Clinical trial NCT02872857
Conditions: Subarachnoid Hemorrhage
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2016-09-01; Completion date: 2019-07-20
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the effects of the study drug--Galantamine-on patients with subarachnoid hemorrhage (SAH). The study will examine how patients with SAH will tolerate the study drug and how it may improve brain functioning in patients after SAH.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Placebo intervention 2: 8mg galantamine twice daily intervention 3: 12mg galantamine twice daily
Intervention descriptions: intervention 1: Placebo will match drug capsules. intervention 2: Drug will be administered within 36 hours of hospitalization and continued for 90 days. intervention 3: Drug will be administered within 36 hours of hospitalization and continued for 90 days.

Protocol documents:
Prot_SAP_000.pdf: 
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A Pilot Parallel Double-Blind, Randomized Trial of Galantamine for Subarachnoid 
Hemorrhage 
 
NCT02872857 
 
Version Date: 5/11/2018 
 
 


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Protocol Title: 
A Pilot Parallel Double-Blind, Randomized Trial of Galantamine 
for Subarachnoid Hemorrhage 
 
 
 
 
 
Principal 
Investigator: 
Huimahn Alex Choi 
 
Co-Investigators: 
James C Grotta MD 
 
Pramod Dash PhD 
Andrew Barreto MD 
Georgene Hergenroeder PhD 
Wamda Ahmed MD 
Kevin Immanuel 
 
Study Coordinator: 
If a coordinator / research nurse / research assistant has been 
identified 
 
Population: 
A total of 60 subjects who present with aneurysmal subarachnoid 
hemorrhage, age 18-75 will be enrolled. 
 
Number of Sites: 
UT Houston Health Science Center, Memorial Hermann Hospital 
System and the Methodist Hospital System 
 
Study Duration: 
3 years 
 
Subject Duration: 
90 days 
 
 
 


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Protocol Summary 
 
Title: A pilot, parallel double-blind, randomized trial of Galantamine for Subarachnoid 
Hemorrhage 
 
Short title: SAHRANG: SubArachnoid Hemorhage Recovery ANd Galantamine 
 
Population: 
Patients with aneurysmal subarachnoid hemorrhage in the age group of 
18-75 years admitted to the Memorial Hermann Hospital System and the 
Methodist Hospital System who meet the eligibility criteria for the study 
will be enrolled. 
 
Number of Sites: 
Memorial Hermann Hospital System and the Methodist Hospital System 
 
Study Duration: 
Duration of the study will be 3 years. 
Subject Duration: 
Duration per subject would be 90 days. 
Objectives: 
Abstract: Subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality. 
Galantamine is a medication used in the treatment of dementia. Preclinical studies have shown 
that galantamine addresses several mechanisms proposed to contribute to worse clinical 
outcomes after SAH. We propose a pilot safety and tolerability study examining the use of 
galantamine to improve outcomes after acute SAH. We hypothesize that galantamine started 
within 36 hours and continued for 90 days will be well tolerated and safe. Our second 
hypothesis is that galantamine treatment will be associated with a decrease in central and 
systemic inflammation after SAH. 
 
Aim 1: To investigate the safety and tolerability of galantamine in SAH patients when given 36 
hours after admission to hospital and continued for 90 days. 
 
Aim 2: To develop an evidence-based hypothesis for efficacy of galantamine on the 90 day 
mRS. 
 
Aim 3: To investigate the effect of galantamine treatment on CSF and serum levels of 
inflammatory cytokines after SAH. 
 
Methods: This is pilot double-blind placebo-controlled randomized trial to evaluate the safety 
and tolerability of galantamine after SAH. 60 patients will be enrolled. The first 30 subjects will 
be randomized to either galantamine 8mg twice a day or placebo. The next 30 subjects will be 
randomized to galantamine 12mg twice a day or placebo. Dose of galantamine will be adjusted 
as needed if tolerability issues occur. An interim analysis for dose tolerability will be performed 
after 30 subjects have been enrolled before proceeding to the second phase of the study. CSF 
and serum samples will be collected at 8 predetermined time points and differences in 


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inflammatory cytokines between groups will be assessed. Clinical outcomes at 30 days, 60 days 
and 90 days will be assessed by the modified Rankin Scale, Montreal Cognitive Assessment, 
EuroQOL. 
 
Conclusion: This is a study to investigate the safety and tolerability of galantamine therapy for 
the treatment of SAH. In addition we will gain insights into preliminary estimates of efficacy and 
possible mechanisms of action. 
 
Background Information 
Subarachnoid hemorrhage (SAH) is caused by a rupture of a cerebral aneurysm. SAH 
represents 5-10% of strokes and is a significant public health problem. Mortality is high (up to 
40%) and morbidity is significant as patients are often young and are left with cognitive and 
functional deficits.1,2 Brain injury as a result of SAH occurs in two stages. The first stage of injury 
occurs within 72 hours and has been coined early brain injury.3  The second stage of injury 
occurs between 4-14 days after rupture and is characterized by cerebral vasospasm (CVSP) 
and delayed cerebral ischemia (DCI). CVSP and DCI are complications that lead to morbidity 
and mortality after SAH.4 Both clinical and animal studies have shown that uncontrolled 
inflammation is an important contributor to both stages of injury.5,6 Recent preclinical studies 
have implicated nicotinic α7 receptors in modulation of inflammation, and have demonstrated 
that stimulation of these receptors can reduce the levels of inflammatory cytokines.7Currently, 
there is no direct α7 receptor agonist that has been approved for use in humans. 
Galantamine is an FDA-approved medication that inhibits acetylcholinesterase and 
allosterically potentiates α7 receptors.8 Studies in animal models of brain injury have shown that 
galantamine can reduce inflammation after brain injury and offers neuroprotective effects.9 
Thus, galantamine has the potential to reduce SAH-triggered inflammation and improve 
outcomes. There are several potential mechanisms of action for the efficacy of galantamine to 
improve outcomes after SAH: 1) Systemic inflammation 2) Central inflammation 3) Improvement 
in cognition. 
 
1) Vagus nerve, nicotinic α7 receptors and systemic inflammation: The recently described 
cholinergic anti-inflammatory pathway (CAP) highlights the robust connection between the brain 
and components of the immune system through the autonomic nervous systems [Figure 1]. 
Studies have demonstrated that direct stimulation of the vagus nerve (the main efferent arm of 
the parasympathetic nervous system) decreases serum levels of pro-inflammatory molecules 
including IL-1ß, TNFα and HMGB-1. Specifically, the α7 receptors present in the celiac ganglion 
and splenic macrophages are important components of the CAP pathway.10,11[Figure 1] After 
Figure 1. Model for the cholinergic anti-inflammatory 
pathway. 1) Activation of the efferent component of the 
vagus nerve releases acetylcholine (ACh) within the celiac 
ganglion.  ACh acts on α7 receptors to enhance splenic 
nerve activity. 2) Splenic nerve terminals release 
norepinephrine (NE) within the spleen. NE acts on splenic T 
lymphocytes causing them to release ACh. 3) ACh activates 
α7 receptors present on splenic macrophages. 4) Activation 
of α7 receptors results in decreased pro-inflammatory 


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brain injury there is an increase in levels of circulating pro-inflammatory cytokines which 
correlate with decreases in spleen size suggesting splenic mobilization of splenic 
macrophages.12 Dr. Pramod Dash’s laboratory has shown that stimulation of the α7 receptors 
after experimental brain injury decreases both systemic and central inflammation, reduces 
blood-brain barrier permeability, and offers neuroprotection after traumatic brain injury (Figure 
2). Another laboratory has shown similar results in an animal model of SAH.13 
 
 
2) α7 receptors and central inflammation: Unregulated cerebral inflammation is associated with 
early and delayed brain injury with high levels of inflammatory cytokines in the CSF (including 
IL-1β, IL-6, IL-8 and TNFα) being associated with poor outcome.14–19 Several lines of evidence 
suggest that α7 receptors in the brain modulate cerebral inflammation.20 For example, in animal 
models of SAH, increased parasympathetic tone either directly through stimulation of the 
sphenopalatine ganglion or by activation of perivascular α7 receptor decreases CVSP and 
improves outcome.21,22 Furthermore, a decrease in cerebral vasospasm has been associated 
with decreases in inflammatory markers including IL-6.23 Ach levels in CSF after SAH are 
significantly lower in the acute phase of illness, suggesting that reduced Ach receptor activity 
may play a role in the development of CVSP.24 Galantamine acts as both an α7 receptor 
potentiator and an inhibitor of acetylcholinesterase that will increase Ach levels.25 These two 
mechanisms of action can work in concert to reduce cerebral inflammation and decrease risk for 
developing delayed neurologic injury. 
Figure 2. Post-TBI administration of the α7receptor agonist PNU-282987 decreases circulating cytokine, HMGB-1 
levels, and reduces the infiltration of inflammatory cells. A) The plasma levels of IL-1ß were found to be significantly 
decreased at 12 hours post-injury in injured animals treated with the nicotinic Ach receptor α7 agonist PNU-282987 (3 
mg/kg i.p.; α7agonist) compared to vehicle-treated injured animals (n=5/time point/group). B) Compared to the levels 
detected in vehicle-treated injured animals, rats treated with PNU-282987 had significantly reduced plasma IL-6 levels 
when assessed 6 hr post-injury (n=3/group). C) Representative image of a composite western blot showing HMGB-1 
immunoreactivity in the plasma of a sham, injured animals treated with vehicle (V), and injured animals treated with 
PNU-282987 (P). Images were taken from 3 separate western blots and combined for presentation. Sham samples were 
run on each membrane and used as a common comparator. D) Quantification of the 30kDa HMGB1 band revealed that 
post-injury administration of PNU-282987 significantly reduced (group main effect by two-way ANOVA) circulating 
HMGB1 levels (n=5/time point/group). 


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3) Nicotinic receptors and cognitive outcome: Cognitive deficit after SAH is a significant cause of 
morbidity and is associated with an inability to function independently and return to work.26 As 
SAH survivors are typically younger than other stroke patients, this places a significant 
economic burden on family and society. Our preliminary work examining early cognitive deficits 
have shown that cognitive dysfunction during hospitalization (defined by the modified Montreal 
Cognitive Assessment Scale (mMoCA)) is associated with worse long term functional outcomes 
as measured by the modified rankin scale (mRS). Preliminary analysis of 102 SAH patients in 
our prospective database showed that 1 point decrease on the mMoCA score was associated 
with a 1.3 times the odds of having a poor outcome (mRS >3) at 6 months when controlled for 
other clinical variables. Patients with cognitive deficit (defined by a mMoCA score of less than 9) 
were at a 7.3 times the odds of having a poor clinical outcome at 6 months compared to patients 
without cognitive deficit. 
These findings suggest that early cognitive dysfunction is a target to improve long-term 
functional outcomes. Galantamine’s ability to improve cognitive function in patients with 
dementia is well established and the mechanism is thought to be from activation of the central 
nicotinic receptors.8 The same mechanism may improve early cognitive function after SAH and 
lead to improvement of functional outcomes. 
 
Galantamine in Neurologic Disease: Galantamine is FDA approved for the treatment of 
cognitive dysfunction after Alzheimer’s disease (AD). It is a potent allosteric potentiating ligand 
of human nicotinic α7 receptors in the brain. It is also a competitive and reversible 
cholinesterase inhibitor in all areas of the body. It modulates nicotinic receptors by enhancing 
Ach activity at the synapse.25 Multiple randomized, placebo-controlled studies in patients with 
probable AD have shown that galantamine treatment in range of 16mg to 24mg daily improves 
cognitive performance.8,27–29 Galantamine has been shown to be well tolerated and improve 
cognitive and functional outcomes in patients with vascular dementia and AD with 
cerebrovascular disease. 30–32 Galantamine is widely used for the treatment of AD and vascular 
dementia. 
In addition to the evidence of safety and efficacy of galantamine for AD, studies have 
examined the effect of galantamine and similar acetylcholine-esterase inhibitors after acute 
brain injury. Specifically galantamine was studied in patients with post-stroke aphasia in a pilot 
randomized clinical trial of 45 patients with chronic post-stroke aphasia. Doses of 8mg twice a 
day titrated to 16mg twice a day was associated with improvement in aphasia symptoms. 33 
Studies have used galantamine in the chronic setting to improved cognitive functioning 
in traumatic brain injury and ischemic stroke.34 
Galantamine was studied in patients after traumatic brain injury in the chronic 
setting to improve cognitive functioning. In an uncontrolled observational study 111 patients 
were given one of three different types of acetylcholinesterase inhibitors. 30 patients received 
galantamine. The endpoints examined was a subjective feeling of improvement which was 
reported by 60% of those receiving galantamine.34 
 
A cholinesterase inhibitor, rivastigmine, has been used in the small study in SAH 
patients. In this study, rivastigmine was used in the chronic stages (at least 9 months after SAH) 
in patients with persistent cognitive deficits after SAH. They found an improvement in cognitive 


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function after 12 weeks, but as this was an observational study with no control arm, only 
speculative conclusions can be made. 35 Our study will be the first to evaluate galantamine (or 
any other α7 receptor agonist) as a treatment to reduce brain injury in the acute and subacute 
stages after SAH. 
 
Pharmacokinetics: Previous studies of galantamine have shown bioavailability from oral 
administration to be 80-100%, with a peak concentration at 1 hour and a half-life of 7 hours. 
Metabolism is through the liver.36 The bioavailability of galantamine in SAH patients who are 
critically ill is not known. However, there is evidence that other medications given orally are 
absorbed when given in this setting. Nimodipine and pravastatin are both medications which 
have been given orally after SAH and have demonstrated clinical effects.37 Although an 
intravenous formulation might provide easier administration in the acute setting, only an oral 
formulation is available. 
 
 
Objectives 
 
Primary Objective: 
 
To investigate the safety and tolerability of galantamine in SAH patients when given 36 hours 
after admission to hospital and continued for 90 days. 
 
Secondary Objectives: 
 
To develop an evidence-based hypothesis for efficacy of galantamine on the 90 day mRS. 
 
To investigate the effect of galantamine treatment on CSF and serum levels of inflammatory 
cytokines after SAH. 
 
 
Study Design 
 
This is a prospective, randomized, placebo-controlled pilot study in adult patients with acute 
SAH. We will meet all requirements of a clinical trial including protection of human subjects and 
a three person Data Safety Monitoring Board (DSMB), The study will continue for 3 years or 
until 60 patients are enrolled. Subjects included will be followed for 90 days. 
 
Primary outcomes: 
 
Primary Tolerability outcome: The ability to stay on study medication 
Primary Safety outcome: Death 
Primary Efficacy outcome: mRS at 90 days used as an ordinal variable 
 
Rate of Improvement in MoCA scores from 1 month to 3 months 
 
Mechanistic outcome: 


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Concentrations of inflammatory markers (IL6, IL10, TNFa) 
Study Scheme 
 


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Assess Eligibility 
Consent and Randomize 
 
 
Clinical events 
Study Protocol (2nd Phase) 
 
 
Securing 
Aneurysm 
 
36 hours 
 
 
 
Screening 
Angiogram 
 
8-10 day 
MoCA, mRS 
 
Discharge 
mRS 
 
If greater than 
9 anti-emetics 
in 48 hours, or 
other serious 
adverse event 
occurs 
PI, Clinical Pharmacist, Treating 
physician to determine if not 
well tolerated 
 
 
30 day FU 
 
 
60 day FU 
 
 
 
90 day FU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening/ 
Randomization 
(<36 hours) 
24-48 
hrs 
3-5 
days 
6-8 
days 
Day 10 
Day 30 
+ 7 Days 
Day 60 
+ 7 Days 
Day 90 
+ 7 Days 
Decrease dose to 4 mg per 
dose 
Randomization 
Permuted 
blocks of 2-4 
Stratified on HH 
Every 7 days attempt to 
increase dose by 4 mg until 
reach goal of 8mg q12 hrs 
90 day outcomes 
Placebo 
Galantamine 12mg q 12 hours 
Monitor for 
side effects 
30 day increase in dose by 4 mg 
60 day outcomes 


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Documentation of 
clinical severity 
Hunt Hess 
SOC 
Medical/Treatment 
History 
SOC 
NIHSS 
SOC 
CT head 
SOC 
CT Angiogram or 
Conventional 
Cerebral Angiogram 
SOC 
Informed Consent 
X 
T1: Blood 
Sample/CSF 
Sample* 
X 
First dose of 
medication- 
continued Q12h 
X 
X 
X 
X 
X 
X 
X 
T2: Blood 
Sample/CSF 
Sample* 
X 
T3: Blood Sample/ 
CSF Sample* 
X 
Surveillance 
Angiography 
SOC 
MoCA/ mRS 
X 
T4: Blood Sample/ 
CSF Sample* 
X 
Blood Sample/ CSF 
Sample *§ 
X 
X 
X 
X 
Follow Up-Clinic 
X 
X 
X 
Urine Pregnancy 
Test 
SOC 
X 
X 
X 
Outcome Scales 
(mRS, MoCA, 
EuroQOL) 
X 
X 
X 


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SOC = Standard of Care 
* CSF only if available 
§ Day 10 blood sample > 10 
days 
 
 
 
 
Study Population 
 
Subjects will be recruited among patients who are admitted to Memorial Hermann Hospital 
System and the Methodist Hospital System with SAH. The neurosurgical/neurocritical care team 
and research staff will screen for patients who are eligible. Patients and/or surrogate medical 
decision makers will be approached by the PI for enrollment into the study. 
 
Inclusion criteria: 
1) Spontaneous subarachnoid hemorrhage 
2) Presentation to hospital within 72 hours of symptoms 
3) Age 18-75 
4) Fisher grade 3 hemorrhage (thick subarachnoid clot) on initial CT scan 
5) Hunt and Hess grade 1-5 at time of randomization 
6) Presence of a cerebral aneurysm on CTA or Angiogram for which clipping or coiling is 
possible 
7) Ability to obtain medication within 36 hours of presentation. 
 
Exclusion criteria: 
1) SAH due to causes other than aneurysm rupture (trauma, AVM, mycotic aneurysms, 
Moyamoya) 
2) Pre-existing disability with mRS≥2, 
3) Renal disease as defined by creatinine clearance less than 9mL/min 
4) History of severe hepatic impairment (Child-Pugh score of 10-15) 
5) History of COPD or asthma 
6) History of dementia 
7) Co-morbid conditions likely to complicate therapy, including clinically significant arrhythmia, 
AIDS, autoimmune disease, malignancy, and expected mortality within 72 hours 
8) Expected mortality within 72 hours as determined by PI, treating neurointensivist and 
neurosurgeon. (Clinically manifested by no attempt at securing aneurysm) 
9) Females who are pregnant. 
 
Study Procedures 
 
This is a pilot study to investigate the safety and tolerability profile of galantamine when given to 
patients after SAH. Patients admitted to Memorial Hermann Hospital System and the Methodist 
Hospital System with aneurysmal SAH will be screened. All patients will be cared for in the 
NSICU as is routine by experienced neurosurgeons and neurointensivists. Those patients or 
legal surrogates of patients meeting study criteria will be offered consent to participate. All 
patients enrolled will receive standard of care in adherence to the American Heart Association 
guidelines for the treatment of SAH patients.38 
 
A total of 60 patients will be enrolled. In the first phase subjects will be randomized to 
galantamine 8mg twice a day or placebo starting within 36 hours and after securing the 


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aneurysm. After 30 subjects are enrolled, an interim analysis will be performed. Close clinical 
monitoring will occur to detect potential side effects of the medication.  Adverse outcomes will 
be examined with the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
When an adverse event occurs determination of causality will be examined. All serious adverse 
events meeting Grade 4 criteria will be communicated to the DSMB. All serious adverse events 
which are unexpected and related will be reported to the DSMB within 7 calendar days of the 
determination by telephone, email or fax. All other SAEs will be collected and submitted with the 
report to the DSMB. 
 
Randomization 
Eligible patients will be approached as early as possible after presentation to the 
hospital. Once consented, randomization will be performed by the respective research 
pharmacy. We plan to randomize using permuted blocks of 2 to 4. The Hunt and Hess Score 
(HH) is a score based on the neurologic examination the strongest predictor of mortality after 
SAH. Patients who present with a HH 4 or 5 are at a much higher risk of dying compared to 
patients who present with a HH1, HH 2 or 3. To account for this we will be stratified based on 
admission HH (HH2 and 3 versus HH4) to assure that groups are balanced with respect to 
clinical severity.39 
 
Galantamine dose and timing 
We will use FDA approved doses of galantamine 8mg every 12 hours in the first phase 
followed by12 mg every 12 hours in the second phase of our study. Studies in AD patients have 
shown as low at 16mg daily up to 24mg daily to be associated improved cognitive outcomes. 8 
As inflammation after SAH occur early after aneurysmal rupture we are targeting an acute time 
period of within 36 hours of hospitalization for the beginning of our treatment.16 Because of the 
potential increased risk of nausea and vomiting with galantamine, first dose of study medication 
will be given after securing the aneurysm. All subjects will be treated with placebo or 
galantamine for 90 days. As the cognitive benefits of galantamine treatment for AD is seen 
usually about 90 days of treatment we will also use this time frame for treatment after SAH.8 
In the first phase of the study we will randomize 30 subjects to either galantamine at 
8mg every 12 hours or placebo within 36 hours of presentation and after securing the 
aneurysm. Subjects will be followed for adverse effects while hospitalized which is generally for 
14 days. At 30 days and at 60 days subjects will be evaluated for tolerability. An interim analysis 
will be performed after the first 30 subjects to determine if galantamine at 8mg every 12 hours in 
the acute setting of SAH is tolerable. Tolerability will be defined by either the subject dropping 
out of the study because of side effects, the physician discontinuing the medication because of 
side effects or a difference in serious adverse effects possibly related to the medication. 
Once 30 patients are enrolled, if the medication is found to be tolerable (see tolerability 
section), the second phase of the study we will randomize 30 subjects to either galantamine 
12mg every 12 hours or placebo within 36 hours of presentation. Similarly, we will have 
evaluate tolerability for this dose population. 
 
 
Potential Adverse Effects 
Cardiovascular: Bradycardia and AV block. 2-3% of patients receiving 24 mg daily have been 
reported to have bradycardia. Our SAH patients are continuously monitored for at least 7 days 
of hospitalization on continuous telemetry as standard of care. 
Gastrointestinal: Increased gastric acid secretion. This may be associated with a higher risk for 
gastric ulcers. We routinely use histamine blockers or proton pump inhibitors in all our SAH 
patients to protect against gastric ulcer. 


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Genitourinary: Urinary retention. This is a frequent problem in the critically ill population. 
Patients routinely have urinary catheters placed as standard of care to monitor urine output. 
Nervous system: Possible seizures. SAH patients are continuously monitored for seizures. In 
addition all patients are routinely started on antiepileptic medications prophylactically. 
Respiratory: Bronchospasm. Respiratory status will be monitored continuously in the 
Neuroscience intensive care unit (NSICU) for at least the first 7 days and subsequently in the 
hospital until discharge. 
Mortality: In two controlled studies in patients with mild cognitive impairment, the incidence of 
death in those randomized to receiving galantamine was higher than placebo. The mechanism 
was unclear and main driver of difference was an unexpectedly low mortality rate in the placebo 
arm of the studies. 8,40 
 
Common adverse effects include nausea, vomiting, diarrhea, anorexia, and weight loss. These 
symptoms are also common after SAH and critical illness. Treatment will be initiated once the 
aneurysm is secured either through endovascular or surgical clipping of the aneurysm. 
 
This necessitates the need for a blinded study to detect differences between groups. 
 
 
Monitoring for Adverse Effects 
Adverse events will be assessed at all subject visits. Adverse events will be recorded in 
CRF’s with causality assessment. 


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Clinical follow-up 
Demographic information including disease severity on presentation as measured by the 
HH score, the occurrence of vasospasm on screening angiogram (performed as standard of 
care) between day 7-8 and the occurrence of DCI will be documented. The MoCA examination 
will be performed between 8-10 days or within 2 days of discharge. Follow up mRS will be 
assessed at discharge. At 45 days, subjects will be assessed for tolerability issues 
At 90 days, subjects will be assessed with the MoCA examination, EQ5D and mRS. 
Treatment arm will be unknown to subjects and investigators. 
At days 30, 60 and 90, a urine pregnancy test will be administered to women of child 
bearing potential. Adverse events will be captured at clinic visits (Day 30, Day 60 and Day 90) 
along with causality assessment. 
 
Outcome measures and statistical analysis 
The primary outcome is tolerability (including death) related to galantamine as 
adjudicated by the DSMB. The primary efficacy outcome will be mRS at 90 days. The modified 
Rankin focused assessment tool will be used to determine the mRS. If a subject is lost to follow- 
up we will use the last observation carried forward technique to fill in missing data for the mRS. 
The MoCA score, and EQ5D at 90 days will be secondary outcomes. The sample size of 60 
subjects is the number of patients we believe we can enroll into the study over a 3 year period. 
We acknowledge the limitations of a small study but plan on using results from this pilot study to 
launch a larger more definitive study. 
 
Tolerability 
Nausea and vomiting are the most likely cause of intolerance to galantamine. However, 
SAH patients frequently have these symptoms. In fact, the usual clinical presentation for 
patients with SAH is headache, nausea and vomiting. In a retrospective examination of 141 
patients admitted with SAH we found 80% of patients received anti-emetic medications with a 
median dose requirement of 4 doses (IQR 2-9). 
The upper 75% quartile of 9 doses will be used as a screening tool for the detection of 
possible intolerability of galantamine. If a patient receives more than 9 doses of anti-emetic 
medications in a 48 hour period we will examine for intolerability. The PI, the treating physician, 
and the treating clinical pharmacist will determine if dose of medication should be decreased 
because of persistent nausea and vomiting. If it is decided that the dose should be decreased 
the dose will be decreased by 4 mg from 8mg to 4 mg or from 12mg to 8 mg. This will occur 
blinded to treatment allocation. The PI will ask the research pharmacy to decrease the dose and 
the dose will be decreased whether the treatment allocation is galantamine or placebo. 
Once a tolerable dose is found the subject will continue on the dose for a total of 6 doses 
and an attempt to increase the dose by 4 mg per dose will be made until we reach the target 
dose of 8 mg twice a day in the first phase or 12mg twice a day in the second phase. If two 
attempts are made to reach the target dose but tolerability issues persist the subject will remain 
on the tolerable dose until the end of the 90 day period. 
 
Serum and CSF biomarker analysis 
 
Rationale: Increased inflammation has been associated with worse outcomes after SAH. Our 
preliminary studies examining subjects from our prospectively collected database show that 
peripheral inflammation is associated with poor clinical outcome. When examining serum from 
87 subjects collected within 48 hours after SAH, we found that inflammatory cytokines IL-6, 
MCP-1(otherwise known as CCL-2) and TNFα were all significantly elevated in subjects with 
SAH who progressed to have poor functional outcomes. In multivariable regression analysis IL- 
6 and MCP-1 were independent predictors of outcome after controlling for known confounders 


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including age, gender and HH grade. This suggests that IL-6 and MCP-1 may be surrogate 
markers for poor functional outcomes after SAH. IL-6 is an inflammatory cytokine with broad 
effects to enhance overall inflammation. It has been shown to be associated with worse clinical 
outcomes in acute brain injury.18,37 MCP-1 is a chemokine which attracts predominantly 
monocytes and modulates blood brain barrier permeability.38,39 Elevated levels in CSF have 
been associated with poor outcome in patients after SAH.38 Studying the effects of galantamine 
on these cytokines will give an indication whether galantamine has an influence on inflammation 
after SAH. 
 
In addition to traditional statistical comparisons network analysis techniques can be used to 
examine the association between multiple variables. The complex nature of cytokine reactions 
lends itself to this type of analysis. Preliminary studies in our laboratory using an array of 9 
cytokines showed differential activation of cytokine networks after SAH between subjects with 
good and poor outcomes as defined by the mRS at discharge. Specifically we found that 
patients with poor clinical outcomes had a higher number of significant associations compared 
to those with good outcomes (18 vs 11) suggesting uncontrolled activation of the inflammatory 
cascade. Additionally, there was an increase in correlation strengths in all common significant 
associations in patients with poor outcomes. For instance, in patients with poor discharge 
outcomes, the IL-6- MCP1β correlation was 78% more compared to patients with good 
outcomes. 
 
 
Methods and analysis: Serum and CSF samples will be collected at 8 different predetermined 
time points. A sample will be collected within 24 hours of admission, (before medication is 
administered), as a baseline to compare changes in cytokines over time. Samples will be 
collected between 24-48 hours (after medication is administered), then between 3-5 days, 6-8 
days and after 8 days. Levels of inflammatory molecules will be determined by a multiplexed 
bead array assay platform from BioRad that interrogates the levels of 40 different cytokines and 
chemokines including IL-6, MCP-1, and TNFα. Samples will be assayed in triplicate and 
compared to simultaneously prepared standard curves to determine concentrations. Cytokine 
levels do not typically show a normal distribution, therefore their levels will be compared using 
the Mann-Whitney U test between subjects who receive galantamine and placebo at each time 
point. As there can be high variability in cytokine levels, we will use each subject’s baseline 
cytokine levels (before medication) and measure changes in cytokine levels over time. 
Differences in changes of cytokine at separate time points between the two groups 
(galantamine and controls) will be compared. 
 
Pairwise Pearson’s correlation coefficients will be computed between all pairs of cytokines and 
a network will be constructed. Networks will be made for subjects who received galantamine 
and those who received placebo. Networks will be examined for qualitative differences. In 
addition we will examine for significant differences in the number of associations and differences 
in strength of associations between those who receive galantamine and controls. A student’s t- 
test and Mann-Whitney U test will be used to test for significant differences in correlation 
strengths between the networks. 
 
Appropriate measures will be used to control for Type-1 errors common in multiple 
comparisons. The Benjamani-Hochberg (BH) method with a critical value of 0.1 will be used to 
adjust p-values to control false discovery rate (FDR). To account for repeated measures over 
time in cytokine levels per subject mixed effects modeling will be used.41 In addition, we will 
examine whether there is a dose effect relationship between cytokine levels and galantamine 


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dose. However, given the small sample size the relationship will be qualitative and not 
quantitative. 
 
 
Collection of Specimen 
 
Plasma for biomarker analysis: Blood will be withdrawn from existing lines or by venipuncture 
and collected into two pink top K2EDTA 6ml (plasma) Vacutainers per time point (36 ml). The 
samples will be placed on ice and will be centrifuged at 1,459 X g for 10min at 4oC. The 
supernatant solution will be removed and centrifuged at 1,459 X g for 10min at 4oC to generate 
platelet-poor plasma. Plasma will be divided into aliquots and frozen at -80°C until needed. For 
those subjects providing consent, any residual sample and buffy coat will be frozen at -80°C for 
future study. 
 
CSF for biomarker analysis: Patients with a ventriculostomy drain will have 1-5 ml of CSF 
sampled from the receptacle at each of 5 time points. The receptacle will be emptied into the 
collection bag (the volume will be noted in the nursing notes) to start with an empty receptacle, 
several drops of CSF will then be allowed to drip into the chamber. The drain will be re- 
clamped; the chamber port will be cleaned with chlorhexidine as per hospital specifications and 
the CSF sample drawn from the port with a sterile syringe. CSF will be centrifuged (4°C, 1,459 
X g for 10 minutes) and portioned into aliquots and frozen at -80oC; any residual sample will be 
frozen at -80°C for future study. The CSF pellet should be covered in a 10% DMSO solution 
(e.g., 100µl CSF plus 11µl DSMO) and frozen at -80oC and transferred to -145°C after 24hrs 
when possible. 
 
Samples will be labeled with bar-coded subject study identification numbers, sample type and 
time point. They will be stored indefinitely at the University of Texas Health Science Center at 
Houston, Neuroscience Research Repository, Hergenroeder Laboratory, The Vivian L. Smith 
Department of Neurosurgery, 6431 Fannin Street, MSB 7.149, Houston TX 77030 
 
 
Data and Safety Monitoring 
 
Safety assessments will consist of monitoring and reporting adverse events (AEs), selected 
adverse events of interest, and serious adverse events (SAEs), both anticipated and 
unanticipated. An Adverse Event is any undesirable and unintended, although not necessarily 
unexpected, event occurring in human subjects as a result of (a) the interventions and 
interactions used in the research; or (b) the collection of identifiable private information under 
the research. A Serious adverse event is an adverse event that led to death, or to serious 
deterioration in the health of the subject, that resulted in death, was life-threatening, required 
hospitalization (initial or prolonged), resulted in disability or permanent damage, congenital 
anomaly/birth defect, required intervention to prevent permanent impairment or damage, or 
other serious events (Important Medical Events). NOTE: Planned hospitalization for a 
preexisting condition, or a procedure required, without serious deterioration in health, is not 
considered a serious adverse event. An unanticipated adverse effect is defined as any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or 


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associated with, a medication, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with 
a medication that relates to the rights, safety, or welfare of subjects. 
Once a SAE occurs then an adjudication process will occur to determine if it was possibly 
related to the study medication. The PI and the treating physician or if the PI is the treating 
physician, the PI and another blinded board certified neurointensivist will come to a consensus 
of whether the SAE was possibly and probably related to the study medication. 
SAE’s that are determined to be unexpected and related will be submitted to the DSMB within 7 
calendar days of the determination by telephone, email or fax; written reports will be submitted 
no later than 15 calendar days of the determination. 
 
Adverse events will be graded according to the USDHHS Common Terminology Criteria for 
Adverse Events V4.0 (USDHHS, Table 2) and summarized according to body system. Primary 
focus for analysis will be on tolerability of galantamine and 3-month mortality rate. For the 
purpose of safety monitoring, adverse events Grade 4 or higher will be classified as important 
AEs. 
Safety/ Stopping Rule 
As galantamine is routinely prescribed for patients with dementia, it is likely to be safe in 
the SAH population as well. In our prospective SAH database, we have a 10% mortality rate in 
patients. This is a much lower mortality rate compared to other published rates (30-40%) mainly 
because we will exclude patients who are likely to die imminently.1 We will use a Bayesian 
approach of probably of harm to stop the study. Using a previous estimate of death in our 
patient population of 10% in both arms and a neutral prior with a 95% CI of 0.22-3.0. Using 
10,000 simulated trials the probability of stopping incorrectly using the decision rule to stop if 
there’s an 80% probability of increased death in the drug group. The chart below is the stopping 
rules for the study. Depending on the number of subjects randomized 
 
Num of 
subjects/arm 
Prob of incorrectly stopping # of excess 
deaths 
6 
1% 
3 
10 
3% 
3 
15 
4% 
3 
20 
5% 
4 
30 
8% 
4 
 
If stopping rules are met enrollment into the study will be stopped. The DSMB will convene and 
determine if excess deaths were related to galantamine and will make the determination about 
continuation of the trial. 


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A Data and Safety Monitoring Board (DSMB) will be established. The DSMB will include a 
biostatistician with expertise in research design and an expert in management of brain injured 
patients. The PI or Co-PI will monitor safety of each enrolled subject. In addition, tolerability will 
be ongoing with each subject as well as a planned interim analysis. Enrollment will be ongoing 
during this assessment. Safety for death will occur according to the table provided for the 
number of excess deaths in the treatment group. 
 
Statistics 
 
Interim analysis: 
 
Interim analysis will be performed after 30 patients are randomized. (15 in each arm). 
Intolerability will be defined as the need to decrease dose of medication because of side effects, 
mainly nausea and vomiting. At this time if the galantamine arm has more than 30% 
intolerability in the first month, defined by dropping out of study because of intolerability, 
decreasing dose to 4mg every 12 hours because of intolerability or difference in SAEs, 
compared to the placebo arm, in the second phase of the study we will decrease the starting 
dose to 4 mg every 12 hours and attempt to increase after 7 days to 8 mg every 12 hours. 
 
 
 
 
Placebo (N=15) 
Active (N=15) 
Action 
 
 
 
% of subjects 
requiring dose 
X 
decreases 
Less than X+30 
Continue to a goal 
of 12mg q12 
 
Greater than 
X+30 
Decrease starting 
dose to 4mg q12 
 
 
 
 
The enrollment will be held only for assessment of intolerability from the first month of 
galantamine as side effects and intolerability is likely to occur during initiation of therapy. 
 
The primary efficacy endpoint will be the mRS used as an ordinal variable (5 and 6 will be 
grouped). Analysis will be stratified based on HH grade. All results will be reported as Relative 
Risks with 95 CI. The estimates of relative risk found in this study will be used for future meta- 
analysis or planning for the next phase clinical trial. In the larger study, utilizing a Bayesian 
approach, the posterior estimate and 95% CrI could be utilized as prior estimates for the larger 
confirmatory trial. Secondary outcomes including the mMoCA performed between 14-21 days or 
within 2 days of discharge, MoCA scores at 30, 60 and 90 days, and the EQ5D at 30, 60 and 90 
days will be also be reported similarly. 
 
 
Ethics 


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This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the University of Texas Health Science Center at Houston IRB. A 
signed consent form will be obtained for every subject either by the subject or a LAR if the 
patient is not able to consent. The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy of the consent 
form will be given to the patient or LAR. 
 
 
Data handling and record keeping 
 
 
Study personnel will collect information on subject characteristics such as demographics, 
medical history, and other clinical information. The initial assessment of the subject will be 
recorded including physical and neurological examination, vital signs, laboratory tests, and 
radiographic imaging. In addition, as part of the baseline data collection, family members will be 
asked to complete a contact information form with the names, addresses and phone numbers of 
other people who could assist in locating him/her if the study coordination cannot locate him/her 
for the scheduled phone interviews. The study will consider the use of a locator service for 
patients potentially lost to follow-up. 
Additional CRFs will be generated to record disease and injury-related events, treatments and 
interventions during the initial hospitalization, and safety data for adverse event reporting. 
Federal law now holds the statute of limitations at six years to bring forward an allegation of 
research misconduct. In response to this extension, research records must be retained for a 
sufficient period to investigate an allegation of research misconduct - - a minimum period of six 
years. Additionally, existing Federal regulations [56 CFR 56.115(b)] require that IRB records be 
retained for at least 3 years after completion of the research. All records must be accessible for 
inspection and copying by authorized representatives of HHS and Food and Drug 
Administration at reasonable times and in a reasonable manner. At the end of the three year 
period, the IRB records may be boxed, labeled and sent to central storage for an additional 3-10 
years. A log of stored records is maintained in the IRB office for retrieval if files are needed for 
audit or other purposes. 
Records will be maintained in a de-identified manner in a secure, locked location to ensure 
confidentiality. Subjects will not be identified in any manner in any publications resulting from 
this project. 
 
De-identified data will be collected from the pre-hospital period through 6 months post injury. A 
linking list will be maintained by the investigative team at each site to allow for patient follow-up. 
Protected health information (PHI) is confidential and not shared outside the study team. Written 
data will be stored in locked areas; electronic data will be password protected in secure zones. 
Patient name and contact information will be separated from subject data. The PI will monitor 
protocol compliance and data integrity.  Routine data audits will be conducted internally to 
assure consistency and integrity of the data. Additionally, an independent data auditor will verify 
data quality. 


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Quality control and assurance 
 
De-identified data will be collected from the pre-hospital period through 3 months post SAH. A 
linking list will be maintained by the investigative team at each site to allow for patient follow-up. 
Protected health information (PHI) is confidential and not shared outside the study team. Written 
data will be stored in locked areas; electronic data will be password protected in secure zones. 
Patient name and contact information will be separated from subject data. The PI will monitor 
protocol compliance and data integrity.  Routine data audits will be conducted internally to 
assure consistency and integrity of the data. 
 
Data will be linked by unique ID. The study statistician will independently review the forms and 
the entered data. The database will incorporate quality control checks at data entry, and quality 
assurance programs will be written for acquisition, management, tracking and retrieval and will 
be run regularly. The database will be backed up onto separate media. The database is 
maintained for statistical analysis purpose only; thus, all electronic files will be de-identified. The 
database will be password protected and maintained in secure research offices in a secure 
research building. Data validation checks identifying outliers will generate queries which will be 
evaluated and if necessary returned to the clinical study site for data validation.  An audit trail 
will be maintained on changes to the database. 
 
Database queries will be designed and implemented to oversee compliance with all study 
documentation and timely completion of CRFs. Protocol deviations, record completion, and 
regulatory compliance will be reviewed the PI. All study documents and pertinent records will be 
available for inspection by the DSMB or other designated monitoring authority. 
 
 
Publication Plan 
 
The study will be reported on clinicaltrials.gov and other scientific medical journals. The results 
will not be returned to specific research subjects. 
 
 
ATTACHMENTS 
 
 
1. Schematic of Study Design 
2. Study Schedule 
3. Consent Document 
4. Case Report Form 


UT Houston Protocol Template 
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