Effects of Clobazam on Sleep and Daytime Function in Patients With Epilepsy
Conditions: Epilepsy
Sponsor: Brigham and Women's Hospital

Cover Page
Official Title:  Effects of Clobazam on sleep and daytime function in patients with epilepsy
NCT #: NCT02911025 
Version date of document: 10/19/2020

Effects of Clobazam on sleep and daytime function in patients with
epilepsy
Principal investigator: Milena Pavlova, M.D.
Co-investigator: Sandra Horowitz, M.D.
Study staff: research coordinator 
Consultants: BWH neuroscience institute statistical services
Background/Rationale
Many studies indicate that patients with epilepsy frequently have fragmented sleep, as well
as excessive daytime somnolence (Holoway et al 2011, Meyer et al 2011, Manni et al 2010, 
Krishnan et al 2012).  Causes include primary sleep fragmenting disorders (sleep apnea, 
movement disorders), nocturnal seizures that contribute to sleep fragmentation, and other 
abnormalities. Sleep complaints are widely reported among patients with various epilepsy 
syndromes (Lopez et al 2013). Insomnia is a particularly frequent complaint, seen in 40-51% of 
epilepsy patients (Vendrame 2013, Lopez et al 2013).  Furthermore, epilepsy patients who have 
insomnia also have a higher frequency of depressive symptoms, as well as poorer quality of life 
(Vendrame 2013).  Insufficient or poor quality sleep increases the risk of a variety of disorders, 
leading to abnormalities of endocrine (Buxton, Pavlova et al 2010) and immune function (Lange 
et al 2011). Insomnia probably has the some of the same consequences as insufficient sleep from 
other causes. For example, in a recent study in our group (Buxton, Pavlova et al, 2011), we found 
that sleep fragmentation, as measured by wake after sleep onset (WASO), predicts diabetes risk 
in insomnia patients.
Antiepileptic treatment may affect sleep (Bazil et al 2008). Effects vary by type of 
medication and comorbidities.  Generally, with improvement of seizure control, the regularity of 
the sleep cycle improves and sleep becomes more consolidated.  However, some antiepileptic 
medications have been associated with insomnia (Bazil et al 2008).  Although sleep has been 
studied in relation to some antiepileptic medications (Bazil et al 2008, 2012, Zou et al 2012), 
there are no currently available published systematic reports on the effect of Clobazam on sleep. 
We propose to study the effect of Clobazam on sleep and daytime alertness.
Hypothesis
Primary hypothesis: Patients with epilepsy have longer, more consolidated sleep after
treatment with clobazam is started.   This hypothesis will be tested in a prospective study, 
using within subject comparisons, where by sleep measures before treatment are compared to 
those after treatment. 
Secondary hypothesis: Sleep improvement will lead to a lesser subjective daytime 
sleepiness and improved quality of life.  This hypothesis will be tested by comparing subjective
measures of sleepiness and quality of life, measured by standard instruments (Epworth sleepiness 
scale score, ESS, Karolinska sleepiness scale KSS, and quality of life in epilepsy, QOLIE) 
relative to total sleep time and wake after sleep onset.  

Methods
Research methods
Subject Population.  We propose to prospectively include patients from our epilepsy 
clinics and inpatient who are starting treatment with Clobazam.  All patients who are considered 
for treatment with clobazam will be approached for participation. We will exclude patients with 
known untreated moderate or severe sleep apnea, or with major circadian rhythm disorders, as 
these may confound our analyses. 
Pre-treatment sleep symptoms will be evaluated using validated instruments including, 
Pittsburgh Sleep Quality Inventory (PSQI), depression symptoms - Beck Depression Inventory 
(BDI), and severity of insomnia - Insomnia Severity Index (ISI). We will also record the subject’s
Body Mass Index (BMI). Subjects will then be asked to complete a one week sleep and seizure 
log, simultaneous wrist actigraphy monitoring, and daytime sleepiness Epworth Sleepiness Scale 
(ESS), and daily visual analog scale (Karolinska sleepiness scale, KSS), as well as quality of life 
(QOLIE), prior to starting treatment – baseline phase.  
Treatment with Clobazam, as well as clinical follow-up will be performed as per standard
of care.  After the effective dose is reached and the treating physician confirms that the 
medication is well tolerated, subjects will repeat the same log, actigraphy and questionnaire 
measurements over a one week period– treatment phase.  We will then compare total sleep time 
(TST), wake after sleep onset (WASO), subjective sleep (from sleep log), and sleepiness prior to 
treatment to the same measures after treatment with Clobazam (Fig. 1).  
Fig 1: Study schema  
Statistical analyses 
Primary analyses will include within subject comparison of total sleep time (TST) and 
wake after sleep onset (WASO), as measured by actigraphy, before versus after treatment.  
Preliminary analysis indicate that 20 subjects will give us 98% power to demonstrate efficacy of 
Clobazam to improve the above sleep measures with effect size of 3, assuming the standard 
deviation is 3 with a two-sided one group t-test at alpha=0.05 level. 
Our secondary hypothesis is that in epilepsy patients, quality of life and subjective 
sleepiness improve with improved sleep.  To test this hypothesis, we will correlate the rate of 
sleepiness with the sleep variable.  The dependant variables will be ESS, KSS (subjective 
Baseline phase
Two weeks actigraphy, screening questionaires
Treatment per standard clinical guidelines
Two week actigraphy, treatment questionaires
Treatment phase

sleepiness measures), and the independent variables will be WASO and TST.  Bonferoni 
correction will be performed to adjust for multiple comparisons.
The Neuroscience Institute at the Brigham and Women’s Hospital provides statistical 
analyses at a reduced rate to neurologists within our department.  
Timeline
Within three months of the start of the funding period, we plan to have recruited study 
staff, purchased equipment and obtained Human Subject’s Committee approval.  At this time, 
recruitment of eligible patients will start.  Testing of each subject requires approximately two 
month of monitoring: one week of actigraphy sensor monitoring before treatment (baseline 
phase), subject’s titration period as dictated by their treating physician, and another 1 week after 
the prescribed dose has been reached - treatment phase.    These two testing phases will be 
approximately a month apart to ensure that the enrolled patients have reached effective dose and 
have not reported serious side effects. We will aim to have two subjects enrolled and actigraphy 
data collection done simultaneously.  Thus, with efficient recruitment and minimal attrition rate, 
20 participants can complete the study within 18 months of the start of the funding period.  
Proposed timeline would be as follows:
Study start: September 2014
First subject enrolled: December 2014
Completion of enrollment: May 2016
Final study report: June 2016 
Challenges and plans to address them
1)
Adverse events to Clobazam.  It is possible that the patients enrolled in the study 
experience adverse effects of Clobazam or for other reasons need to change the 
medication.  In these cases, we may need to exclude these participants.   In this case, the 
overall number of enrolled participants will need to be adjusted to allow adequate 
analyses.  
2)
Interactions with other medications and medication changes.  The patients who are 
eligible for the study may be on other medications.  Some may need medication change 
during the data acquisition. In these cases, treatment will follow standard clinical care 
guidelines (to avoid any adverse medical outcomes).  Any medication changes will be 
recorded for post-hoc analyses.  
3)   Recruitment. We aim to approach all eligible patients from our clinic and inpatient for 
participation.  However, it is possible that too few will volunteer to participate.  In this 
case, advertisement will be broadened and neurologists and epileptologists from around 
the Greater Boston approached for recruitment of eligible patients.  As more than 1000 
patients are seen by epileptologists within our division, and we have successfully 
recruited patients for other studies on sleep and epilepsy (Pavlova et al, 2013), we 
anticipate little difficulties.
Alternate analyses if challenges cannot be addressed
In case our study is under-powered to detect a statistically significant difference in the 
primary outcome measures, more detailed analyses will be performed on the secondary outcome 
measures – the subjective improvement of sleepiness or of depressive symptoms, as well as 
overall quality of life.

Publication plans
Meetings/Congresses
We will aim to submit an abstract to the major annual academy meetings – American 
Epilepsy Society and American Academy of Neurology. A more detailed sleep analysis may 
additionally be presented to the American academy of sleep medicine.   
Scientific/Medical Journals
We will prepare a manuscript from the acquired results and submit for publication to the 
journal Epilepsia (a major journal for research on epilepsy).  An alternative journal may be 
Epilepsy Research or Epilepsy and Behavior. 
Study impact
The strengths of our study include the importance and the physiological plausibility of the 
hypotheses to be tested, the compelling background studies that have lead to the hypotheses, the 
prospective study design and within subject comparisons, which will provide a strong and 
efficient test of the hypotheses. The issue of quality of life, resulting from healthy sleep is of 
crucial clinical importance when treating patients with epilepsy.  Therefore, we anticipate that the
findings of our study will have a major impact the field of epilepsy.
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