Clinical trial NCT02334722
Conditions: Brain Neoplasms Brain Cancer Brain Tumors Cancer of the Brain Cancer of Brain Seizure
Sponsor: University of Florida
Start date: 2015-08-05; Completion date: 2020-10-07
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to see if there are any differences in patient reported neurotoxicity between patients who receive Levetiracetam tablets for one week after surgery to remove a brain tumor versus those who receive Levetiracetam tablets for six weeks after surgery. Specifically, we will see if one group has less side effects than the other, and whether or not one group has more seizures than the other.

Detailed description:
Because seizures are one of the leading neurologic complications in brain tumor patients, neurosurgeons prescribe antiepileptic drugs (AEDs) to help prevent them. Although the American Academy of Neurology (AAN) guidelines recommend that AEDs be stopped after the first post-operative week in patients without seizures, there is no standard length of treatment and some patients may stay on AEDs indefinitely.

In an attempt to develop clinical guidelines for AED use in post-operative brain tumor patients, we will try to determine if taking levetiracetam for 1 week results in less neurotoxicity than taking it for 6 weeks.

Arms: arm 1: Levetiracetam taken by mouth at a daily dose of 1000 mg for one week. arm 2: Levetiracetam taken by mouth at a daily dose of 1000 mg for six weeks.
Interventions: intervention 1: Levetiracetam
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Coversheet for ClinicalTrials.gov 
Title: A shortened antiepileptic drug (AED) course in surgical brain tumor patients: a 
randomized trial 
NCT02334722 
Principal Investigator: Maryam Rahman MD MS 
Version Date: 30 October 2019 


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Version Date: 30 October 2019 
IRB Protocol 
Title: A shortened antiepileptic drug (AED) course in surgical brain tumor patients: a 
randomized trial 
Principal Investigator: Maryam Rahman MD MS 
SubInvestigators: Gregory J.A. Murad MD, Jean Cibula MD 
Study Coordinator: Marcia Hodik, RN, BSHS, CCRC 
Abstract: Seizures are one of the leading neurologic complications in brain tumor patients.  
This has led neurosurgeons to use antiepileptic drugs (AEDs) as prophylaxis.  However, the 
drugs are often not withdrawn right away and patients are referred to oncologists for 
follow-up care.  Neither specialty has particular expertise dealing with antiepileptic drugs 
and as a result, there has been no standardized protocol used to discontinue the drugs and 
many patients stay on them indefinitely.  The result has been considerable practice 
variation in regard to the use and length of AEDs in the post-operative period2.  The 
American Academy of Neurology (AAN) guidelines recommend the discontinuation of 
Antiepileptic Drugs (AEDs) after the first post-operative week in patients without 
seizures1.  In an attempt to develop Neurosurgery clinical guidelines for AED use in post-
operative brain tumor patients, we will evaluate two different courses of levetiracetam. 
Patients who have had a surgical resection of a brain tumor will be randomized to 
levetiracetam for one week or for six weeks.  The primary study endpoint will be 
performance on a validated neurotoxicity scoring system at 6 weeks post-op.  We 
hypothesize that patients on a shortened AED course (1 week) will have less neurotoxicity 
as measured by a validated neurotoxicity scoring instrument compared to patients on 6 
weeks of treatment.  Secondary endpoints will include number of seizures and adverse 
events. We will also measure medication adherence, and mood alterations to determine if 
these have any correlation with AEDs.  


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Version Date: 30 October 2019 
Background: Up to 35% of patients undergoing craniotomy for non-acute traumatic 
pathology experience post-operative seizures within the first week1.  A recent Cochrane 
database systemic review by Pulman et al. reviewed six randomized control trials that 
aimed to determine the efficacy and safety of prophylactic AED use in patients undergoing 
craniotomy for non-traumatic pathology.  Only one trial reported a significant difference in 
early seizure outcomes between patients on prophylactic AEDs and control patients2.  The 
authors concluded that evidence is limited to suggest prophylactic AEDs are effective in 
preventing post-operative seizures.  This systematic review included patients with non-
traumatic pathology rather than with brain tumors alone, who may be at further increased 
seizure risk compared to other non-traumatic pathologies. 
 
Prophylactic use of AEDs for patients undergoing craniotomy for brain tumors is common 
practice, and in a recent survey conducted by Glantz et al., 81% of practicing 
neurosurgeons reported that they prescribed prophylactic AEDs post operatively to 
patients without a history of seizures3.  However, there are no clear clinical guidelines to 
support this practice, raising the question of whether prophylactic AEDs improve seizure 
incidence or subject patients to unnecessary medication side effects. Ansari et al. 
performed a retrospective analysis of seizure occurrence with and without post-operative 
AED prophylaxis over a six-year period and found no statistically significant benefit to 
prophylactic post-operative AEDs for intra-axial tumors4.  Additionally, their study 
observed a trend (not statistically significant) of higher seizure incidence in patients 
receiving prophylactic AED therapy. Garbossa et al. performed a retrospective two-center 
cohort study of AED prophylaxis in surgically treated high-grade gliomas to assess 
effectiveness of perioperative AED use5. They reported that AED use does not provide 
substantial benefit. Wu et al. performed a prospective randomized clinical trial of 
phenytoin for perioperative seizure prophylaxis in patients with intra-axial tumors6. They 
found no benefit from AED use and increased adverse events post-operatively with AED 
use.  Additionally, their study found a low overall incidence of post-operative seizures. 
Therefore, the traditional factors that are felt to increase seizure risk such as intra-axial 
tumors, cerebral edema, etc., have not been found to justify the routine use of AEDs in 
surgical brain tumor patients.  


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Version Date: 30 October 2019 
 
Hypothesis: We hypothesize that patients on a shortened AED course (1 week) will have 
less neurotoxicity as measured by a validated neurotoxicity scoring instrument compared 
to the patients on 6 weeks of keppra. 
 
Primary Objective: To determine the difference in patient reported neurotoxicity 
associated with a shortened course (1 week) of levetiracetam compared to a longer course 
(6 weeks).  
  
Secondary Objectives: To determine if seizure rates, medication adherence and mood 
alterations correlated with a shortened or longer course of levetiracetam.  
  
Patient selection criteria: 
Inclusion criteria –  
• Adult (>18 years of age and older) patients who have or will have undergone 
surgical resection or biopsy of a supratentorial brain tumor and are able to consent 
for themselves.  During the informed consent process subjects with perceived 
cognitive disability will be excluded from study participation. 
• Able to be randomized prior to or up to 48 hours after surgery. 
 
Exclusion criteria –  
• Known history of seizure activity 
• Pregnant or breastfeeding 
• Renal dysfunction (CrCl<30ml/min) 
•  Beck’s Depression Inventory (BDI) ≥14.(Subjects will have the BDI administered at 
baseline visit, prior to randomization. Those who score ≥14, will be excluded from 
the study and referred to clinical psychology. Subjects who select “2” or “3” on 
question 9, will be referred to clinical psychology without regard to the overall total 
score.) 
• Allergy to levetiracetam 
 


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Version Date: 30 October 2019 
Research Plan:  
After obtaining informed consent, subjects will be randomized into one of the following 
arms to receive study drug as follows:  
1) Levetiracetam (Keppra at a daily dose of 1000mg (administered as one 500 mg 
tablet )PO twice daily  for one (1) week. 
2) Levetiracetam (Keppra ) at a daily dose of 1000mg (administered as one 500 mg 
tablet)PO twice daily for six (6) weeks. 
 
A simple randomization scheme will be used and will be generated by our statistician.   All 
patients will be weaned off of the AED over 2 days by decreasing the dose to 500mg po 
every day for 2 days and then stop. The taper is to commence at day 5 for the one week 
group and at 2 days prior to the stop date for the 6 week group. The taper will be included 
on their prescription instructions and in the patient’s discharge instructions to ensure 
proper taper of the drug. As is protocol, patients are given verbal instructions of all of their 
discharge medications prior to discharge along with a “teach back” method to confirm they 
understand how to take and stop their medications when they go home. Patients will begin 
study medication 48 hours post-op, regardless if they are discharged or remain 
hospitalized.  At discharge, they will continue the medication regimen for the amount of 
time they were randomized.  
 
 
Participants will maintain a diary that will collect seizure occurrences and daily medication 
intake. The RedCap database will be used to collect patient data.  Participants will also 
complete the Beck Depression Inventory (BDI) and Neurotoxicity Scale7 to assess mood 
changes and level of cognitive functioning at baseline (preoperatively or 24-48hrs 
postoperatively) and at 6 weeks postoperatively. Patients with a BDI score suggestive of 
mild mood disturbance or depression (BDI score ≥ 14) will be further evaluated by the 
Principal Investigator. This evaluation may include discontinuing leveteracitam, the 
initiation of antidepressant medications, or referral to clinical psychology. Patients will be 
followed until study completion and study activities will be conducted per the following 
Table of Events. 


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Version Date: 30 October 2019 
 
 
Activity 
Baseline 
(24-48 hours post-op) 
Study Completion** 
6 weeks postop (+/- 4days) 
Inclusion/exclusion criteria 
X 
 
Informed consent 
X 
 
Dispense prescription 
X 
 
Dispense diary 
X 
 
Collect or record diary data  
 
X 
Beck Depression Inventory (BDI) 
X 
X 
Neurotoxicity Scale 
X 
X 
**May be completed during a routine office visit or by telephone  
 
Data will be collected by the clinical trial coordinator and kept in an encrypted and 
password protected database in the coordinator’s locked office.  Only the investigators and 
study coordinator will have access to the data with identifiers.  At the conclusion of the 
study, the data will be deidentifed and the key will be kept in a secure location in the 
coordinator’s locked office. The key will be kept until the study is completed and the 
manuscript is accepted for publication.  
Subjects will be assigned a unique ID number and the following data points will be 
captured in the RedCap database: 
• Unique study ID number 
• Complete past medical and surgical history  
• Family history of seizures 
• Tumor pathology results 
• Tumor imaging findings  
• Concomitant Medications 
• Neurotoxicity scale scores 
• BDI scores 
• Seizure Diary responses 


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Version Date: 30 October 2019 
• Records of side effects or symptoms experienced 
 
Adverse events will be collected by the study coordinator at the six week evaluation or 
sooner if the patient contacts their physician/study team about new symptoms/problems. 
These events will be documented in the RedCap database. To ensure subject safety, each 
adverse event will be reviewed by an independent medical monitor (Dr. Stephan 
Eisenschenk) to determine if it is treatment-related. After each treatment-related adverse 
event that is “Serious and probable” or “Serious and definite” is identified, the study 
statistician will use a dynamic sequential testing method to determine if the proportion of 
enrolled patients who have experienced these types of adverse events up to that time has 
statistically exceeded a maximum acceptable proportion of 10%8. This method employs a 
concave alpha-spending function that allows a greater chance of detecting an unacceptably 
high adverse event rate earlier in the study while maintaining a nominal one-sided Type I 
error rate of 10% over the entire sequence of tests. Using a similar sequential testing 
approach, the   odds ratio for experiencing a treatment-related adverse event between the 
two arms of the study will be tested for difference from 1 .after each adverse event, at a 
nominal two-sided sequence-wide Type I error rate of 20%. If either the maximum 
acceptable adverse event rate is exceeded, or  odds ratio foradverse events between the 2 
study arms is found to differ from one, study enrollment will be stopped for further 
evaluation of patient safety. 
 
At the completion of the study, the scores on the neurotoxicity scale will be compared 
between the two groups. The analysis will be performed in an intent-to-treat manner. The 
groups will be compared using the Mann-Whitney test for the neurotoxicity scores and 
Fisher’s exact test for the seizure rates. Using the neurotoxicity scale, we will need 38 
patients in each group to show a difference of 5.4 points in the scale with a power of 80%. 
The maximum score on the scale is 817. 
 
Possible discomforts or risks: Study participants may suffer from seizures related to 
their brain tumor or demonstrate side effects from using levetiracetam which may include: 


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Version Date: 30 October 2019 
• Sleepiness  
• Weakness 
•  Infection  
•  Dizziness 
 
Other possible risks of levetiracetam may include: 
• Mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, 
mood swings, depression, hostility, irritability and psychotic symptoms 
• Hallucinations delusions and unusual behavior.  
• Extreme sleepiness, tiredness, and weakness 
•  Problems with muscle coordination (problems walking and moving)  
•  Skin rash or serious dermatological reactions such as Stevens-Johnson syndrome  
and toxic epidermal necrolysis.    
• Suicidal behavior or ideation 
 
These side effects are uncommon. If participants demonstrate side effects from 
levetiracetam that are not tolerable, they may be weaned off and kept off AEDs if they are 
seizure free. The seizure rate and medication related side effect is not expected to be any 
higher than other patients treated for brain tumors.  
 
Possible Benefits: The patients who are taken off of levetiracetam after one week will 
have lower medication costs and may experience less medication side effects.  
 
Conflicts of Interest: None 
 
 
 
References 
 
 
 
1. 
Matthew E, Sherwin AL, Welner SA, Odusote K, Stratford JG. Seizures following 
intracranial surgery: incidence in the first post-operative week. Can J Neurol Sci. Nov 
1980;7(4):285-290. 


Page 8 of 8 
 
 
Version Date: 30 October 2019 
2. 
Pulman J, Greenhalgh J, Marson AG. Antiepileptic drugs as prophylaxis for post-
craniotomy seizures. The Cochrane database of systematic reviews. 
2013;2:Cd007286. 
3. 
Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis 
in patients with newly diagnosed brain tumors. Report of the Quality Standards 
Subcommittee of the American Academy of Neurology. Neurology. May 23 
2000;54(10):1886-1893. 
4. 
Ansari SF, Bohnstedt BN, Perkins SM, Althouse SK, Miller JC. Efficacy of 
postoperative seizure prophylaxis in intra-axial brain tumor resections. Journal of 
neuro-oncology. May 2014;118(1):117-122. 
5. 
Garbossa D, Panciani PP, Angeleri R, et al. A retrospective two-center study of 
antiepileptic prophylaxis in patients with surgically treated high-grade gliomas. 
Neurology India. Mar-Apr 2013;61(2):131-137. 
6. 
Wu AS, Trinh VT, Suki D, et al. A prospective randomized trial of perioperative 
seizure prophylaxis in patients with intraparenchymal brain tumors. J Neurosurg. 
Apr 2013;118(4):873-883. 
7. 
Aldenkamp AP, Baker GA. The Neurotoxicity Scale--II. Results of a patient-based 
scale assessing neurotoxicity in patients with epilepsy. Epilepsy research. Jun 
1997;27(3):165-173. 
8.  
Kramar A and C Bascoul-Mollevi, 2009. Trials based on sequential monitoring of 
serious adverse events. Med Decis Making 29:343-350.