Clinical trial NCT05201703
Conditions: Catamenial Epilepsy
Sponsor: University of Florida
Start date: 2022-03-09; Completion date: 2023-12-15
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the proposed investigation is to carry out a pilot study of add-on perampanel (Fycompa) in women with perimenstural (C1) catamenial epilepsy. Perampanel, a noncompetitive AMPA receptor antagonist, is uniquely positioned to decrease progesterone receptor mediated excitotoxicity. This mechanism of action would allow a novel use of perampanel as an effective treatment of C1 catamenial epilepsy.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Fycompa intervention 2: Fycompa with a boost
Intervention descriptions: intervention 1: Fycompa 4 mg daily intervention 2: Fycompa 4 mg daily with a boost to 6 mg daily a week before the start of your menstruation cycle until Day 4 of your cycle.

Protocol documents:
SAP_002.pdf: 
Title: Pilot Study of Add-On Fycompa (perampanel) Treatment for Catamenial Epilepsy 
NCT number: NCT05201703 
Date of document: 3/17/2022 
 


Statistical analysis plan: 
The primary outcome (50% responder rate) will be analyzed using Chi square analysis. The 
secondary outcome, changes in seizure frequency from baseline to treatment, will be analyzed 
using paired t-test or ANCOVA. The pilot should provide data for calculation of the required 
sample size for demonstration of a significant difference or equivalence between the two groups 
with 80% power. 
 

Prot_000.pdf: 
 
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INVESTIGATOR INITIATED STUDIES (IIS) APPLICATION FORM 
 
 
Protocol Title:  
Pilot Study of Add-On Fycompa (perampanel) Treatment for 
Catamenial Epilepsy  
Principal 
Investigator Name: 
Katherine Zarroli MD 
Principal 
Investigator Contact 
Information: 
University of Florida - Jacksonville 
580 West 8th Street, T17 
9th Floor, Tower I 
Jacksonville, FL 32209 
Office: (904) 244-9841 
Study Coordinator (Yasmeen Shabbir): (904) 244-9856 
Fax: (904) 244-9481 
E-mail: katherine.zarroli@jax.ufl.edu 
 
Institution Name(s): 
University of Florida-Jacksonville 
Sub-Investigator 
Name, if applicable: 
Ramon Bautista MD MBA, Suparna Krishnaiengar MD 
Do you plan on using 
other Institutions or 
centers to conduct 
study?   
If yes, please list 
name(s) and 
address(es): 
 YES          
 NO 
 
N/A 
 
 
 
 


 
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Rationale: 
Approximately one-third of WWE have catamenial epilepsy, or cyclic seizure exacerbations in 
relation to the menstrual cycle. In women with ovulatory cycles, catamenial seizure exacerbations can 
occur either during the perimenstrual (catamenial 1, C1) or the preovulatory (catamenial 2, C2) phases 
of the menstrual cycle (Herzog et al., 1997; Herzog 2008).  
C1 seizure exacerbations are thought be related to the rapid premenstrual withdrawal of 
progesterone (Herzog 2008) (Figure 1). Progesterone has been found to have dual actions on the brain. 
First, the progesterone neurosteroid metabolite allopregnanolone exerts an anticonvulsant effect by 
binding to the gamma-amino-butyric acid (GABA) type A receptor to enhance GABA action (Herzog et 
al., 1997; Joshi at al., 2013). The rapid withdrawal of allopregnanolone premenstrually may impair 
GABAergic inhibition and therefore precipitate seizures. Second, progesterone has recently also been 
found to exert a proconvulsant effect. Shiono et al. (2019) found that progesterone receptor activation 
increased seizure frequency in epileptic animals. Joshi et al. (2018) discovered that progesterone 
receptor activation increased excitatory transmission by upregulating a-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptor GluA1 and GluA2 subunit expression in the rat model. The 
use of a progesterone and glucocorticoid receptor blocker then attenuated neurosteroid withdrawal 
seizures.  
C2 seizure exacerbations, alternatively, may be secondary to the preovulatory estrogen surge 
(Figure 1). In the animal model, estradiol has been found to act as proconvulsant by potentiating 
excitatory synaptic transmission by increasing the probability of glutamate release; this may be 
enhanced via AMPA mediated conductance (Smith, 1989; Smejkalova and Woolley, 2010). Estradiol 
has also been found to increase neuronal metabolism and discharge rates (Smith, 1989; Hardy, 1970).  
 
 
Figure 1. Illustration of how fluctuations in progesterone and estradiol concentration contribute to 
perimenstrual (catamenial 1, C1) and preovulatory (catamenial 2, C2) cyclic seizure exacerbations.  
 
 
 


 
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The role of hormonal treatment of catamenial epilepsy was previously investigated in the NIH 
Progesterone Trial, a randomized, double-blinded clinical trial of progesterone versus placebo therapy in 
the treatment of intractable focal seizures in ovulatory women with and without catamenial epilepsy 
(Herzog et al., 2012). The principal outcomes were the proportion of ≥50% responders and the change in 
seizure frequency between the 3-month baseline and 3-month treatment phases. Unfortunately, no 
significant differences were found between progesterone and placebo therapy, though women with both 
C1 and C2 seizure exacerbations were included in the catamenial arm. Of note, on post hoc analysis, 
women with high levels of perimenstrual seizure exacerbation were found to be responsive.  
Apart from trial design issues (the level of catameniality may have been insufficient for inclusion 
in the catamenial arm and women with C2 seizure exacerbations were also in the catamenial arm), the 
lack of effectiveness of progesterone suggests that the anticonvulsant effects of progesterone alone are 
insufficient in preventing catamenial seizure exacerbations. As previously described by Joshi et al. 
(2018), progesterone receptor activation may contribute to excitotoxicity by increasing AMPA receptor 
mediated glutamatergic transmission. The rapid withdrawal of allopregnanolone may therefore provoke 
seizures by disrupting the homeostatic balance of excitatory and inhibitory regulation, as in vivo and in 
vitro studies suggest that central neurons regulate excitatory and inhibitory balance slowly, over hours to 
days (Turrigiano 2011). Therefore, limiting the excitotoxicity of progesterone receptor activation may be 
particularly efficacious in treating perimenstrual catamenial seizure exacerbations.  
The purpose of the proposed investigation is to carry out a pilot study of add-on perampanel 
(Fycompa) in women with perimenstrual (C1) catamenial epilepsy. Perampanel, a noncompetitive 
AMPA receptor antagonist, is uniquely positioned to decrease progesterone receptor mediated 
excitotoxicity. This mechanism of action would allow a novel use of perampanel as an effective 
treatment of C1 catamenial epilepsy.  
 
Of note: Future studies should investigate the use of perampanel in women with preovulatory 
(C2) catamenial epilepsy, as estradiol’s proconvulsant effect is potentially being mediated through the 
enhancement of AMPA. This population is not included in this study. Women in clinic typically report 
clustering of seizures specifically around their menses (perimenstrual) so I chose to target this 
population (C1 pattern) first as I find this more clinically relevant. 
 
Study Design:  
This is an unblinded pilot study enrolling women with C1 catamenial focal epilepsy. Subjects will chart 
menses and seizures for a 2 month baseline period and then be randomized into 2 parallel arms: (1) 
Fycompa 4 mg daily and (2) Fycompa 4 mg daily to be increased to 6 mg daily peri-menstrually (Day -7 
until Day 4 of menstruation where Day 1 is the first day of menstrual flow). During this treatment phase, 
subjects will continue to chart menses and seizures. Other anticonvulsant medication doses will not be 
changed during the baseline or treatment study period. 
 
Objectives:  
Primary: To determine the responder rate in each group (percent of patients experiencing a 50% or 
greater reduction in seizures) relative to baseline seizure frequencies. 
Secondary: Changes in seizure frequency in each group relative to baseline seizure frequencies. 
Tertiary: Comparisons of primary and secondary outcomes between two groups. 


 
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Study Schema: 
Subjects and Centers: 
  
This a single site study at a tertiary care academic center, the University of Florida at Jacksonville. 50 
total female subjects will be enrolled. 
 
Inclusion Criteria: 
1. Female 
2. Diagnosis of focal onset seizures (FOS) 
i. 
Established by clinical history and an EEG 
ii. 
Patients with a normal EEG may be included if they met other diagnostic 
criteria based on clinical history 
3. Presumably ovulatory women based on menstrual cycles of 21-35 days from 
beginning of menstrual flow to the beginning of the next menses 
4. ≥18-50 years old 
5. ≥2 unprovoked seizures per month despite drug trials with ≥1 first-line anti-
epileptic drugs (AED) 
6. Seizures must show a C1 catamenial pattern in 2 of 3 documented cycles 
i. 
C1 pattern will be defined as a two-fold increase in average daily seizure 
frequency during the menstrual phase, as compared to the follicular and 
luteal phases of the ovulation cycle, in 2 of 3 documented cycles. The 
menstrual phase will be defined as days -3 to +3 of the menstrual cycle 
(where onset of menstruation is defined as day 1) (Herzog et al, 1997). Of 
note, in the NIH Progesterone Trial, the level of catameniality was 1.69 
based on Herzog et al. (1997) criteria though this trial will use a level of 2 
to include women only with high levels of perimenstrual catamenial 
exacerbation. 
7. Willingness and ability to comply with scheduled visits and study procedures 
Exclusion Criteria: 


 
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1. Progressive neurologic or systemic disorder 
2. Use of systemic hormonal contraception during 3 months prior to enrollment 
(however, subjects with a progestin-releasing IUD who still have monthly 
periods may be enrolled) 
a. Women on system hormonal contraception will be excluded as these 
women are not ovulatory 
3. Subject is pregnant or breastfeeding 
4. Active suicidal or homicidal ideation 
5. Decisionally impaired orC comatose individuals. 
Other Therapy:  
N/A 
Efficacy Measures:  
1. Primary: To determine the responder rate (percent of patients experiencing a 
50% or greater reduction in seizures) relative to baseline seizure frequencies.  
2. Secondary: Changes in seizure frequency relative to baseline seizure 
frequencies.  
3. Tertiary: Comparisons of primary and secondary outcomes between two groups. 
Safety Measures: 
1. We do not plan to have an internal Data Safety Monitoring Board. PI and study 
coordinator to be in charge of safety measures. 
2. There will be a baseline Columbia-Suicide Severity Rating Scale (C-SSRS) at 
enrollment to screen for suicidal ideation and behaviors. If suicidal ideation or 
behaviors are present, subjects will not be enrolled in the study. At each follow-
up visit, we will screen for changes in this scale. During each telephone call, we 
will screen for depressive symptoms and suicidality by asking patients if they 
are suicidal. 
1. Suicidality plan: 
a. C-SSRS will be performed at each visit by study coordinator. 
Study coordinator to contact PI if there is a change in the C-
SSRS.  
b. For suicidal ideation and/or behaviors, we will refer subject to 
the Emergency Department for emergent evaluation and 
treatment. Phone number for suicide hotline will also be 
provided. Will also discontinue enrollment in trial and study 
drug. 
3. We will screen for behavioral changes at each visit and during each telephone 
call.   
1. Will screen by asking specifically if patient is having: 
a. Thoughts of harming others, physical assault, or threating 
behavior 
b. Worsening anger, aggression, or irritability 


 
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2. If thoughts of harming others, physical assault, or threating behavior 
develops in a subject, will discontinue enrollment in trial and study 
drug. Subject will be referred to the Emergency Department. 
3. If worsening anger, aggression, or irritability is mild or moderate, will 
continue enrollment and continue monitoring subject. 
4. If worsening anger, aggression, or irritability is severe, will 
discontinue enrollment in trial and study drug. 
4. We will check a serum pregnancy prior to enrollment in baseline phase and then 
a urine pregnancy test prior to enrollment in treatment phase to ensure pregnant 
women are excluded. 
5. Subjects who are not status post tubal ligation or who do not have an IUD must 
agree to use a double barrier contraceptive method while enrolled in study (e.g. 
condom +spermicide OR condom + diaphragm/cervical cap). 
a. During monthly telephone calls while enrolled in the study (see “Data 
Collection” below), subjects will be reminded to utilize the double barrier 
contraceptive method while enrolled in the study. 
Adverse Events: 
1. Serious FDA definition: A serious adverse event results in death, is life-
threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability / incapacity, results 
in a congenital anomaly / birth defect.  
2. Severity: Severity describes the intensity of a specific event and will be graded 
as: 
a. Mild: easily tolerated, causing minimal discomfort. 
b. Moderate: sufficiently discomforting to interfere with every day activities. 
c. Severe: prevents normal every day activities. 
3. Relationship will be detailed as: 
a. Unrelated: There is no association between the study intervention and the 
reported event. 
b. Related: A definite causal relationship exists between the event and the 
study, and other conditions (concurrent illness, progression of disease or 
concomitant medication use do not appear to explain the event).  
c. Cannot be ruled out: The event might be related to the intervention, but 
could also have been produced by other factors. 
Correlative Science: N/A 
Statistical Analysis:  
The primary outcome (50% responder rate) will be analyzed using Chi square 
analysis. The secondary outcome, changes in seizure frequency from baseline to 
treatment, will be analyzed using paired t-test or ANCOVA.  
The pilot should provide data for calculation of the required sample size for 
demonstration of a significant difference or equivalence between the two groups 
with 80% power. 


 
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Data Collection:  
Subjects will be seen in the clinical trial clinic for three separate visits. Subjects 
will be seen at enrollment and then also after the completion of baseline (first 2 
months of charting) and treatment phases (second 2 months of charting). 
Subjects will also be contacted by phone on a monthly basis to verify 
compliance with charting and treatment and to monitor for any adverse effects. 
[Subjects will also be reminded to utilize double barrier contraceptive methods 
during these phone calls]. Data will be obtained via paper charting on printed 
calendar and then entered into an electronic database (REDCap) for analysis. 
All adverse events will be reported to the IRB. 
 
Study Drug 
Regimens: 
During the treatment phase, subjects will be randomized into 2 parallel 
arms: (1) Fycompa 4 mg daily and (2) Fycompa 4 mg daily to be 
increased to 6 mg (4-mg pill and 2 mg pill) daily peri-menstrually (from 
Day -7 until Day 4 of menstruation where Day 1 is the first day of 
menstrual flow). This treatment phase will last for two menstrual cycles. 
Study Drug 
Requested Per 
Patient: 
Group 1 (n=25), to take 4 mg daily for 2 menstrual cycles or 60 days, 
1500 tablets (25 subjects x 60 days). 
Group 2 (n=25), to take 4 mg daily (1 tablet) with6 mg daily (1 4-mg 
tablet and 1 2-mg tablet) for 11 days around menses for 60 days. This 
would be 1500 tablets (25 subjects x 60 days) of 4 mg tablets and 550 
tablets (25 subject x 22 days) of 2 mg tablets. 
 
Are Clinical/Drug Supplies Requested? (check only 1 box): 
 ‘YES’   
 ‘NO’         
 
 
 
Estimated Length of 
Enrollment: 
I plan to enroll 50 patients within a 6 month time period. 
 
Total study drug amount in units (tablets, capsules, vials, etc.): 
 
 
Total Active Drug 
3000 tablets of 4 mg tablets needed 
550 tablets of 2 mg tablets needed 
 
 
Amount of Pure Substance 
(if applicable) 
 
 


 
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Description of Site 
Enrollment Capabilities: 
University of Florida-Jacksonville is a busy Level 4 National Association 
of Epilepsy Center (NAEC) with thousands of epilepsy patients seen per 
year. Patients seek care at three differential UF locations within the 
Jacksonville area covering a large catchment area that includes southern 
Georgia. 
Estimated Study 
Duration: 
~ 1 year 
Potential written 
outcomes of this study 
(check all that apply): 
 Final Study Report          
 Submit for Presentation at scientific 
conference  
 
 Submit for Publication    
 Submit Abstract/Poster at scientific 
conference 
Publication Plan (if 
applicable): 
Goal of being published in either Neurology or Epilepsia, to be submitted 
for publication within 1-1.5 years of contract execution. 


 
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Manuscript Publication 
Assistance: 
DO YOU REQUIRE MANUSCRIPT PUBLICATION ASSISTANCE, AS OUTLINED 
BELOW?: 
 YES  
 NO   ⁪ 
Eisai supports the exercise of academic freedom and transparency 
regarding the results of clinical studies of its products, and therefore 
encourages Investigators to publish study results, whether or not the 
results are favorable to the Study Drug.  In furtherance of the 
development of robust scientific literature regarding its marketed 
products, Eisai offers manuscript publication assistance to 
Investigators/Institutions in the form of a nominal payment of up to a 
maximum amount of $5,000.00 to help defray editorial costs or other 
outlays or publication expenses which are directly related to 
preparing and submitting manuscripts for research funded under 
Eisai’s IIS Program.  The amount of this manuscript publication 
payment is not negotiable and no payment is available for the 
preparation or submission of abstracts, posters, or any related travel 
costs or presentation costs for any abstracts or posters.  This payment 
is not conditioned in any way on the achievement of any specific 
scientific outcomes or the inclusion of any specific conclusions in 
any such manuscript.  In order to be eligible for such payment, the 
Investigator/Institution must comply with recognized ethical 
standards concerning publication and authorship, including the 
Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals, www.icmje.org, established by the International Committee 
of Medical Journal Editors, and must, in the form of manuscript 
disclosure statements, appropriately disclose funding and other 
support received in connection with the Study and the preparation of 
any manuscript.  Prior to publication of such manuscript, Institution 
agrees to provide Eisai with a copy of such manuscript disclosure 
statements so that Eisai may have a reasonable opportunity to review 
and confirm that such statements fully and accurately describe Eisai’s 
relationship with the author(s), including the funding and other 
support received in connection with the Study and the preparation of 
any manuscript.  This additional payment will be paid upon Eisai’s 
receipt of a copy of the final draft manuscript with a signed 
Publication Certification, a copy of which is attached as Appendix 1, 
[along with a reasonably detailed invoice for the payment]. 


 
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FUNDING requested: 
 
$93775 
Other sources of funding: 
Other sources of funding for this study are: 
None 
The following are other pending sources of funding: 
None 
Other sources of study 
drug: 
None 
Intellectual Property 
Disclosure: 
None 
Research Team 
Members/Co-
Investigators and all 
others’ Responsibilities: 
Ramon Bautista MD MBA, sub-investigator, 
Ramon.bautista@jax.ufl.edu 
Suparna Krishnaiengar MD, sub-investigator, 
Suparna.krishnaiengar@jax.ufl.edu 
Felicia Smith, Epilepsy Research/Clinical Coordinator, 
Felicia.smith3@jax.ufl.edu 
Yasmeen Shabbir, Research Coordinator, Yasmeen.shabbir@jax.ufl.edu 
Insurance: 
As a University of Florida faculty member, I am protected by the 
University of Florida Self-Insurance Program (UFSIP). No additional 
insurance will be purchased for this study. 
Past History and 
Experience: 
I have never been a Principal Investigator on an IIS prior, though I have 
assisted during residency and fellowship with creation of IIS proposals 
and with ongoing IIS. I have never had any disciplinary actions against 
my medical license.  


 
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References: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND: 
Hardy, R.W. (1970). Unit activity in premarin-induced cortical 
epiletogenic foci. Epilpesia, 11:179-86. 
Herzog, A. G. (2008) Catamenial epilepsy: definition, prevalence 
pathophysiology and treatment. Seizure, 17, 151-9. 
Herzog, A. G., K. M. Fowler, S. D. Smithson, L. A. Kalayjian, C. N. 
Heck, M. R. Sperling, J. D. Liporace, C. L. Harden, B. A. 
Dworetzky, P. B. Pennell, J. M. Massaro & P. T. S. Group (2012) 
Progesterone vs placebo therapy for women with epilepsy: A 
randomized clinical trial. Neurology, 78, 1959-66. 
Herzog, A. G., P. Klein & B. J. Ransil (1997) Three patterns of 
catamenial epilepsy. Epilepsia, 38, 1082-8. 
Joshi, S., K. Rajasekaran & J. Kapur (2013) GABAergic transmission in 
temporal lobe epilepsy: the role of neurosteroids. Exp Neurol, 
244, 36-42. 
Shiono, S., J. Williamson, J. Kapur & S. Joshi (2019) Progesterone 
receptor activation regulates seizure susceptibility. Ann Clin 
Transl Neurol, 6, 1302-1310. 
Smith, S.S. (1989). Estradiol administration increases neuronal response 
to excitatory amino acids as a long-term effect. Brain Res, 
503:354-7. 
Smejkalova, T., C.S. Woolley (2010). Estradiol acutely potentiates 
hippocampal excitatory synaptic transmission through a 
presynaptic mechanism. J Neurosci 30(48):16137-48. 
Turrigiano, G. (2011) Too many cooks? Intrinsic and synaptic 
homeostatic mechanisms in cortical circuit refinement. Annu Rev 
Neurosci, 34, 89-103. 
 
 IND Exemption    
 IND Number