Clinical trial NCT03371836
Conditions: Epilepsy Anxiety
Keywords: pediatrics
Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
Start date: 2017-10-01; Completion date: 2019-12-31
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is an open label, adjunctive, proof of concept, pilot clinical trial. Pediatric patients with epilepsy and clinically significant anxiety will be recruited and if enrolled will receive active treatment, involving flexible dose titration of clobazam and will be monitored for a period of four months. The study will be monitored and overseen by the Johns Hopkins Hospital Institutional Review Board.

Detailed description:

Arms: arm 1: open label (single treatment arm)
Interventions: intervention 1: Clobazam
Intervention descriptions: intervention 1: Clobazam is used as an adjunct medicine for all participants.

Protocol documents:
Prot_SAP_000.pdf: 
Use of Clobazam in Treating Anxiety Comorbid with Pediatric Epilepsy  
 
 
 
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Clinical Trial:  Use of Clobazam in Treating Anxiety Comorbid with 
Pediatric Epilepsy 
December 12, 2017 
 
 
 
 
 
Contact: 
 
Clinical Trials Unit at Kennedy Krieger Institute—(443)-923-3850 
Kennedy Krieger Institute 
716 N. Broadway 
Baltimore, MD 21205 
Email: ResearchTrials@kennedykrieger.org 
Website: www.kennedykrieger.org/research-training 
Study PI: Dr. Jay Salpekar; JHM-IRB Study No.: IRB00090037 
Sponsor: Lundbeck, LLC  
 
 


Use of Clobazam in Treating Anxiety Comorbid with Pediatric Epilepsy  
 
 
 
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Abstract 
 
Certain mood stabilizer/anticonvulsant medications may be better suited for 
epilepsy with comorbid psychiatric illness. Many anticonvulsants are broad-
spectrum and are well established as improving outcome for epilepsy as well as 
for behavioral disorders.  The intuitive choice for treatment in patients with such 
comorbidity would be medications with an established track record in 
successfully treating both conditions independently.  Benzodiazepines are a 
mainstay of anxiety treatment as well as for epilepsy treatment.   
 
Given its unique molecular structure, clobazam (Onfi®) is an example of a 
medication that theoretically could serve a “dual role” in terms of treating epilepsy 
as well as anxiety disorder.  Anxiety is prominent in children and adolescents 
with epilepsy although the evidence base is underdeveloped.   
 
This study would assess the utility of clobazam, which may represent a more 
effective and better tolerated treatment option for the numerous patients with 
seizure disorders who also have anxiety.  This study is an investigator initiated 
proposal submitted by the PI and is a prospective open-label clinical trial of 20 
children and adolescents with epilepsy.  The assessments include standardized 
questionnaires widely used in clinical practice as well as structured psychiatric 
diagnostic tools.  Overall, this study will contribute valuably to an understudied 
patient population and add key information to the evidence base that potentially 
will make an immediate clinical impact. 
 
 
Overview of Study Design  
 
This study is an open label, adjunctive, proof of concept, pilot clinical trial.  
Prospective participants will be identified from chronic epilepsy clinical 
populations of Johns Hopkins Hospital and Kennedy Krieger Institute.   Pediatric 
participants will be considered for the study if neurologic status suggests the 
need for additional treatment, and behavioral characteristics are clinically 
significant.  All participants will receive active treatment, involving flexible dose 
titration of clobazam and will be monitored for a period of four months.  The study 
will be monitored and overseen by the Johns Hopkins Hospital Institutional 
Review Board.  
 
Study Population 
 
Prospective research participants will be identified from the chronic epilepsy 
clinic population of the Neurology Departments of Johns Hopkins Hospital and 
Kennedy Krieger Institute in addition to clinic populations recruited in the region.   
Pediatric participants will be recruited between the ages of 6 and 17 years, 
inclusive, in order to allow valid completion of behavioral measures.  No 
exclusion will be made on the basis of gender or minority status.   


Use of Clobazam in Treating Anxiety Comorbid with Pediatric Epilepsy  
 
 
 
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Participants will be considered for the study if anxiety disorder symptoms appear 
to be prominent in children and adolescents with existing epilepsy.  Subjects will 
be included in the study if they fulfill diagnostic criteria for an anxiety disorder 
with functional impairment.   
 
Study Visits 
 
After initial telephone contact and pre-screening is completed, the screening 
study visit will be scheduled.  At that visit, study details will be reviewed and 
informed consent will be obtained by the PI.  The screening study visit will 
include detailed medical and psychiatric history review, pertinent, physical 
examination (vital signs, neurologic exam), and assessment including semi-
structured diagnostic interviews and rating scales. 
 
Following the screening visit, participants who qualify and continue consent will 
enter into the active treatment phase of the study.   The initial treatment phase 
will begin with a dispensing visit.  It is expected that the dispensing visit may 
occur on the same day as the screening visit.  However, if it does not occur on 
the day of the screening visit, it may occur within two weeks of the screening 
visit.   
 
Continued contact with research participants will be done at regular intervals over 
a period of approximately 4 ½ months.  In-person visits will occur biweekly for the 
first six weeks.  In-person visits will occur monthly for the next two months.  A 
total of seven in-person visits will occur including the baseline or screening visit.  
Participants who will continue on the drug, managed by their primary clinician, 
may have their care transitioned to their primary clinician before the time frame of 
the seventh in-person study visit.   
 
At each contact, inquiry regarding adverse events, physical and mental health 
status, and compliance with treatment will take place.  Safety assessment 
including mental health status and seizure diary review will take place at each 
subject contact.  Safety assessment will include assessment of suicidal thoughts 
or actions.  The PI will be involved with safety assessment at all study visits for 
each participant. 
 
Telephone contacts will also be arranged at weeks 8, 12 and 16 to assess safety, 
adverse events and tolerability.  Subject contact will occur every two weeks for 
the duration of the study.   
 
All participants will receive adjunctive clobazam as active treatment.  Initial 
titration will occur at standard dosage schedules, expected to be 5-10mg daily 
with 5-20mg biweekly increases.  Increases may progress to a total of 40 mg 
daily, either in single dosages or divided dosages.  Mimicking clinical practice, a 
flexible dose paradigm will be utilized to allow titration to effect and mitigation of 


Use of Clobazam in Treating Anxiety Comorbid with Pediatric Epilepsy  
 
 
 
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potential adverse events.  Flexibility with minimum or maximum dosages will be 
employed in order to meet clinical needs.   
 
Participants will be considered to have completed the study if they have 
successfully completed in-person visits.  Participants will be free to withdraw from 
the study at any time by their choice, or if adverse events are intolerable or other 
risks outweigh potential benefits then participants will be terminated from the 
study.  Participants who withdraw early for any reason will be assessed for 
safety, discharged from the study and returned to the care of their primary 
neurologist.   
 
Inclusion criteria: 
 
 Established diagnosis of epilepsy, characterized by focal seizures with 
suspected or documented localization in the temporal lobe.  All participants 
will have active epilepsy that requires treatment with anticonvulsant 
medication.  
o Although it is not necessary to be seizure free, a seizure baseline period will 
be established in the 60 days prior to enrollment into the study. 
o Current regimen of anticonvulsant drugs must have been stable for 30 days 
prior to entry into the study. 
 No episodes of seizure clusters of status epilepticus within 30 days prior to 
entry into the study. 
 Established symptoms of anxiety with functional impairment.   
 Baseline behavioral criteria for inclusion will include subscale scores above 
the norm for age and gender on one of the following: 
o Pediatric Anxiety Rating Scale (PARS). 
o Multidimensional Anxiety Scale (MASC) 
 Male or female participants equal to or above age 6 and below age 18 at the 
start of the study.  No exclusion will be made on the basis of gender or 
minority status.       
 Good general health as determined by medical history and physical 
examination. 
 Ability to swallow pills (participant will receive pill swallowing instruction if 
necessary).  The medicine may be cut into pieces and/or mixed with 
applesauce. 
 If female of childbearing age, a negative urine or serum pregnancy test 
must be established or assured at baseline.  Additionally, the participant 
must agree to use abstinence or appropriate contraception methods or be 
otherwise incapable of pregnancy for the duration of the study.  Pregnancy 
test results will be shared with parent or guardian.  Pregnancy status (or 
prevention) and abstinence or contraception methods will be addressed 


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throughout the study for females of childbearing age as well as for post-
pubertal males.   
 Previous subjects who failed at any point to meet continuation criteria and 
withdrew early may be considered for re-enrollment by the PI on a case-by-
case basis.  
 Participant or legal caregiver capable of providing informed consent and 
fully capable of monitoring the subject’s disease process and compliance 
with treatment. 
Exclusion criteria: 
 
 Previous allergic or hypersensitivity reactions to Onfi® or benzodiazepines 
 Active substance abuse or dependence within 30 days of enrollment 
 DSM-V diagnosis of psychotic illness or imminent risk of harm to self or 
others.  
 Current use of antidepressants  
 Current standing use of benzodiazepines (except as “rescue” medicine)  
 Serious or unstable medical or neurologic conditions such as HIV, liver or 
kidney disease, cancer or diabetes. 
 Participation in a previous experimental drug study within 30 days of 
baseline visit. 
 Estimated IQ<70 as indicated by initial clinical assessment (rendering rating 
scales invalid) 
 Insufficient capacity of caregiver or legal guardian to understand and 
appropriately consent for study procedures 
  
 
Statistical Analysis Plan 
 
Change from baseline will be analyzed statistically to test the main study 
hypotheses--that Onfi® has a dual role of improving both behavioral/psychiatric 
status, namely anxiety symptoms, as well as seizure control, in patients with 
epilepsy.  
 
Outcome measures will encompass behavioral and neurologic status.  The 
primary outcome variable will be Clinical Global Assessment of Functioning 
Improvement from baseline.  CGI ratings will be attributed both to neurological 
status including seizure control, as well as behavioral status.  CGI-Improvement 
ratings of a 1 or 2 (on a 7 point scale) will be considered positive responses.  
Paired student’s t-tests will be used to compare baseline and study endpoint 
ratings for response versus non-response.   
 


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Secondary outcome measures will include changes from baseline in overall and 
subscale ratings of the Pediatric Anxiety Rating Scale (PARS), Multidimensional 
Anxiety Scale (MASC), and the Quality of Life in Epilepsy Scale.   Positive 
outcomes will be defined as 10% score reduction or scores that drop below 
threshold of clinical significance.  Paired student’s t-tests will be used to compare 
baseline and study end outcomes for each measure.   
 
Risks 
 
The clearest risk is of potential side effects or other adverse effects of clobazam 
(Onfi®) drug treatment.  Clobazam is a widely available anticonvulsant medicine 
with FDA indication for seizures associated with Lennox Gastaut Syndrome in 
pediatrics.  All participants will have active epilepsy that requires treatment with 
anticonvulsant medication, so the risks incurred with drug treatment are equivalent 
to that experienced in typical neurologic clinical care for epilepsy.  Close clinical 
monitoring and active side effect and adverse event monitoring at each contact will 
minimize risks due to drug side effect. 
Specific risks notable for clobazam include rare but serious skin reactions, called 
Stevens-Johnson and toxic epidermal necrolysis.  The skin reaction is very rare, but 
more likely to occur within the first 8 weeks of treatment or if clobazam is stopped 
and then restarted.  Participants will be instructed to contact the 24 hour information 
line or emergency health care services for any occurrence of skin rash.  In this 
circumstance, sudden stoppage of the medication is indicated. 
Like other antiepileptic drugs, The U.S. Food and Drug Administration has reported 
that anticonvulsants including clobazam may increase the risk of suicidal thoughts 
or behaviors in a very small number of people taking the drug. Participants will be 
closely monitored for depression, suicidal thoughts or behavior, and unusual 
changes in mood or behavior. Psychiatric assessment will occur on each contact 
with participants to address this potential adverse reaction.   
Clobazam may slow thinking and impair motor skills; so participants will be 
cautioned not to drive, operate heavy machinery, or engage in other dangerous 
activities until they know how the drug affects them. Given its structural similarity to 
other benzodiazepines, clobazam can also theoretically cause abuse and 
dependence. It has been categorized as a Schedule IV drug under the Controlled 
Substances Act, and thus should not be discontinued suddenly. Onfi should not be 
discontinued suddenly. Stopping clobazam suddenly can cause serious withdrawal 
problems, such as seizures that will not stop, hallucinations, shaking, nervousness, 
and stomach or muscle cramps.  
Questions about medical and psychiatric history reveal private information, so there 
is a risk concerning confidentiality. The information gathered on the questionnaires 
will only be identified by a subject number and will be kept in a locked file cabinet in 
a locked office, or in a password protected computer.   
Some questions might make children or parents think about things that are anxiety 
provoking or uncomfortable.  In our experience, these reactions are mild and pass 


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very quickly.  If a participant reports any problems or concerns about their behavior 
or mood, we will offer them information for further evaluation.  We will report 
concerns to parents and treating physicians if concerns are significant. 
 
 
Benefits 
 
There is no guarantee of direct benefit.  However, participants may reasonably 
expect to have improvement in seizure control and/or anxiety symptoms.  
Participation in the study may also contribute to a better understanding of the 
treatment effects of anxiety comorbid with epilepsy.  Individual participants have 
reasonable potential to have improvement in their disease conditions as a result 
of participation in this study.     
 
Participation in this study will also lead to increased knowledge base in the field 
and increased understanding of treatment options for children and adolescents 
with anxiety comorbid with pediatric epilepsy.   
 
We will be happy to share results of standardized questionnaires, etc. with 
parents when the results are available.  This may be very useful to subjects and 
their clinicians; however, we are clear to state that participation in this study 
should not be considered as a substitute for a formal mental health evaluation. 
 
 
Payment and Remuneration 
 
Study participants will not be paid for participating in this study.   
 
Costs 
 
There are no direct costs for participating in this study.  Neither the patient, nor 
their insurance provider, will be charged for the costs of any of the procedures 
performed exclusively for the purpose of this research study.  The patient and/or 
insurer will be billed for routine medical care services, or services not connected 
with the study. They will be responsible for any applicable copays, coinsurances 
and deductibles.   
 
Routine clinical care will continue with the participants usual neurologists and 
primary care providers.  If additional assessments including lab tests are 
necessary for clinical care purposes, these will be done outside of the context of 
this study.  
 
Study medication will be provided to the participants at no charge for the duration 
of the study.  Efforts will be made to continue treatment based upon clinical 
justification and in collaboration with the participant’s clinical treatment team. 
 


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Parking is available free of charge to study participants at the facilities of Kennedy 
Krieger Institute.  
 
Contractual Agreements      
 
 
The study is funded by Lundbeck Pharmaceuticals based upon an investigator 
initiated proposal submitted by the principal investigator. 
 
Confidentiality 
 
Any information about the parent, child or their family obtained from this research 
will be kept as confidential (private) as possible.  All records related to them or 
their child’s involvement in this research study will be stored either in a password 
protected computer or in a locked file cabinet stored in a locked office. The 
patient’s identity on these records will be indicated by a case number rather than 
by a name, and the information linking these case numbers with an identity will 
be kept separate from the research records. Neither the parent nor child will be 
identified by name in any publication of research results unless a separate form 
giving us their permission (release) is signed.  Any data communicated to 
coordinating or collaborating sites will be fully de-identified, e.g. age in years, 
gender, etc., such that information cannot be personally linked to an individual 
subject. 
 
Facilities and Equipment 
 
This study will be conducted in the outpatient treatment facilities of the Departments 
of Psychiatry and Neurology at Kennedy Krieger Institute and Johns Hopkins 
Hospital.