Clinical trial NCT01554683
Conditions: Alzheimer's Disease Seizures
Keywords: Alzheimer's Disease Seizures Memory Executive
Sponsor: Beth Israel Deaconess Medical Center
Start date: 2012-02-01; Completion date: 2017-07-01
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this research project is to study how seizure-like activity affects the blood flow in the brain of patients with Alzheimer's disease (AD). Changes in blood flow can change memory and thinking ability, as happens in Alzheimer's disease. The investigators are using a study drug called Levetiracetam, which helps control seizure-like activity to see if it can help change the abnormal blood flow in the brain that is seen in some people with Alzheimer's disease.

Detailed description:
Subjects will make four separate visits to BIDMC. Subject will come to the Clinical Research Center. All of the visits will take around 5 hours apiece.

If subjects agree to be in this study, subjects will be asked to read and sign the consent form. After subjects sign the consent form, the following things will happen:

1. Screening Procedures: Screening procedures are tests and procedures that will be done to determine if subjects are eligible to take part in the research study. For this research study, the screening procedures include:

   * A thorough medical history. Investigators will ask if subjects have any medical problems. Investigators will ask about subjects Alzheimer's disease and if they have had any seizures.
   * A physical examination. Investigators will take your blood pressure and your heart rate. They will examine your heart and lungs and take your height and weight
   * Investigators will also assess the subject's nervous system. Investigators will examine subject's speech, memory, strength, coordination, and reflexes.
   * Investigators will ask you to take some paper and pencil tests. This will help us to understand your memory and mood
   * Subjects will have a blood test to check how your kidneys are functioning.

   Subjects may have already had some of these tests done by their doctor when they were diagnosed with Alzheimer's disease.

   The information we learned will help to decide whether subjects could join the study. Investigators will explain the reason if they decide subjects should not join the study. Our decision does NOT mean that subjects have a health problem or disorder .
2. Randomization Procedures: Investigators will meet with one of the study doctors if subjects continue in the study. The study doctor will explain to subjects when they are expected to come to the research center for study testing or to take the study drug. Subjects will come to the BIDMC Clinical Research Center for three visits. These visits will occur within one month.

   All study participants will receive the same study drugs over the three (3) visits.
   * Subjects will receive levetiracetam, the study drug, in a low dose, 2.5 milligrams for each kilogram of body weight, at one visit.
   * Subjects will receive levetiracetam, the study drug, in a high dose, 7.5 milligrams for each kilogram of body weight, at one visit.
   * Subjects will receive a placebo at one visit.

   A placebo is an inactive injection that looks like the study drug, but a placebo contains no active medication. In this study, the placebo is a saline (sterile salt water) injection.

   Sometimes study results are truly due to the study medication. Sometimes the study results are not due to the study medication. Investigators are using a placebo to help us understand the reason for the results in this study.

   The order of the above visits will not be the same for all study participants. There are six different orders to receive the study drugs. For example, subjects could receive the placebo at the first visit, the high dose of levetiracetam at the second visit, and the low dose of levetiracetam at the third visit. Another example is that subjects could receive the low dose at the first visit, the placebo at the second visit, and the high dose at the third visit.

   Deciding the order in which you get the study drugs will be done by to a method called "randomization." Randomization means that a computer will assign patients to study drugs in a random manner, like flipping a coin. Another way to say randomization is "by chance." When you flip a coin, you get heads or tails by chance. The chance of getting any dose of study drug or placebo is about equal. After the randomization, Subjects will be assigned to get one study drug or placebo at each visit. Subjects will not be able to choose which study drug you will get at each visit.

   Subjects will not know which study drug dose or placebo will be given at a visit. The study doctor will not know which study drug dose or placebo will be given at a visit. The study doctor can find out this information quickly if there is an emergency.
3. Research Procedures: Subjects will come to the BIDMC Clinical Research Center three times if they continue in this study. A member of the study team will meet subjects when they arrive. Subjects will first have an intravenous catheter (also called an IV) put into a vein. A nurse will check blood pressure and heart rate. Subjects will have a brief physical exam and a nervous system exam by a doctor

   Subjects will then have an electroencephalogram (EEG). An EEG gives investigators information about the nervous system - specifically the brain. Subjects will have their scalp cleaned with alcohol and small discs - called electrodes - placed on the scalp using gel. Then the head will be will be wrapped with gauze to. keep the discs from moving. The discs will be attached by wires to an EEG machine. The EEG machine will be at the bedside and will give investigators information about the electrical activity in the brain. Subjects will need to lie quietly with eyes closed during the one hour that the EEG machine is attached. Investigators will clean the gel from hair and skin when the EEG is over.

   Investigators will give subjects either levetiracetam -- the study drug -- or placebo while subjects are having EEG. Investigators will give subjects the study drug or placebo through the intravenous catheter ("IV") in the arm. This will take around 20 to 30 minutes. The subjects nurse will take the subject's blood pressure and heart rate two times while the study drug is being given to the subject and again after it is finished. The subject will note any side effects they have during this time and after.

   Subjects will then review what will happen during the MRI scan with the Investigator. The MRI study will be conducted at the Magnetic Resonance Imaging Center of the Department of Radiology at the Beth Israel Deaconess Medical Center.

   The MRI is a method of taking pictures of the brain and of the blood flow in the brain, using a large magnet and radio signals. Subjects will be asked to lie down on a platform that can be slid into the magnet. An MRI imaging coil, which is made from special wires that are covered in plastic, will be placed around the head. Foam pads will be placed around the head to limit head movement during the scan. During the scan, subjects will be asked to lie still on their back for about 45 to 60 minutes. They will hear a loud knocking or hammering noise while the MRI is taking pictures, but the process itself will be painless. They will be given disposable earplugs to use to help lessen the noise. During the procedure, subjects will be in constant contact with the MRI technician through an intercom. If at any time during the scan you feel too uncomfortable to continue, no matter what the reason, the study will be immediately stopped and subjects will be removed from the magnet (MRI Scanner).

   Subjects will return to the Clinical Research Center after the MRI. They will take a few pencil-and-paper tests for about one hour. These tests will tell the investigator about memory and mood. They will also learn about your attention skills. Investigators will also learn about the subjects= language skills and "handedness" (a tendency to favor right or left hand).

   As the medication (levetiracetam) may make the subject drowsy, they will not be able to drive. Someone will need to accompany them to and from the hospital for the three study visits.

   The second and third study visits will have the same sequence of events.

   SUMMARIES

   Here is a summary of the Screening Visit

   Screening visit / informed consent Review your medical history. Brief physical and neurological exam. Paper and pencil tests. Blood drawn to check the functioning of kidneys. Review and sign the informed consent form.

   Here are summaries of the three Study Visits

   Visit One

   :

   Vital signs. 2 minutes Brief physical and neurological exam. 10 minutes An intravenous catheter placed in your arm. 5 minutes EEG. 60 minutes Intravenous dose of the medication, levetiracetam, or placebo. 20 minutes MRI scan. 60 minutes Paper and pencil tests. 60 minutes

   Study Visit Two: (This visit will occur one to two (1-2 )weeks after Study Visit One)

   Vital signs. 2 minutes Brief physical and neurological exam. 10 minutes Intravenous catheter placed in your arm. 5 minutes EEG. 60 minutes Intravenous dose of the medication, levetiracetam, or placebo. 20 minutes MRI scan. 60 minutes Paper and pencil tests. 60 minutes

   Study Visit Three: (This visit will occur one to two (1-2 )weeks after Study Visit Two)

   Vital signs. 2 minutes Physical and neurological exam. 10 minutes Intravenous catheter placed in your arm. 5 minutes EEG. 60 minutes Intravenous dose of the medication, levetiracetam, or placebo. 20 minutes MRI scan. 60 minutes Paper and pencil tests. 60 minutes

   Each visit will take a total of approximately 5 hours. This includes the time for the EEG, MRI imaging and neuropsychological tests. Subjects will be allowed time to rest between activities on a bed if they become tired. The CRC staff will serve lunch.
4. Monitoring/Follow-Up Procedures. Procedures performed to evaluate the effectiveness and safety of the research procedures are called "monitoring" or "follow-up" procedures. Subject follow-up procedure will be a phone call from the study doctor one week after the third visit. They will ask if any side effects from the study or study medication occurred

Timing: If subjects are enrolled into the study following the initial screening visit, each of the three study visits will be separated by 2-3 week intervals. Therefore, the entire study will last approximately 6-9 weeks.

Arms: arm 1: Low Dose Levetiracetam administration via IV infusion over 20 min arm 2: High Dose Levetiracetam administration via IV infusion over 20 min arm 3: Saline administration via IV infusion over 20 min
Interventions: intervention 1: Low/High/Placebo Dose Keppra (Levetiracetam)
Intervention descriptions: intervention 1: Low Dose (2.5 mg/kg) High Dose (7.5 mg/kg) Placebo (Saline)

Protocol documents:
Prot_SAP_000.pdf: 
(CCI) Committee on Clinical Investigations 
Page 1 of 18 
 
Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
Seizure-like Hippocampal Activity in Alzheimer’s Disease 
Neurodegeneration 
Principal Investigator 
Daniel Z. Press, M.D. 
Co-Investigators 
Susan T. Herman, MD; David C. Alsop, PhD; Sanjin 
Tunovic 
Mailing Address 
330 Brookline Ave, KS-446, Boston, MA, 02215 
E-Mail Address 
dpress@bidmc.harvard.edu 
P.I.’s Telephone   
7-0459 
P.I.’s Pager  3-4448 
Fax: 7-7981 
Sponsor/Funding Source 
Fidelity Biosciences Research Initiative; Neurology 
Department internal funding 
 
 
B1. 
PURPOSE OF PROTOCOL 
 
To test the hypothesis that increased hippocampal perfusion on arterial spin labeling 
MRI in patients with Alzheimer’s Disease (AD) is partially driven by focal epileptiform 
activity, and that this abnormal activity contributes to memory dysfunction. 
 
Here we propose applying an imaging technique, arterial spin labeling MRI (ASL-MRI), ideally 
suited for testing this hypothesis.  We will utilize a pharmacological probe, levetiracetam, to test 
whether sub-clinical epileptiform activity is driving increases in hippocampal perfusion and 
contributing to the declarative memory impairment in AD.  Levetiracetam is an antiepileptic 
drug (AED) that inhibits epileptiform activity.  Levetiracetam inhibits burst firing without 
affecting normal neuronal excitability.  We will study patients with mild AD in three sessions, 
counterbalanced for order, in a crossover design. In each session, participants will undergo a 
baseline electroencephalogram (EEG).  They will then be given either a placebo or 
intravenous levetiracetam low dose (2.5 mg/kg) or high dose (7.5 mg/kg). After drug 
administration, repeat EEG, ASL-MRI perfusion imaging, and behavioral testing will be 
conducted.  Participants will return at 1-2 week intervals for the second and third sessions in 
the other conditions (levetiracetam low dose / levetiracetam high dose / placebo). This study 
will test whether increased hippocampal perfusion in AD is caused by epileptiform activity, 
whether this activity is contributing to memory impairment, and whether antiepileptic 
medications might be a new avenue of treatment in AD. If validated, ASL-MRI would be an 
ideal tool to non-invasively determine whether antiepileptic medications are effective in 
decreasing aberrant excitatory activity in the hippocampus in AD.  
 
Aim 1: To determine whether increased hippocampal perfusion in AD is caused by 
epileptiform activity. 
 
Hypothesis 1: Hippocampal perfusion in AD will be decreased after the administration 
of an antiepileptic medication, levetiracetam, but not after placebo.  
 
Aim 2: To determine whether inhibition of burst firing can improve cognitive 
performance and neural function in cortical regions beyond the hippocampus. 
 
Hypothesis 1: Decreases in hippocampal perfusion will correlate with improvements in 


(CCI) Committee on Clinical Investigations 
Page 2 of 18 
 
Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
measures of declarative memory and spatial memory. 
 
Hypothesis 2: Decreases in hippocampal perfusion will correlate with increases in 
cortical perfusion, particularly in lateral temporal and parietal association cortices. 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Seizures and Alzheimer’s Disease 
 
Alzheimer’s disease (AD) is associated with an increased risk of unprovoked seizures and 
accounts for approximately 2% of all epilepsy 1. Clinical seizures develop in 1.5 -17% of long-
term AD survivors, most commonly in those with early age at disease onset and with familial AD 
2-4.  In familial AD due to mutations in presenilin, epilepsy is much more prevalent, approaching 
80% of affected members 5-7.  Seizures may be more common in sporadic AD, however, than 
previously reported 8.  Seizures may be under-recognized in patients with dementia.  Subjective 
seizure auras such as déjà vu, olfactory hallucinations, and other auras are uncommon in AD 3.  
Clinical manifestations of temporal lobe seizures are often subtle.  For example, focal seizures 
restricted to the hippocampus may produce only mild confusion or amnesia without other 
outward signs 9.  Fluctuations in memory or wandering in AD can be due to unrecognized complex 
partial seizures 10.  Such seizures might easily be missed in patients with baseline memory and 
cognitive deficits.  Seizures in AD are usually considered to be rare and late byproducts of a 
diffuse neurodegenerative process, but recent evidence from animal studies has raised the 
intriguing possibility that epilepsy plays a more central role in the pathophysiology of AD. 
 
The exact mechanism of epileptogenesis (development of spontaneous seizures) in AD is not 
known, but new data from transgenic mice expressing human amyloid precursor protein (APP) 
in neurons suggest that high levels of beta amyloid (Aβ), the amyloid protein tightly linked to AD, 
are sufficient to elicit epileptiform activity and seizures 11.  The excitatory connections within the 
perforant pathway of the hippocampus also promote focal epileptic activity. Inhibitory connections 
outside the hippocampus and entorhinal cortex can prevent the propagation of seizures beyond 
the medial temporal lobes. Epileptic activity directly damages the hippocampus via hypoxia and 
ischemia 12. Ischemia in turn increases amyloid deposition in a potential feedback loop 13 (see 
Figure 1). 
 
Human amyloid precursor protein (hAPPJ20) mice have high levels of Aβ peptides in the brain 
without significant neuronal loss, and develop cognitive deficits comparable to those seen in 
human AD.  Continuous video-EEG monitoring with intracranial electrodes in hAPP mice 
demonstrates frequent epileptiform activity including spikes, sharp waves, and spontaneous 
nonconvulsive seizures in both hippocampus and multiple neocortical regions.  These seizures 
have no outward clinical manifestations.  Epileptic activity leads to hypoxia-ischemia, which can 
then lead to increased amyloid deposition 13.  Animal studies show that amyloid acts as an 
excitatory epileptogenic stimulus in the hippocampus, leading to compensatory upregulation of 
inhibitory, GABAergic interneurons 11.  Network changes in hAPP mice include both aberrant 
network excitability and compensatory inhibitory mechanisms, such as GABAergic sprouting, 
enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus.  The interplay 
of excitatory and inhibitory changes prevents seizure generalization, but inhibits proper 
hippocampal function.  Similar epileptiform activity has been identified in independent transgenic 
mouse models of AD 14-17, further highlighting the importance of APP and Aβ for the genesis of 
epileptiform activity. 


(CCI) Committee on Clinical Investigations 
Page 3 of 18 
 
Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
 
Could a similar pathophysiological chain be occurring in patients with AD and, if so, could these 
events contribute to the pathological changes in the hippocampus and connected regions (figure 
1)?  In hAPP mice, the degree of network changes is correlated with deficits in learning and 
memory 11, 18.  More importantly, many of the Aβ-induced neuronal alterations as well as 
learning and memory deficits could be prevented by blocking excitotoxin-induced overexcitation 
19.  These findings raise the possibility that hippocampal epileptiform and seizure activity may 
not be solely an epiphenomenon of progressive neurodegeneration, but may play a causal role 
in the cognitive deficits in hAPP mice and possibly also humans with AD.  Confirmation of a 
relationship between excitatory neuronal activity and cognitive deficits in humans with AD would 
provide new insights into the pathogenesis of AD as well as open new potential avenues for 
therapy.  
 
 
 
Arterial spin-labelling MRI to detect hippocampal blood flow changes 
 
Demonstrating whether similar epileptiform activity and seizures occurs in the hippocampus of 
humans with AD is challenging.  Surface EEG, dense array EEG, and magnetoencephalography 
are extremely limited in their ability to detect hippocampal epileptic activity 20-22. The 
hippocampus can be recorded with intracranial depth electrodes, but these are invasive and 
carry a risk of hemorrhage and infection.  For this reason, indirect measures of hyperexcitability, 
such as increases in cerebral blood flow by functional MRI or SPECT, are commonly used to aid 
in localization of deep epileptic foci.  The mechanism of hyperperfusion due to seizure activity is 
not completely understood, but may be related to transient loss of autoregulatory function in 
surrounding vasculature or to the release of excitatory neurotransmitters such as glutamate in 
areas of increased neuronal firing.   
 
In this project, we hypothesize that aberrant epileptiform and seizure activity occurs in the 
hippocampus in patients with AD, and that suppression of epileptiform activity will improve 
memory deficits. We will study hippocampal activity using a proxy for epileptiform activity, 
Arterial Spin Labeling MRI (ASL-MRI), as well as EEG.  We have completed a study of brain 
perfusion in mild-AD using Arterial Spin Labeling MRI (ASL-MRI), a non- invasive technique to 
quantifiably measure cerebral blood flow 23. We found decreases in cerebral perfusion in lateral 
temporal and parietal cortex, in agreement with previous PET studies. In addition, we found 
increased perfusion in the hippocampus, particularly when the perfusion measure was corrected 
for atrophy 23, Figure 2.  These unexpected findings were recently corroborated 24, 25.  A similar 
pattern of increased hippocampal activity has been seen with functional MRI, where patients 
with mild cognitive impairment show increased activation, a finding recently extended to 
presymptomatic patients with familial AD 26, 27.  Hippocampal hyperperfusion can also be seen in 
Figure 1. Possible pathway linking AD with 
aberrant epileptic activity.  Amyloid deposition 
leads to epileptic activity.  


(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
mild cognitive impairment and even in healthy elderly patients with apoE4 allele, which 
predisposes to development of AD. 
 
 
 
In our previous study of 22 AD participants (mean age=75.6, MMSE 22.2) and 16 
demographically matched controls (mean age=72.6, MMSE 27.9), we measured hippocampal, 
amygdala, and parahippocampus CBF as a % of visual cortex. In addition, we corrected for 
atrophy on a voxel-by-voxel basis by measuring gray matter volume in each voxel using T1 
maps that were acquired in the same sequence as the perfusion maps. A region of interest 
analysis was performed using an a priori template, with left and right regions averaged together. 
The table below shows the results of the atrophy-corrected perfusion measurements as a 
percentage of visual cortex perfusion. 
 
 
Hippocampus 
Amygdala 
Parahippocampus 
Mean AD (SD) 
0.96 (0.29) 
0.61 (0.19) 
0.74 (0.20) 
Figure 2.  Arterial spin labeling is a non-invasive technique to measure cerebral perfusion by 
applying a magnetic “tag” to arterial blood without requiring administration of a contrast agent 
(panel A).  We have previously found increased hippocampal perfusion in AD participants that was 
visible at the individual level (top of panel B is AD participant, bottom is age-matched control).  The 
perfusion change was prominent at the group level (panel C shows individual data points, panel D 
shows statistical maps of group data and panel E shows areas of both decreased perfusion in 
temporal-parietal cortex (in red) and increased perfusion in medial temporal structures (in green). 


(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
Mean CN (SD) 
0.77 (0.17) 
0.52 (0.11) 
0.62 (0.14) 
Prob of difference 0.008 
0.043 
0.017 
 
Choice of levetiracetam as a pharmacologic probe 
 
In this pilot study, we aim to determine whether the hippocampal hyperperfusion seen on ASL-
MRI reflects abnormal epileptiform activity by using levetiracetam as a pharmacological probe.   
Even intermittent epileptic discharges, in the absence of clinically obvious seizures, may lead to 
memory impairment.  If so, a reduction of hippocampal epileptiform activity could improve 
declarative memory and potentially alter progression of AD. 
 
Levetiracetam, a newer antiepileptic drug, decreases the frequency and limits propagation of 
epileptiform activity without affecting normal neuronal excitability 28, 29.  The mechanism of action 
of levetiracetam is not fully understood, but it binds specifically to synaptic vesicle protein SV2A 
and likely modulates its function 30.  Levetiracetam may also have an indirect effect on GABA-A 
inhibitory neurotransmission and on high-voltage activated calcium channels.  Levetiracetam 
decreases cortical excitability measured by transcranial magnetic stimulation 31.  In a study of 
levetiracetam in photosensitive epilepsy, 250mg oral doses decreased epileptiform activity 
induced by photic stimulation within 1 hour, and 750mg oral doses completely abolished 
epileptiform activity 32.  Acute dosing of levetiracetam 500mg caused significant reduction in the 
frequency of interictal epileptiform activity in 8/10 patients with epilepsy 33.  Because of its rapid 
onset of action and effect on interictal epileptiform activity as well as seizures, levetiracetam is 
an excellent candidate AED to examine changes in perfusion on ASL-MRI. 
 
Levetiracetam is FDA-approved for the treatment of partial epilepsy in adults and children > age 
4 years.  Levetiracetam has a serum half-life of 10-11 hours in healthy elderly subjects 34.  
Excretion is 100% renal; the half-life is prolonged in patients with renal impairment.  There is no 
significant plasma protein binding.  Because levetiracetam is not metabolized by hepatic 
microsomal P450 enzymes, it has no known drug interactions and kinetics are linear 35.  
Levetiracetam intravenous infusion is bioequivalent to oral tablets 36.   
 
Cognitive effects of acute administration of levetiracetam have been studied in healthy 
volunteers, ages 20-50 years 37.  There was no difference between levetiracetam and placebo in 
the summary score for the cognitive neurophysiologic test (CNT), which combines 
electroencephalography (EEG), evoked potential (EP), and cognitive performance measures. 
 
Levetiracetam is a well-tolerated and safe AED in elderly patients.  In 166 elderly patients with 
cognitive disorders (post-stroke or post-traumatic cognitive disorder or memory disorders), 
asthenia (16.9%), somnolence (7.8%), headache (7.2%), and dizziness (7.2%) were the most 
common adverse effects 35.  In an open label phase IV study of patients > 65 years with 
epilepsy, approximately 40% of patients reported one or more adverse events, usually mild or 
moderate in severity, with 19.2% discontinuing levetiracetam because of side effects 38.  
Somnolence (16.7%) and dizziness (9%) were the most commonly reported adverse effects.  In 
24 cognitively impaired elderly patients with epilepsy treated with levetiracetam for 12 weeks, 
significant overall improvements were observed for the Folstein's Mini-Mental State Examination 
and the Alzheimer's Disease Assessment Scale-Cognitive 39.  A study comparing AED retention 
rates in patients > age 55 found levetiracetam to have the second-highest one-year retention 
and seizure-free rate (73%), at a median daily dose of 1500mg 40.  In an open label study in 


(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
patients with AD and epilepsy, levetiracetam was effective and well tolerated 41.  Of 25 patients 
with severe AD treated with levetiracetam 1000–1500 mg daily, 72% were seizure-free for at 
least one year, 16% discontinued for adverse effects, 8% were unresponsive, and 4% were lost 
to follow-up.   
 
Data on acute use of intravenous levetiracetam in elderly patients is limited.  Levetiracetam is 
well tolerated in healthy young subjects (< 65 years) after 15 minute (2000-4000mg) and 5 
minute (1500-2500mg) infusions 42.  One retrospective observational study included 14 older 
patients (mean age 73.9 years) with a series of complex partial seizures or convulsive or non-
convulsive status epilepticus needing emergent intravenous (IV) treatment 43.  Seizure control 
was achieved in 11/14 patients (78.6%) at a mean dosage of 1,643 mg/day (range 500-4,000). 
The only adverse effect was sedation.  
 
Levetiracetam was recently tested in animal models of AD and in adults with mild cognitive 
impairment.  Levetiracetam 5 mg/kg reduced epileptiform discharges and improved memory 
performance in hAPP mice, while sodium channel blocking AEDs resulted in worsened memory 
performance.  In a recent study in patients with mild cognitive impairment, levetiracetam 250mg 
twice daily for two weeks normalized hippocampal hyperperfusion, as measured by blood 
oxygen level dependent (BOLD) MRI.  For this study, we chose two doses of levetiracetam (low 
2.5 mg/kg and high 7.5 mg/kg) based on the information above. 
 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
1.  Study Overview 
 
This double-blind, within-subject crossover pilot study will test whether increased 
hippocampal perfusion on ASL-MRI in AD is caused by epileptiform activity.  If epileptic 
activity is occurring and impairing hippocampal function, then levetiracetam should lead to 
decreased rCBF in the hippocampus and improved declarative memory.   
 
Twenty subjects with mild AD (MMSE≥20) will participate in this study in the Clinical 
Research Center at Beth Israel Deaconess Medical Center.  Subjects will be screened to 
ensure they meet inclusion and exclusion criteria and will provide written informed consent 
before any study procedures are performed.  Each eligible subject will undergo three 
sessions, held 1-2 weeks apart, in a double blind, within-subject crossover design, 
counterbalanced for order (placebo / levetiracetam 2.5 mg/kg /  levetiracetam 7.5 mg/kg), 
Figure 3.  During each session, placebo or levetiracetam will be administered intravenously 
over 20 minutes.  Drug administration will occur during EEG recording so that 
neurophysiological recordings can be acquired before, during, and after administration.  
Changes in EEG background frequency and level of synchrony will be analyzed 44-46.  After 
drug administration and EEG recording, hippocampal perfusion and functional connectivity 
will be measured with ASL-MRI and resting BOLD fMRI.  Finally, participants will undergo a 
cognitive battery with memory tests particularly sensitive to hippocampal function (declarative 
memory, attention, working memory and executive function).   
 


(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
 
 
2.  Study Rationale 
 
This protocol has three primary goals: to test the hypothesis that increased hippocampal 
perfusion in AD is at least partially driven by epileptic activity, that lowering epileptic activity 
may improve cognitive performance, and that perfusion MRI can be used as a non-invasive 
assay of the effects of medications that decrease epileptic activity in AD.  
  
3.  Subject Recruitment and Screening     
We plan on testing twenty AD participants (> age 50 years) meeting the NINCDS-ADRDA 
criteria for probable AD from the Cognitive Neurology Unit at BIDMC.   All participants will 
have mild AD by the Mini-Mental Status Examination (MMSE≥20).  The P.I., who specializes 
in neurodegenerative disorders, maintains an active clinic and treats over 100 patients with 
AD.  In addition, the Cognitive Neurology Unit has over 13,000 patient visits per year.  
Exclusion criteria include a history of seizures prior to the onset of AD, current use of an 
antiepileptic medication, current use of a medication known to lower seizure threshold (e.g. 
bupropion or a neuroleptic), presence of parkinsonism, significant cerebrovascular disease, 
other CNS disease or major depression.  Subjects will be screened for depression with the 
Geriatric Depression Scale and excluded if they score greater than 9 47.  Participants 
receiving standard treatments for dementia including cholinesterase inhibitors, memantine 
and serotonergic selective reuptake inhibitors may participate.  
 
4.  Crossover Design, Randomization, and Blinding 
This is a within-subject, crossover study.  Each subject will receive one of 3 study drug 
regimens at each session:  
a. Placebo 
b. Low dose levetiracetam (2.5 mg/kg) 
Figure 3. Overall paradigm.  Participants will undergo testing in 3 sessions counterbalanced for 
order,  with placebo, low dose LEV or higher dose LEV.  Drug will be administered intravenously 
during EEG recording.   Imaging will be acquired with anatomical, perfusion and resting state bold 
MRI.  Cognitive testing will be performed with a battery including a memory test particularly 
sensitive to hippocampal function as well as other tests of frontal function. 


(CCI) Committee on Clinical Investigations 
Page 8 of 18 
 
Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
c. High dose levetiracetam (7.5mg/kg) 
A computer-generated, blocked randomization list will be generated that will randomly assign 
subjects to one of 6 groups.  The order of drug administration will be counterbalanced to 
avoid pitfalls of the crossover repeated measures design.   
     Group 1: A, B, C 
     Group 2: A, C, B 
     Group 3: B, A, C 
     Group 4: B, C, A 
     Group 5: C, A, B 
     Group 5: C, B, A 
The BIDMC research pharmacy will provide for randomization and blinding.  Patients and 
investigators will be blinded to study group. 
 
5.  Study Procedures 
 
Details and timing of the study procedures are listed below in the section “Study Plan”. 
 
a. Demographics and baseline characteristics 
b. Medical history 
c. Neurologic history, including date of onset and progression of AD, history of prior 
seizures, and history of other neurological disorders. 
d. Recent and concomitant medications 
e. Assessment of renal function (blood urea nitrogen and creatinine) 
f. Vital signs 
g. At screening and at each visit: Systolic and diastolic blood pressure, heart rate, and 
respiratory rate; weight 
h. 20 minutes before each dose of study drug, and at 10, 20, and 30 minutes after start of 
intravenous infusion of study drug:  Systolic and diastolic blood pressure, heart rate, and 
respiratory rate 
i. Physical exam: appearance, cardiovascular, lung/chest, abdomen, extremities, and 
musculoskeletal. 
j. Neurological exam: mental status, cranial nerves, motor system, sensory system, 
reflexes, coordination, stance, gait 
k. Mini-Mental Status Examination 
l. Electroencephalogram 
A 21-electrode array (Fp1, Fp2, F3, F4, C3, C4, P3, P4, O1, O2, F7, F8, T3, T4, T5, 
T6, Fz, Cz, Pz, reference, ground) of gold disc electrodes will be placed using paste 
technique, with electrode positions determined by the 10-20 International System.  
Additional electrodes will be placed to monitor eye movements (superior and inferior to 
outer canthus of each eye) and electrocardiogram.  EEG will be sampled at 250 Hz 
and band-pass filtered from 0.1-70Hz.  EEG will be recorded for 20 minutes before, 20 
minutes during, and 20 minutes after administration of study drug.  During each 20 
minute session, EEG will be recorded for 5 minutes with eyes open and 15 minutes 
resting with eyes closed.  EEG will be analyzed using both visual and quantitative 
techniques 44-46.  EEG will be visually inspected to determine 1) whether baseline 
epileptiform activity is present and is altered by study drug, and 2) whether study drug 
has other effects on EEG (such as diffuse slowing), which might affect the results of 
cognitive testing.  Automated artifact detection and artifact decontamination filters will 
be used to minimize contributions of eye movements and other artifact sources.  Data 


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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
segments containing possible artifacts will be excluded from analysis.  For each 
session, EEG measures will include alpha peak power, beta band power, and 
delta/theta band power.  will be determined for each session. 
m. Study drug administration 
For each session, the BIDMC research pharmacy will prepare study drug (intravenous 
levetiracetam 2.5mg/kg, levetiracetam 7.5mg/kg, or identical-appearing placebo) 
according to the subject’s assigned group.  Commercially-available levetiracetam will 
be purchased using study funds.  All IV study drug will be prepared, labeled, and 
dispensed by the research pharmacy in accordance with clinical GMP guidelines.  All 
study drug will be stored in a secure location.  The study drug will be administered 
over 20 minutes by a research nurse in the BIDMC General Clinical Research Center.  
Study drug will be infused at room temperature.   
n. Imaging paradigm 
All participants will undergo brain imaging with a structural MRI, a resting brain 
perfusion MRI using arterial spin labeling, and a resting BOLD fMRI for functional 
connectivity.   Imaging will be acquired on a 3.0T research-dedicated General Electric 
scanner. 
 
1. Structural MRI - A high-resolution MPRAGE sequence will be performed with 
1x1x1mm isotropic voxels to allow for accurate measures of atrophy.  This sequence 
requires 7 minutes for acquisition. 
 
2. Perfusion MRI - Arterial spin labeling perfusion MRI will be performed using a 
custom sequence that employs several features to increase reliability for clinical 
studies:  background suppression to reduce motion related noise and artifacts; fast 
spin echo imaging to eliminate distortion and susceptibility related signal attenuation; 
and a long post-labeling delay to insure labeled blood actually reaches brain tissue of 
interest (Dai et al., 2008). For quantification of the blood flow corrected for atrophy, a 
second, anatomical imaging acquisition with the identical imaging sequence as the 
perfusion sequence will be performed but with two inversion preparations replacing the 
ASL. We have successfully employed this sequence and method of atrophy correction 
in patients with Alzheimer’s disease (Alsop et al., 2008).  This sequence requires 10-
15 minutes for acquisition. 
 
3. Functional Connectivity MRI- A resting BOLD fMRI sequence will be applied 
a rapid-acquisition echoplanar sequence (TE 25msec, TR 2500ms, 3.75mm isotropic 
voxels) over a 10 minute epoch to measure correlated activity at low frequencies, a 
measure of the strength of functional connectivity.   
o. Behavioral testing 
Participants will undergo declarative memory testing with the Free and Cued Selective 
Reminding Test, a task that is particularly sensitive to hippocampal function 48.  In 
addition, a short battery will be administered to test executive function, naming, 
visuospatial ability and semantic function (Trail Making Test Parts A+B, Phonemic 
fluency Test, Boston Naming Test 15-item version, clock drawing, category fluency).  
The primary endpoint for memory testing will be the free recall score from the Free 
and Cued Selective Reminding Test. This battery is fairly brief (30 min) but sensitive to 
both hippocampal function and changes in other cognitive realms impaired in AD. 
p. Adverse events observed by investigator or reported spontaneously by the subject 
 
6.  Study Plan 
The following assessments and procedures will be done at each study visit: 
a. Screening visit  


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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
1. Informed consent 
2. Demographics and baseline characteristics 
3. Medical history 
4. Neurologic history 
5. Recent and concomitant medications 
6. Blood collection for blood urea nitrogen and creatinine) 
7. Vital signs: Systolic and diastolic blood pressure, heart rate, and respiratory rate; 
weight 
8. Physical exam 
9. Neurological exam 
10. Mini-Mental Status Examination 
 
b. Visits #1-3 (identical procedures, visit length 5-7 hours) 
1. Vital signs: Systolic and diastolic blood pressure, heart rate, and respiratory rate; 
weight 
2. Physical exam 
3. Neurological exam 
4. IV catheter placement 
5. EEG (60 minute recording) 
6. Study drug infusion (20 minutes) 
7. Vital signs at 10, 20, 30 minutes after infusion 
8. Imaging paradigm (60 minutes) 
9. Behavioral testing (60-90 minutes) 
10. Adverse events 
There will be scheduled breaks between tests and scheduled lunch 
 
c. Telephone follow-up  
1. Follow up for adverse effects 
 
B. 
Statistical Considerations 
Sample Size Justification:   
 
We plan to study 20-25 subjects at BIDMC.  We anticipate screening 25 subjects to enroll 
and randomize 20 eligible subjects.  We have performed a power calculation based on our 
previous study finding hyperperfusion of the hippocampus in AD as compared to controls 23. 
With a sample size of 20 AD participants, we will have a 72% probability of detecting a 
decrease in perfusion after levetiracetam, assuming administration of the drug lowers 
hippocampal CBF only to normal levels. This estimate is likely overly conservative for two 
reasons. First, the within subject design should markedly decrease variance. Second, if 
epileptiform discharges are contributing to hippocampal hyperperfusion and damage, then 
briefly ceasing the abnormal activity with drug should reveal underlying hypoperfusion like 
that typically seen in temporal lobe epilepsy.  
 
Data Analysis:   
The primary study outcomes are: 
Differences in hippocampal perfusion on ASL-MRI  
Differences in memory performance  
 
The secondary study outcomes are: 


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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
Differences in whole brain regional cerebral blood flow on ASL-MRI  
Differences in working memory and executive functions 
Differences in EEG measures (alpha peak power, beta band power, delta/theta band 
power, coherence) 
 
 
Behavioral Data 
Measures of memory encoding, retrieval and storage will be analyzed using repeated 
measures ANOVA. We will test our a priori main hypothesis of improved memory 
performance after drug. In a secondary analysis, we will measure effects of drug on 
working memory and executive functions in a similar manner. 
 
Imaging Data  
We will do two analyses, one focused specifically on hippocampal perfusion and a 
second analyzing regional CBF throughout the whole brain. First, we will use a 
repeated measures ANOVA with hippocampal perfusion and session (placebo, 
2.5mg/kg and 7.5mg/kg) being the factors.   Hippocampalm perfusion is measured as 
a percentage of visual cortex perfusion, using a template available within the 
Statistical Parametric Mapping package. Second, we will measure regional CBF 
throughout the whole brain using SPM5 and measure changes after drug vs. placebo 
using a random effects model and accounting for the repeated measures design. In 
addition to direct analysis of perfusion, we will examine cortical changes in CBF 
correlated with our seed region in the hippocampus. We predict that decreases in 
perfusion in the hippocampus after levetiracetam will correlate with increases in 
perfusion in association cortical regions. Lastly, we will test for correlations between 
behavioral measures of memory and regional changes in CBF in hippocampus and 
whole brain. We predict that decreases in hippocampal perfusion will paradoxically 
correlate with improved declarative memory performance. 
 
 
EEG Data 
EEG will be visually analyzed for presence of epileptiform activity.  Peak alpha power, 
beta band power, delta/theta power, and coherence will be calculated using BESA 
(Brain Electrical Source Imaging) software and Persyst MagicMarker software.  
Measures will be analyzed using repeated measures ANOVA.  We hypothesize that 
levetiracetam will decrease source coherence in temporal regions. 
 
Analyses will be performed in the Cognitive Neurology Unit, Magnetic Resonance Imaging 
Center of the Department of Radiology, and EEG Laboratory at Beth Israel Deaconess 
Medical Center. 
 


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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
C. 
Subject Selection 
Subjects will be recruited from the Cognitive Neurology Unit at BIDMC. The P.I., who 
specializes in neurodegenerative disorders, maintains an active clinic and treats over 100 
patients with AD. In addition, the Cognitive Neurology Unit has over 13,000 patient visits per 
year.  
 
Inclusion Criteria: 
• Meets the NINCDS-ADRDA criteria for probable Alzheimer’s disease 
• Mild AD (MMSE≥20) 
• Age >= 50 years 
• English as first language 
 
Exclusion Criteria:  
• A history of seizures prior to the onset of AD 
• Familial Alzheimer’s Disease due to known genetic mutations 
• Current use of an anti-epileptic medication 
• Current use of a medication known to lower seizure threshold (e.g. bupropion or a 
neuroleptic) 
• Presence of parkinsonism 
• Significant cerebrovascular disease 
• Other Central Nervous System disease (e.g. stroke, severe traumatic brain injury) 
• Major depression or other psychiatric or behavioral disorders (psychosis, agitation) 
• Medical contraindication to MRI (e.g. cardiac pacemaker, intraocular or intracranial 
metallic objects) 
• Severe claustrophobia or inability to lie flat for MRI 
• Known allergy to levetiracetam, or history of previous adverse reaction to levetiracetam.  
• Serum creatinine >= 2 
 
Participants receiving standard treatments for dementia including cholinesterase inhibitors, 
memantine and serotonergic selective reuptake inhibitors may participate. 
 
  
 
 
B4. 
POSSIBLE BENEFITS 
The present study is designed to enhance our understanding of the role of epileptiform activity 
in Alzheimer’s disease.  There is no direct benefit to the subject from participating in this study. 
 
Confirmation of a relationship between excitatory neuronal activity and cognitive deficits in 
humans with AD would provide new insights into the pathogenesis of AD.  If levetiracetam 
decreases this excitatory activity, antiepileptic drugs may be a new potential avenue for 
treatment or prevention of AD.  
 
 


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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
Several aspects of this trial have a potential for subject discomfort or injury.  All study 
procedures are low- to moderate-risk procedures, as described below.  These risks are 
balanced by the potential benefit that the knowledge gained from this research may help to 
determine new methods to treat or prevent Alzheimer’s Disease.   
 
Study drug:  Levetiracetam has been approved by the FDA as safe and effective in the 
treatment of seizures and epilepsy and is generally well tolerated.  No laboratory monitoring is 
recommended by the FDA for patients receiving levetiracetam for seizures.  Levetiracetam may 
cause some, all, or none of the side-effects listed below.  Subjects will receive only one dose of 
study medication at each visit, so side effects should not last longer than 12-24 hours. 
 
More Common:  The most frequently reported side effects from levetiracetam are 
drowsiness, dizziness, nausea, and headache.  Other side effects can include vomiting, 
tremor, irritability, or depression.  More than 10% of subjects may experience these side 
effects when levetiracetam is given intravenously.  The side effects are usually mild and 
temporary.  The medication will be given slowly over 20 minutes to minimize these side 
effects.   
 
Less Common: Less common side effects (occurring in 1-10% of subjects) include 
anger, anxiety, decreased appetite, diarrhea, and infection (colds or viral infections).  
 
Rare: Rare side effects (occurring in less than 1% of subjects) include severe depression 
or the development of suicidal thoughts, effects on blood cells (low blood counts, low 
platelets or white blood cells), liver failure and weight loss. 
 
Blood draws:  The risks and discomforts of blood drawing from a vein include the possibility of 
pain or bruising at the site of the blood draw; occasional feeling of lightheadedness; and rarely, 
infection at the site of the blood draw. 
 
Intravenous catheter placement and medication infusion:  Levetiracetam and placebo will be 
given through an intravenous catheter.  Possible risks of the catheter or infusion include: skin 
infection at the catheter site; redness, swelling, discomfort, pain, or bruising at the injection (IV) 
site; bruising of the skin caused by broken blood vessels leaking blood under the skin; or local 
thrombosis. 
 
EEG:  EEG is a commonly used procedure which has low risk.  Some subjects experience mild 
discomfort during scalp preparation for electrode placement, or have itching or skin irritation at 
the electrode site.  Some subjects find it difficult to lie still during the EEG, which will last 
approximately one hour. 
 
MRI scans are safe and routinely used in medical diagnosis.  Exposure to strong, static 
magnetic fields is accepted as safe.  Subjects will be screened for MRI safety, including 
presence of metal in their body.  For this protocol, all MRI studies will be performed on a 3T 
General Electric research magnet that has received FDA approval.  There is no exposure to 
ionizing radiation.  This technique is non-invasive and does not require administration of 
exogenous contrast agents. The most common adverse event associated with MRI is 
claustrophobia.  Subjects will have voice contact with the technologist performing the study at 


(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
all times, and the MRI scan can be immediately stopped at the subject’s request.     
 
If subjects are injured as a direct result of participation in this study, BIDMC will provide the 
necessary care to treat the injury.  The subject or his/her insurance company will be billed for 
medical care and/or hospitalization related to this injury.  Subjects will be responsible for all 
copayments and deductibles required under their insurance.  BIDMC will consider 
reimbursement of injury related expenses not covered by insurance on a case-by-case basis.  
There is no reimbursement for items such as lost wages or lost time from work.   
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
Recruitment 
Investigators will recruit from their own patient population as well as screen the neurology 
clinical research database and appointment books for patients who qualify for the study.  The 
investigators will reach out to other neurology physicians to inform them about the study so that 
they may refer patients who are interested in participating to the investigators.  Flyers describing 
the study will be placed in the Cognitive Neurology Unit and in the outpatient neurology clinic.   
 
A neurologist in the Cognitive Neurology Unit at the Beth Israel Deaconess Medical Center will 
approach potential study participants.  The Principal Investigator will then contact those patients 
who express an interest in participating in the study.  The Principal Investigator will tell potential 
subjects about the ongoing study, including the specific aims of the study, outline of the study 
design, techniques to be used, and anticipated risks and benefits.  If the potential subject 
expresses an interest in the study, Dr. Press will ensure that exclusion and inclusion criteria are 
met and that there are no contraindications for study participation by reviewing the patient’s 
medical record and/or completing a full neurological history and physical examination of the 
patient.  If the potential subject meets these criteria, he or she will be invited to participate in the 
study.  Written informed consent will be obtained after all of the subject’s questions have been 
completely answered.  
 
Consent/Subject Protection 
The Principal Investigator will obtain informed consent from all subjects up to one week prior to 
their participation in this study.  The consent form describes the study and provides sufficient 
information for subjects to make an informed decision about their participation in this study.  
The principal investigator or his designee will discuss the study with the subject.  Patients 
with mild AD (MMSE≥20) are able to understand a consent form and over 95% can supply 
true consent (Buckles et. al, Neurology 2003).  Participants will be reminded at the start of 
each session that they may discontinue at any time and that this will not affect their care in 
any way.  In addition, we will engage a health care proxy, spouse, or close family member, 
where available.  The subject will be given time to read the consent form and to ask 
questions.  Upon entry into the study, the subject or surrogate will receive a copy of the 
consent form, and a copy will be filed with their study binder. 
 
 
 


(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
B7. 
STUDY LOCATION 
Privacy  
The subjects’ privacy will be protected by ensuring that the conditions under which information 
will be collected afford protections against interactions with participants being witnessed, 
overheard or inadvertently intercepted or viewed. Furthermore, the information being collected 
will be minimized to include only the data necessary to accomplish the research. 
 
 
A unique identifier code will be assigned to each subject.  All information, including EEG data 
files, will be stripped of personal identifying information.  Patient confidentiality will be strictly 
maintained, and results of all testing will be available only to subjects and/or their health care 
providers, if requested by the subjects. 
 
Physical Setting 
Study sessions will in the Clinical Research Center on the East Campus of BIDMC.  MRI 
scans will be conducted in the Research Radiology department in an adjoining building ( 
Rabb Building). Drug administration will take place at the Clinical Research Center and the 
Research Pharmacy will be responsible for counterbalancing. 
 
B8. 
DATA SECURITY 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.   
 
Subject binders will be kept in in a locked cabinet accessible only to the investigators.  For 
data analysis, data will be entered into a password-protected computerized database behind 
the BIDMC firewall.  The investigator will retain study essential documents for at least 2 
years after completion of the study. 
 
General Safety 
All safety considerations were included as part of the design of this study. 
 
Data Safety Monitoring Plan   
Monitoring of Adverse Events:  While levetiracetam is not used in treating Alzheimer’s disease, 
it is widely used in the treatment of epilepsy, including epilepsy that develops in patients with 
Alzheimer’s disease. We will be using a single dose, so the risk of side effects is low. 
Participants will complete the side effects questionnaire prior to and after every session in order 
to evaluate side effects.  
 
The occurrence of any unexpected undesirable side effect will result in holding the trial until 
communication with the IRB, the CRC administrative staff, and the Research Subject Advocate 


(CCI) Committee on Clinical Investigations 
Page 16 of 18 
 
Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
has taken place, and the risk for participants reassessed. Participation in the study for any 
given participant will stop in the event of any unexpected side effects or any cognitive 
deterioration as measured by the serial assessments described above.  
 
Reporting of Adverse Events: All adverse events will be reported and reviewed every week 
according to laboratory policies. Information about all adverse events relating to this study will 
be collected and reported on the attached Report of Adverse Event Form. Any adverse event 
occurring in participants after they sign the consent form and until two weeks after the trial will 
be reported according to the following guidelines: 
 
(1) All fatal, life-threatening or serious adverse events will be reported verbally (7-1764) 
and faxed (7-5953) to the CRC RSSO Director and the CCI within 24 hours. 
(2) Unexpected serious adverse events will be reported verbally in real time to the CCI and 
the CRC RSSO Director. 
(3) Unexpected moderate adverse events will be reported in writing to the CCI and the 
CRC RSSO Director within 10 days of occurrence or recognition. 
(4) The PI will provide the CRC RSSO with any copies of adverse event reports that are 
sent to any entity such as the CCI,FDA, and NIH within the same time constraints. 
 
The PI will also provide the CRC RSSO with an annual summary of adverse events (including 
anticipated, non-serious adverse events). 
 
B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site or is the BIDMC PI the lead investigator of the multi-site study?      
 Yes    
 No  
 
 
 


(CCI) Committee on Clinical Investigations 
Page 17 of 18 
 
Study Description – Part B 
CCI Form:  6-2011 
 
PI Revision Date: 08/01/2011 
 
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