases will help researchers better understand 
how genes affect the risk of developing diseases such as asthma, cancer, diabetes, and heart 
disease and may lead to better methods to select the best treatment options. Before your 
information is sent to the dbGaP data repository, it will be de-identified, which means that we 
will remove any identifying information such as your name, date of birth, address, etc. Thus, 
researchers using your DNA and clinical data will not be able to link this information back to 
you. 
In the future, people who do research may need to know more about your health. While the study 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 7 of 14
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02.05.2021
investigator may give reports about your health, he/she will NOT be given your name, address, 
phone number, or any other identifying information about who you are, unless you agree to be 
contacted in the future.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for about 12 months. 
You can stop participating at any time. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the drug (fingolimod) we are studying 
include:
Common side effects:
o
Risk of side effects from the medication, all of which occur in < 1% of people 
who take the medication on a regular everyday basis for > 2 months: temporary 
slowing of the heart rate, increase in risk of infections, liver problems or 
temporary abnormal liver tests, increased blood pressure, headache, diarrhea, 
cough, sinus inflammation, back pain, abdominal pain, or pain in arms and legs.
Rare:
o
Risk of serious side effects occurring in < 0.5% of people who take the 
medication on a regular everyday basis for > 2 months: lymphoma (blood cancer), 
progressive multifocal leukoencephalopathy (very rare brain infection), posterior 
reversible encephalopathy syndrome (swelling and narrowing of the blood vessels 
in the brain that can lead to stroke), macular edema (swelling of the part of the 
eye responsible for detailed vision) which is reversible, or shortness of breath.
o
Death
Discomforts:
o
You may experience discomfort that is part of the routine medical care for 
participants with your condition in the intensive care unit. 
o
During the follow up visits, you may get tired or bored when we are asking you 
questions or you are completing questionnaires. You do not have to answer any 
questions you do not want to answer. 
There may be side effects and discomforts that are not yet known. 
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 8 of 14
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02.05.2021
any medical conditions you have. This may help avoid side effects, interactions and other risks.
The risk associated with gene analysis studies would be the loss of confidentiality of the results. 
Your information and sample that are shared with other researchers for future uses, are coded so 
that the researchers have no known way to know the sample and information are yours except if 
they were to compare the DNA to another DNA sample provided by you. Unless required by 
law, we will not release information that identifies you to other researchers without your written 
permission. A federal law, called the Genetic Information Nondiscrimination Act (GINA), makes 
it illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information:
-Health insurance companies may not request or use individual genetic information that we 
get from this research when making decisions regarding eligibility or premiums.
-Employers with 15 or more employees may not use genetic information from this research 
when making a decision to hire, promote, or fire or when setting the terms of your 
employment.
Be aware that this new law does not protect you against discrimination on the basis of your 
genetic information by companies that sell life insurance, disability insurance, or long-term care 
insurance. There is a risk that being in a genetics study can cause psychological distress or 
tension with other family members, or that broad data sharing could risk identification of 
populations or groups.  There are no plans to provide you with the results of the gene analysis. 
Clinical and genetic data may be kept anonymously in a public database. There is always some 
risk that even de-identified information might be re-identified, however extensive efforts are 
made by all study personnel to ensure confidentiality of all subjects.
If you are randomized to the study group that receives the placebo, you will not be at risk for 
increased brain swelling compared to what has already been reported in other studies. You will 
be at the same risk of developing an infection in the hospital compared to what has already been 
reported in other studies.  
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
As part of this study, you will be asked questions about your mood, sleeping patterns, appetite, 
energy level, ability to concentrate, your level of interest in activities and hobbies, and if you 
have any thoughts of being hopeless or hurting yourself. If we learn that you or someone else is 
in danger of harm, the study team is required to report that information to the proper authorities. 
You may experience discomfort, bruising and/or bleeding where the needle is inserted for blood 
draws. Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on 
rare occasions.  Frequent donation of blood can result in low iron in your blood (iron deficient 
anemia).  
Reproductive Risks and other Issues to Participating in Research
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


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Standard of Care follow up for your ICH includes monitoring your condition with CT scans. We 
will also be collecting blood samples at these follow up visits.  The drug fingolimod may take up 
to 2 months to completely clear from your body, and there is potential risk to a baby if the drug 
is still in your system. Due to unknown risks and potential harm to the unborn fetus from the CT 
scans and medication or the inflammatory processes that may be identified in the blood 
collection, sexually active women of childbearing potential are recommended to use a reliable 
method of birth control while during their follow up period for their ICH and while participating 
in this study. Reliable methods of birth control are: abstinence (not having sex), oral 
contraceptives, intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the 
partner (with confirmed negative sperm counts) in a monogamous relationship (same partner). 
An acceptable, although less reliable, method involves the careful use of condoms and 
spermicidal foam or gel and/or a cervical cap or sponge. We encourage you to discuss this issue 
further with your physicians if you have any questions.
If you become pregnant during the 6 month follow up period, we will ask you to complete the 
interviews and questionnaires, but you will not have the CT scans done.
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required at least 10 days from your last normal 
menstrual period, if you are a sexually active woman of childbearing potential.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. The benefit of 
participating in this study may be less inflammation or brain swelling from ICH after 
administration of fingolimod, which could lead to better neurologic recovery. 
Based on experience with fingolimod in patients with multiple sclerosis, animal models of ICH, 
and a small clinical trial using fingolimod to treat the inflammation after ICH, researchers 
believe that this medication may be beneficial to subjects with your condition. Because 
individuals respond differently to therapy, no one can know in advance if it will be helpful in 
your particular case. 
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment for your ICH. You should talk to your 
doctor about all the choices you have. Currently, there are 2 standard of care options to treat 
ICH. Instead of being in this study, you have these options:
The first option is standard medical management without the use of the study medication. You 
will be observed and any causes of your ICH will be treated with standard of care medications. 
Swelling of the brain will be treated with standard medications commonly used in treating the 
swelling as much as is possible.
If you require surgery, standard surgical removal of the blood clot can be performed without 
additional administration of any study medication to treat the inflammation.  
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 10 of 14
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WHAT ARE THE COSTS?
All study costs, including any study medications and procedures related directly to the study, will 
be paid for by the study. Costs for your regular medical care, which are not related to this study, 
will be your own responsibility.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
The purpose of this research study is to obtain data or information on the safety and/or 
effectiveness of fingolimod (Gilenya); the results will be provided to the sponsor, the Food and 
Drug Administration, and other federal and regulatory agencies as required.  The Food and Drug 
Administration (FDA), for example, may inspect research records and learn your identity if this 
study falls within its jurisdiction.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study.
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by Wake Forest University Health Science. The researchers do 
not, however, hold a direct financial interest in any sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A RESULT OF PARTICIPATING IN 
THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


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Adult Consent Form
02.05.2021
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Dr. Stacey Wolfe at 
 (after hours 
numbers 
).
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: name, date 
of birth, phone numbers, medical record numbers, date of surgery, and medical conditions.  
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS) and similar agencies in other countries.  
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


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02.05.2021
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups, it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. Any research information entered into your medical record will be kept for as long as 
your medical record is kept by the Medical Center. You will not be able to obtain a copy of your 
Protected Health Information in the research records until all activities in the study are 
completely finished. 
You can tell Dr. Stacey Wolfe that you want to take away your permission to use and share your 
Protected Health Information at any time by sending a letter to this address:
Dr. Stacey Wolfe
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form, you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial. Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record. This part of the medical record will only be available to people 
who have authorized access to your medical record. If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 13 of 14
Adult Consent Form
02.05.2021
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A Wake Forest Baptist Health (WFBH) medical record will be created for all study participants. 
Information about your participation in the study will be placed in the WFBH medical record, 
along with any routine medical test results that were obtained at WFBH as part of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because:

Staying in the study would be harmful. 

You need treatment that is not allowed in the study

Your condition worsened

You failed to follow instructions

The study is cancelled 

There may be other reasons to take you out of the study that we do not know at this time. 
Information that identifies you may be removed from the materials collected from this study, and 
may be used for future research without additional consent from you. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Stacey Wolfe, MD at 
. If you cannot reach the principal investigator 
or wish to talk to someone else, call the IRB office at 
.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023


Page 14 of 14
Adult Consent Form
02.05.2021
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _______________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent: _____________________ Date: _________ Time: ________ am pm
OR
Legally Authorized Representative Name (Print):_________________________
 
The above named Legally Authorized Representative has legal authority to act for the research 
subject based upon (specify health care power of attorney, spouse, parent, etc.)
Relationship to the Subject: _____________________________
Legal Representative Signature: _________________ Date: _________ Time: ________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00060619
Meeting Date Approved 8/18/2022          
Version Valid Until: 8/17/2023