Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam

Journal Pre-proof Efficacy of Cannabidiol in Subjects with Refractory Epilepsy Relative to Concomitant Use of Clobazam Taylor E. Savage, Jo Sourbron, Patricia L. Bruno, Lauren A. Skirvin, Emma S. Wolper, Christina J. Anagnos, Elizabeth A. Thiele

PII:

S0920-1211(19)30377-8

DOI:

https://doi.org/10.1016/j.eplepsyres.2019.106263

Reference:

EPIRES 106263

To appear in:

Epilepsy Research

Received Date:

3 July 2019

Revised Date:

23 October 2019

Accepted Date:

27 December 2019

Please cite this article as: Savage TE, Sourbron J, Bruno PL, Skirvin LA, Wolper ES, Anagnos CJ, Thiele EA, Efficacy of Cannabidiol in Subjects with Refractory Epilepsy Relative to Concomitant Use of Clobazam, Epilepsy Research (2019), doi: https://doi.org/10.1016/j.eplepsyres.2019.106263

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

Efficacy of Cannabidiol in Subjects with Refractory Epilepsy Relative to Concomitant Use of Clobazam

Taylor E. Savagea, Jo Sourbron, Ph.D.a,I, Patricia L. Bruno, RN, BSNa, Lauren A. Skirvin, RN, BSNa, Emma S. Wolpera, Christina J. Anagnos, RN, BSNa, Elizabeth A. Thiele, M.D, Ph.D.a

Massachusetts General Hospital, Boston, Massachusetts, U.S.A, 02114

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Elizabeth A. Thiele, M.D., Ph.D. Massachusetts General Hospital 175 Cambridge Street, Suite 340 Boston, MA, 02114 Phone: 617-726-6540 Fax: 617-726-0230 [email protected]

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1. Number of text pages: 28 2. Number of words: 7659

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3. Number of references: 25 4. Number of figures: 3 5. Number of tables: 3

T. Savage 1

Highlights:



Data analyses compared two groups, those taking CBD with and without concomitant CLB



Concomitant AEDs used remained similar in both groups, regardless of CLB usage



With or without concomitant CLB, CBD may be effective in reducing seizure frequency



Changes in CLB and nCLB levels do not correlate with seizure frequency reductions

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ABSTRACT

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Objective: To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB)

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as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels. Methods: Data were examined retrospectively, in patients who either used CBD with

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concomitant CLB or without concomitant CLB after two months of treatment with CBD and

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at the point of best seizure control within the first year of treatment with CBD. Responder rates (percentage of subjects with a 50% or greater reduction in weekly seizures from their baseline) and mean reduction in weekly seizure frequency were calculated and compared between those

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who concomitantly used CLB and those who did not. The relationship between the change in CLB and nCLB levels and change in mean weekly seizure frequency was also investigated

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within the group of subjects using concomitant CLB and CBD. Results: We analyzed data from 47 subjects between the ages of 2.5-51 years. There was no significant difference between the concomitant CLB (n=32) and no concomitant CLB (n=15) groups in terms of demographics (age (p=0.4344), race (p=1.0000), sex (p=0.7507)) or most epilepsy characteristics (underlying condition (all p>0.05), mean baseline seizure frequency (p=0.6483)). There was only one significant difference between groups regarding seizure types (more subjects with epileptic spasms in concomitant CLB group (p=0.0413)). Concomitant

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AED usage was not significantly different in the two groups (all p>0.05). Mean reduction in weekly seizure frequency was greater at the best point of seizure control within the first year than at two months of treatment with CBD, regardless of concomitant CLB usage (all p>0.05). There was no significant difference in reduction of mean weekly seizure frequency between those who took concomitant CLB and those who did not at either time point (all p>0.05). There was a significantly greater responder rate for subjects taking CBD and CLB than those taking CBD without CLB only at the point of best seizure control within the first year of CBD

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treatment (p=0.0240). There was no strong, significant correlation between change in nCLB or

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CLB levels and change in seizure frequency at either time point (all |p|<0.22).

Significance: With or without concomitant CLB, CBD can be effective in reducing seizure

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frequency. Changes in nCLB and CLB levels do not have a clinically significant correlation

INTRODUCTION

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1.

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with changes in weekly seizure frequency for those taking CBD with CLB.

Approximately one third of patients with epilepsy will develop a refractory form and do not achieve adequate seizure control.1 Refractory epilepsy has associated worsened morbidity and

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mortality, with issues ranging from the negative health effects of uncontrolled seizures, including Sudden Unexplained Death in Epilepsy (SUDEP), to decreased quality of life to

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increased familial and societal burden.1 New safe and effective treatments are therefore greatly needed. Cannabidiol (CBD) is a promising treatment and was recently approved by the Food and Drug Administration (FDA) for the treatment of seizures associated with Dravet Syndrome and Lennox Gastaut syndrome in patients two years and older.2-4 However, limited data are available characterizing the impact of drug-drug interactions of other antiepileptic drugs (AEDs) and CBD on its efficacy and tolerability.

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A prospective, open-label expanded access study suggested that the interaction between clobazam (CLB) and CBD could improve seizure control by increasing the levels of the active metabolite of CLB, norclobazam (nCLB). This would suggest that the efficacy of CBD has been overestimated.5 Although the study maintained that CBD may still be effective in controlling seizures, critics have questioned whether the entire efficacy of CBD could be attributed to the associated increase in nCLB levels.6,7

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Previous research by Porcari et al. and Pietrafusa et al. suggests that artisanal CBD is effective

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as an adjunctive treatment for refractory epilepsy in pediatric populations, both with and without concomitant CLB use. They note that although CBD has a favorable safety profile

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overall, CLB use may contribute to issues with tolerability, specifically sedation.8,9 However, these results are influenced by variability in an unregulated, artisanal CBD supply so additional

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research into the efficacy of a consistent supply.

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Pooled post hoc analyses of the GWPCARE3 and GWPCARE4 trials suggested that adjunctive CBD treatment results in clinically significant reductions in drop seizure frequencies as compared to adjunctive treatment with placebo, regardless of concomitant CLB usage. These

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meta-analyses suggested that the CBD-CLB interaction may impact issues with tolerability, particularly in terms of somnolence, more than the efficacy of CBD itself.3,4 While they support

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the idea that CBD has an intrinsic anti-seizure effect, these analyses have limited applicability as they were done using aggregate results from the trials using non-randomized subgroups. Individual patient level analyses could therefore be helpful in clarifying the role of concomitant CLB in the efficacy of CBD. Patients in the subgroups analyzed were taking placebo or CBD in doses of either 20 mg/kg/day or 10 mg/kg/day so whether or not their results are generalizable to higher dosages must also be investigated.3,4

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Previous publications have also indicated that treatment with CBD may be associated with a number of positive effects on behavior and cognition.3,10 One study investigated whether these improvements in quality of life were associated with treatment response, i.e. changes in seizure frequency, seizure severity, or adverse event profile. Those results suggested that CBD may in fact have beneficial effects on quality of life and mood that are independent from treatment response. However, these results are confounded by the CBD-CLB interaction potentially causing an antianxiety effect similar to those of benzodiazepines.10 Understanding the

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implications of the CBD-CLB interaction therefore has relevance in terms of CBD efficacy in

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improving both seizure control and quality of life.

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CBD interacts with several cytochrome P450 (CYP) enzymes and therefore has the potential to alter the metabolism and serum concentrations of many different AEDs and their active

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metabolites.11,12 Specifically, CBD is known to inhibit CYP2C19, an isozyme that catalyzes

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the metabolism of nCLB, and therefore leads to a buildup of nCLB in the system.12 CYP2C19 is the main enzyme that metabolizes nCLB and testing suggests that strong and moderate inhibitors of this enzyme may result in an up to five-fold increase in nCLB levels.13 An

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expanded access study of CBD also reported similar two to six-fold increases in nCLB levels in their subjects.14 This increase in nCLB serum levels can lead to somnolence, ataxia, and

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irritability. These effects can often resolve with reduction of CLB dose.14 PK interactions between CBD and CLB resulting in elevated nCLB plasma levels were reported in a recent randomized, dose-ranging safety trial for in Dravet syndrome. This study suggested that elevated nCLB could contribute to increased seizure control and adverse events of sedation and fatigue in those taking concomitant CLB and CBD.15

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While the existence of an interaction between CBD and CLB has been established, as of now, only a correlation with concomitant CLB and CBD use and reduction of seizure frequency has been observed. Whether or not this medication combination specifically causes more significant reductions in seizure frequency has not been established. Therefore, the question of the clinical significance of this interaction remains largely unanswered. In this study, we evaluate the efficacy of CBD in treating refractory epilepsy relative to the concomitant use of CLB and try to determine if there is a relationship between the changes in nCLB or CLB levels

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and reduction in mean weekly seizure frequency.

MATERIALS AND METHODS

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2.1 Subjects

The Partners Healthcare Institutional Review Board approved this research protocol prior to its

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initiation and informed consent was obtained from all subjects and/or their legal guardians prior

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to enrollment.

The Pediatric Epilepsy Program at Massachusetts General Hospital (MGH) has been studying the use of CBD as adjunctive treatment for refractory epilepsy under an expanded access

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Investigational New Drug (IND) application with the FDA. Data from 47 subjects was analyzed over the course of the first year of treatment with CBD. Thirty-two subjects who

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concomitantly used CLB were compared to 15 subjects who did not use CLB. All patients completed at least one year of treatment with CBD. Demographic information was collected for each subject at the start of the study based on electronic medical records and parent/caregiver report. This information included age, sex, race, medical and epilepsy history, and concomitant AEDs.

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Data from this patient population has been analyzed in two prior publications. The first publication evaluated the CBD-CLB interaction in thirteen children with refractory epilepsy over the first eight weeks of treatment with CBD.17 The second publication focused on efficacy of CBD in eighteen patients with tuberous sclerosis complex (TSC) over the first year of treatment with CBD.19 This study will expand upon the previous publications from this data set and will investigate a larger group of patients, both children and adults with varying AEDs and underlying conditions, over the course of the first year of treatment with

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CBD.

2.1.1 Inclusion and Exclusion Criteria

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All subjects included had a documented diagnosis of drug-resistant epilepsy as evidenced by failure to control seizures despite appropriate trials of two or more AEDs at therapeutic doses.

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Study inclusion or exclusion did not depend on subjects’ reported age, sex, race, or ethnicity.

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To be enrolled in the study, subjects had to be taking between 1-7 baseline AEDs at stable doses and had to have stable dietary therapy ratios and vagus nerve stimulator (VNS) settings if applicable. In addition to being unchanged throughout the study baseline, the patients’

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epilepsy treatments were required to have been stable prior to baseline as well. Baseline AEDs were initially considered stable if they remained unchanged for four weeks prior to baseline

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but this requirement was later shortened to unchanged for two weeks prior to baseline. Dietary therapy ratios and VNS settings were initially considered stable if unchanged for three months prior to baseline but this was later shortened to being unchanged for four weeks prior to baseline.

2.1.2 Study Protocol

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After a baseline period of four weeks (28 days), subjects were started on an open-label, pharmaceutical formulation of highly purified cannabidiol (CBD) derived from Cannabis sativa L. plant in oral solution (100 mg/mL; Epidiolex® in the U.S.; GW Research Ltd, Cambridge, United Kingdom). They were initially given CBD at a dosage of five mg/kg/day, which was increased by five mg/kg/day weekly, as tolerated, up to a maximum dose of 50 mg/kg/day. Alterations to this titration schedule were made only if clinically indicated. Compliance was determined by subject and/or caregiver self-report. Subjects were seen in our

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clinic initially every two and later 12 weeks and parents kept daily diaries of seizures,

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medication changes, and all adverse events. At the clinic visits, when possible, blood samples were drawn for laboratory assessments. These labs included assessments of complete blood

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count (CBC), comprehensive metabolic panel (CMP), and concomitant AED plasma concentrations. If the subject was taking concomitant CLB, CLB and nCLB serum levels were

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also obtained. CBD serum levels were not assessed in this study as the MGH laboratory was

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not capable of performing this laboratory test. Due to this, serum levels throughout the course of the study were unavailable for the majority of the patients. The time between CLB and CBD administration and the blood draws was not controlled as it was thought that this was unlikely

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to affect this evaluation due to half-lives of at least a day of CBD, CLB, and nCLB.16

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2.2 Change in Seizure Frequency

The mean weekly seizure frequency at each visit was established from the daily seizure logs completed by the parent since the previous study visit. Responder rates (percentage of subjects with a 50% or greater reduction in weekly seizures from their baseline) and mean changes in weekly seizure frequency were calculated and compared between the subjects who concomitantly used CLB and those who did not. The mean changes in weekly seizure frequencies were determined by calculating the percent change from the mean weekly seizure

T. Savage 8

frequency at baseline. These values were compared between the two groups at two timepoints, at two months of treatment with CBD and at the point of best seizure control within the first year of treatment with CBD. The best point of seizure control within the first year of treatment with CBD was considered the time point with the best mean weekly seizure frequency when compared to baseline (expressed as a percent change). The two-months of treatment with CBD timepoint was chosen as subjects would be treated with a CBD dose of 25 mg/kg/day and doses of all concomitant AEDs remained stable at this time, unless a change to either the CBD

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titration schedule or concomitant AED dose had been clinically indicated. After two months of

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treatment with CBD, concomitant AED doses could be altered to optimize seizure control. When medication changes could be made, CLB dosing was adjusted for clinically significant

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2.3 Change in CLB and nCLB Levels

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side effects, including drowsiness, ataxia, irritability, and urinary retention.17

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Changes in CLB and nCLB levels were investigated for the subjects using CBD with concomitant CLB. These values were assessed at the same time points as the change in mean weekly seizure frequency, i.e. at two months of treatment with CBD and at their point of best

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seizure control within the first year of treatment with CBD.

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2.4 Statistical Analysis

GraphPad Prism 6 software (GraphPad Software, Inc.) was used for statistical analyses. Data processed in contingency tables were analyzed by Fisher’s exact tests. The difference between the two groups was analyzed by an unpaired t-test if the data passed the normality test (D’Agostino & Pearson omnibus normality test). If this was not the case, then a Mann–Whitney U test was used. The Spearman’s rank correlation coefficient (p) between changes in weekly seizure frequency and changes in both CLB and nCLB levels were calculated at both the two-

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month point and the point of best seizure control within the first year of treatment with CBD. Given the power of the correlation analysis due to the sample size (n=32), only transformations of the correlations greater than 0.5 could be detected. None of these correlations were indicated

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and an outlier was present, so Spearman’s rank correlation was used.

RESULTS

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3.1 Subjects

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Table 1. Subject demographics by concomitant CLB usage group. Mean age at study baseline of subjects in each group was calculated as was sex and race. Significant p-values (<0.05) are bolded and marked with an asterisk.

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Concomitant CLB Use (n=32) 15.3 (10.9)

Age (years, mean ± SD)

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Sex (%)

No Concomitant CLB Use (n=15)

p-value

15.5 (6.9)

0.4344 0.7507

62.5

53.3

Female

37.5

46.7

Caucasian

96.9

100.0

1.0000

Biracial (Caucasian and Asian)

3.1

0.0

1.0000

Other Non-Caucasian

0.0

0.0

1.0000

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Race (%)

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Male

Data were analyzed from 47 subjects who either used CBD with concomitant CLB (n=32) or without concomitant CLB (n=15) in addition to other AEDs. There were no significant differences in the subject demographics between the two groups in terms of mean subject age (p=0.4344) or in terms of the distribution of subject sexes (p=0.7507) or races (p=1.0000) (Table 1).

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Table 2. Characteristics of subjects’ refractory epilepsy by concomitant CLB usage group. The mean number of seizure types per subject as well as the proportion of subjects with the underlying conditions and seizure types listed were calculated. Mean weekly seizure frequency at baseline was calculated as was mean reduction in seizure frequency at two time points: two months of treatment with CBD and at the best point of seizure control within the first year of treatment with CBD. Statistically significant p-values (<0.05) are bolded and marked with an asterisk. Concomitant No Concomitant p-value CLB Use (n=32) CLB Use (n=15) Proportion of Subjects with Underlying Condition (%) 34.4

40.0

0.7526

Dravet Syndrome (DS)

15.6

13.3

1.0000

Other Genetic Disorders

6.3

Congenital Brain Malformations

12.5

Generalized Epilepsy of Unknown Etiology

18.8

1.0000

20.0

0.6638

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6.7

1.0000

12.5

0.0

0.2909

2.4 (1.2)

2.0 (0.9)

0.2189

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20.0

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Other Number of Seizure Types/ Subject (mean ± SD)

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Tuberous Sclerosis Complex (TSC)

Proportion of Group with Seizure Type (%)

37.5

13.3

0.1698

Tonic-Clonic

50.0

40.0

0.5501

Atonic

25.0

6.7

0.2363

Myoclonic

6.3

20.0

0.3088

Absence or Atypical Absence

25.0

33.3

0.7278

Focal with Impaired Consciousness

40.6

60.0

0.3473

Focal Seizures to Generalized Tonic, Clonic, or Tonic-Clonic Components

12.5

26.7

0.2455

Epileptic Spasms

28.1

0.0

0.0413*

62.3 (141.4)

45.0 (52.3)

0.6483

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Tonic

Mean Weekly Seizure Frequency at Baseline (mean ± SD)

Mean Weekly Seizure Frequency Reduction (mean % ± SD) At Two Months

26.8 (77.0)

26.2 (36.1)

0.3469

At Best Point within First Year

58.5 (40.8)

49.5 (29.9)

0.3004

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There was no significant difference in the mean weekly seizure frequency at baseline between the concomitant CLB and no concomitant CLB groups (p=0.6483), with the overall population having a mean of 56.8 ± 120.6 seizures per week at baseline (Table 2). There was also no significant difference between the groups in the distribution of underlying etiologies or mean seizure frequency reductions (Table 2). Underlying etiologies, in order of prevalence in the overall study population, included: tuberous sclerosis complex (TSC), generalized epilepsy of unknown etiology, Dravet Syndrome (DS) and congenital brain malformations. Other

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etiologies included perinatal stroke, mitochondrial disorder, and neonatal encephalitis. Subjects

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had between one and five different seizure types at baseline, with no significant difference in the mean number of seizure types per subject between the concomitant CLB and no

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concomitant CLB groups (p=0.2189) (Table 2). The seizure types observed, in order of prevalence in the overall study population, included: focal with impaired consciousness, tonic-

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clonic, tonic, absence or atypical absence, atonic, epileptic spasms, focal evolving to

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generalized tonic, clonic, or tonic-clonic components, and myoclonic seizures. There was no significant difference between the groups in the proportion of subjects who had each seizure type listed, with the exception of epileptic spasms (p=0.0413) which were only present in the

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concomitant CLB group (Table 2).

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Table 3. Concomitant AEDs used by subjects in the concomitant CLB and no concomitant CLB Groups. The mean number of concomitant AEDs used other than CLB and the proportion of subjects using each concomitant AED in each group was calculated. Statistically significant p-values (<0.05) are bolded and marked with an asterisk. Concomitant Clobazam Use (n=32)

No Concomitant Clobazam Use (n=15)

pvalue

2.2 (1.0)

2.7 (1.5)

0.3670

Number of Concomitant AEDs (except CLB), (mean ± SD)

Proportion of Subjects Using Each Concomitant AEDs (%) 3.1

0.0

1.0000

clonazepam

3.1

13.3

0.2353

diazepam

12.5

6.7

1.0000

ethosuximide

3.1

13.3

0.2353

felbamate

6.3

6.7

1.0000

gabapentin

3.1

0.0

1.0000

66.7

0.5423

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56.3

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lacosamide

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clorazepate

25.0

40.0

0.3239

lamotrigine

28.2

26.7

1.0000

lorazepam

12.5

26.7

0.2455

oxcarbazepine

3.1

0.0

1.0000

phenobarbital

0.0

6.7

0.3191

rufinamide

15.6

6.7

0.6484

stiripentol

3.1

0.0

1.0000

topiramate

12.5

13.3

1.0000

vigabatrin

12.5

6.7

1.0000

sodium valproate

18.8

26.7

0.7042

zonisamide

6.3

0.0

1.0000

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levetiracetam

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Subjects were using between one and seven concomitant AEDs other than CLB, with no significant difference in the mean number used across the two groups (p=0.3670) (Table 3). No significant differences in concomitant AED usage were found between the groups (Table 3). Lacosamide (LCS; 57.4%), levetiracetam (LEV; 31.9%), lamotrigine (LTG, 27.7%), and valproic acid (VPA; 21.3%) were the most frequently used concomitant AEDs in the overall population. Stiripentol (STP) was only used by one subject in the concomitant CLB group

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(Table 3).

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Overall, six out of 47 subjects had a change in their LCS/VPA/STP drug regimen, drugs known to have CYP involvement, before their best point of seizure control within the first year of

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treatment with CBD. Of those six subjects with these changes, five were subjects using concomitant CLB (15.6% of group), one was not using concomitant CLB (6.7% of group).

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Three of those five concomitant CLB subjects with changes were also considered responders

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in this study. Of those three responders using concomitant CLB, the changes made to the LCS/VPA/STP drug regimen were as follows. One subject discontinued VPA, one discontinued LCS, and the other had a 37.5% dose reduction of LCS. The two non-responders

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with changes in the concomitant CLB group both had dose reductions of LCS, by 62.5% and 37.0%. The one subject in the no concomitant CLB group with changes made to their

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LCS/VPA/STP drug regimen was a non-responder and discontinued LCS.

Figure 1. The number of subjects in the concomitant CLB and no concomitant CLB groups who changed concomitant AEDs used by the best point of seizure control within the first year of treatment with CBD. Changing an AED used is considered adding or discontinuing an AED. A difference between the usage groups in the proportion of subjects who made changes was assessed with the Fisher’s exact test. Statistically significant p-values (<0.05) are bolded and marked with an asterisk.

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No subjects added or discontinued any AEDs before two months of treatment with CBD in either usage group as the protocol did not allow medication changes prior to that point. There was no significant difference between the two groups in the number of subjects who either added a new AED or discontinued a baseline AED by the best point of seizure control within the first year of treatment with CBD (Figure 1).

3.1.1 Side Effects

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The most common side effects seen in this study population were diarrhea, somnolence, and

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fatigue. Increased serum aminotransferases were also seen in the setting of concomitant valproic acid use. Side effects of somnolence, ataxia, irritability, and urinary retention were

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common in the setting of concomitant CLB use and typically resolved after dose adjustments

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3.2 Change in Seizure Frequency

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to either CLB or CBD.17

3.2.1 Change in Seizure Frequency at Two Months of Treatment with CBD At two months of treatment with CBD, subjects were treated with a CBD dose of 25 mg/kg/day,

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unless a change to a subject’s CBD titration schedule had been clinically required. At two months of treatment with CBD, there was no significant difference in mean CBD dose between

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the two groups (p=0.3851). At that time point, the group treated with concomitant CLB had a mean CBD dose of 23.5 ± 3.8 mg/kg/day and the group treated without concomitant CLB had a mean CBD dose of 24.3 ± 2.5 mg/kg/day. Figure 2. Percent change (Δ) in mean weekly seizure frequency from baseline at two months of treatment with CBD (blue) and at the best point of seizure control within the first year of treatment with CBD (red) in subjects treated with and without concomitant CLB. A difference between the two groups at each timepoint was assessed with the Fisher’s exact test. Statistically significant p-values (<0.05) are bolded and marked with an asterisk.

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After two months of treatment with CBD and concomitant CLB, the mean reduction in weekly seizure frequency was 26.8 ± 77.0%, with 75.0% (n=24) of the subjects experiencing some reduction in seizure frequency and 50.0% (n=16) being responders (Figure 2). Within this responder group, there was a mean reduction in weekly seizure frequency of 79.7 ± 15.9%. One subject taking concomitant CLB was seizure free at the two months of treatment with CBD time point.

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After two months of treatment with CBD without concomitant CLB, the mean reduction in

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weekly seizure frequency was 26.2 ± 36.1%, with 86.7% (n=13) of the subjects experiencing some reduction in seizure frequency and 26.7% (n=4) being responders (Figure 2). This

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responder group experienced a mean reduction in weekly seizure frequency of 71.6 ± 16.3%. No subjects receiving CBD without CLB were seizure free at the two months of treatment with

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CBD time point. There was no significant difference in the mean reduction in weekly seizure

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frequencies of the groups (p=0.3469) nor was there a significant difference in their responder rates at this time point (p =0.2065).

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3.2.2 Change in Seizure Frequency at the Best Point of Seizure Control within the First Year of Treatment with CBD

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Within the first year of treatment with CBD, subjects’ CBD doses could be optimized up to a maximum dose of 50 mg/kg/day. At the best point of seizure control within the first year of treatment, the group treated with concomitant CLB group had a mean CBD dose of 25.9 ± 10.9 mg/kg/day (5-50 mg/kg/day) and the group treated without concomitant CLB group had a mean CBD dose of 30.1 ± 14.2 mg/kg/day (5-50 mg/kg/day). There was no significant difference in the mean CBD doses of the two groups at this time point (p=0.3359). All subjects treated with CBD and concomitant CLB had their CLB dose adjusted within the first year of treatment with

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CBD. Adjustments were made due to side effects of the CBD and CLB interaction, such as sedation, fatigue, and ataxia, or made prophylactically to prevent these side effects. These adjustments were made after the first two months of treatment with CBD, during which all AEDs remained stable.

At the best point of seizure control within the first year of treatment with CBD and concomitant CLB, the mean reduction in weekly seizure frequency was 58.5 ± 40.8%, with 84.4% (n=27)

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of the subjects experiencing some reduction in seizure frequency and 71.9% (n=23) being

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responders (Figure 2). Two subjects were seizure free at some point in their first year of treatment with CBD and concomitant CLB. This responder group experienced a mean

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reduction in weekly seizure frequency of 81.9 ± 15.1%.

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At the best point of seizure control within the first year of treatment with CBD without

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concomitant CLB, the mean reduction in weekly seizure frequency was 49.5 ± 29.9%, with 100.0% (n=15) of the subjects experiencing some reduction in seizure frequency and 33.3% (n=5) being responders (Figure 2). No subjects receiving CBD without CLB were seizure free

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within their first year of treatment with CBD. This responder group experienced a mean reduction in weekly seizure frequency of 88.4 ± 8.1%. There was no significant difference in

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the mean reductions in weekly seizure frequency of the groups (p=0.3004) at the best point of seizure control within the first year of treatment with CBD. However, there was a significant difference in responder rate between the groups (p=0.0240) at this time point, with the concomitant CLB group having a greater proportion of responders.

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3.3 Change in CLB and nCLB Levels Figure 3. The relationship between the percent changes in CLB (A, B) and nCLB (C, D) levels and the percent changes in mean weekly seizure frequency. Change (Δ) from baseline in weekly seizure frequency and in CLB and nCLB serum levels were calculated and compared at two months of treatment with CBD (A, C) and at the best point of seizure control during the first year of treatment with CBD (B, D). Linear trendlines and associated correlation (p-values) are indicated. At two months of treatment with CBD, subjects’ CLB serum levels had decreased a mean of 3.5 ± 50.3% from baseline (Figure 3A, -73.6 - 137.0%) and their nCLB serum levels had

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increased a mean of 271.3 ± 320.0% from baseline (Figure 3C, -17.5 - 1694.8%). At the best point of seizure control within the first year of treatment with CBD, subjects’ CLB levels had

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decreased a mean of 9.1 ± 52.8% (Figure 3B, -74.8 – 159.3%) and their nCLB levels had

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increased a mean of 219.6 ± 241.3% (Figure 3D, -53.4 – 1137.1%).

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Change in CLB serum levels and reduction of mean weekly seizure frequency do not have a

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strong correlation or relationship at either two months of treatment with CBD (Figure 3A, p=0.1528) or the best point of seizure control within the first year of CBD treatment (Figure 3B, p=-0.1984). Change in nCLB levels and reduction of mean weekly seizure frequency also

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p=0.2194).

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showed a similar weak correlation at both time points (Figure 3C, p=-0.1996; Figure 3D,

4. DISCUSSION

4.1 Subjects

When comparing the concomitant CLB and no concomitant CLB groups, there were no significant differences regarding mean age, weekly seizure frequency, or number of seizure types per subject at baseline or in the distribution of subjects’ sexes, races, or underlying conditions (Table 1-2). The study population demographics are thought to be representative of

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the demographics of the study site overall. This suggests that the two groups’ populations are suitably similar for comparison and that such comparisons are not likely to be skewed by variance in the demographics of each group. It also supports the claim that differences in the mean reductions in seizure frequency are likely due to the intervention of adding CBD.

Regarding the distribution of seizure types, there was only a significant difference between the two groups with one seizure type, epileptic spasms. While 28.13% of the subjects treated with

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concomitant CLB had epileptic spasms as one of their seizure types, none of the subjects in the

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group not treated with concomitant CLB had this seizure type (Table 3). Epileptic spasms are notoriously difficult to treat and CLB is thought to be a particularly effective AED for

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controlling this seizure type. In a previous study with subjects with TSC, all subjects with epileptic spasms were taking concomitant CLB.19 It is therefore consistent with previous

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literature that the concomitant CLB group would have a significantly greater proportion of

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patients with epileptic spasms than the no concomitant CLB group.

There was no significant difference in the mean CBD dose between the concomitant CLB group

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and the no concomitant CLB group when compared at two months of treatment with CBD (p=0.3851) and at the best point of seizure control within the first year of treatment with CBD

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(p=0.3359). This suggests that CBD dosing remained similar between the two groups and that differences in seizure frequencies were not a result of different CBD dosages.

When comparing AED regimens, there were no significant differences between the two groups regarding the use of any concomitant AEDs, including with those known to have CYP involvement like STP, VPA, LCS, TPM, and PHEN, or in the number of concomitant AEDs used per subject (Table 3). Optimization of concomitant AEDs was not allowed per protocol

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until after the first two months of treatment with CBD, unless a change was clinically required due to significant adverse events. Once this optimization was allowed, the majority of subjects did not add or subtract any AEDs prior to the point of best seizure control within the first year (Figure 1). There was also no significant difference in the proportion of subjects that did add or subtract AEDS within the first year of treatment with CBD across the concomitant CLB or no concomitant CLB groups (p=1.0000, Figure 1). This finding suggests that throughout treatment, the distribution of which concomitant AEDs were used remained similar in both the

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concomitant CLB and no concomitant CLB groups. This result also supports our theory that

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concomitant AEDs make up the subjects’ drug regimen.

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differences in the mean reductions in seizure frequency are likely not due to changes in what

To ensure that our results were not biased by changes to made to other concomitant AEDs,

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changes made to LCS, VPA, and STP were analyzed with regards to our two timepoints as

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those AEDs are known to have clinically significant effects on drugs that are metabolized by CYP, such as CBD.20 CBD inhibits CYP2C19 and LCS is inactivated by CYP2C19. Thus, a higher responder rate could be expected when LCS is increased. However, five out of 47

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subjects had a significant decrease in LCS dose, two of those five subjects were nonresponders. Only two subjects had a change of their VPA regimen, reduction or

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discontinuation, both of which were responders. By that point of best seizure control within the first year, only 15.63% of the concomitant CLB group (n=5) and 6.67% of the no concomitant CLB group (n=1) had changes in LCS and/or VPA dosing. Additionally, only one subject was using concomitant STP concomitantly. This subject was a non-responder in the concomitant CLB group and did not make any changes to STP dosing prior to their best point of seizure control within the first year of treatment with CBD. Overall, due to the low number of subjects with changes in their LCS/VPA/STP regimen (n=6) and the equal proportion of responders

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(50%), our results do not indicate that changes in LCS/VPA/STP contribute to changes in seizure frequency. This is consistent with previous research reporting that CBD is not thought to cause clinically significant increases in blood concentrations of AEDs other than CLB, suggesting they do not play a role in the efficacy of CBD.4,10,21

4.1.1 Side Effects Although the primary aim of this research is not to assess safety or tolerability, tolerability does

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influence the efficacy of CBD in controlling seizures as it influences dosing changes. Within

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the first year of treatment with CBD and concomitant CLB, all subjects reduced their CLB dose due to either side effects of the CBD-CLB interaction previously mentioned or in an effort to

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avoid those interactions. Consistent with previous studies, these side effects related to the CBDCLB interaction included somnolence, ataxia, irritability, and urinary retention. Overall, other

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side effects attributable to CBD reported included diarrhea, fatigue, and elevated serum

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aminotransferases, particularly in the setting of concomitant valproic acid use. These results are also consistent with tolerability data reported in other studies.3,4,17,18,8,15

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4.2 Change in Seizure Frequency

At the best point of seizure control within the first year, mean reduction in weekly seizure

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frequency was greater than at two months of treatment with CBD, regardless of concomitant CLB usage. There were no significant differences in the mean seizure reduction of those with and without concomitant CLB at either time point, suggesting a similar efficacy for CBD with or without concomitant CLB. There was also a greater proportion of responders at the best point of seizure control within the first year than at two months of treatment with CBD, regardless of concomitant CLB use. These results are consistent with previous meta analyses assessing Epidiolex efficacy and with studies investigating the efficacy of artisanal CBD.3,4,9,10

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This suggests that the time it takes to reach an optimal dose of CBD, and what dose is optimal, may vary depending on individual subject’s metabolism. Given that the majority of these subjects are on multiple concomitant AEDs, this may also suggest the importance of optimizing other concomitant AEDs after the addition of CBD as well.

Consistent with prior research by Devinsky et al, there were greater responder rates at both timepoints for subjects taking CBD and concomitant CLB than those taking CBD without

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concomitant CLB.18 This difference was not statistically significant at two months of treatment

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with CBD (p=0.2065) but was significant at the point of maximal efficacy during the first year of treatment with CBD (p=0.0240). This finding would suggest that the at the best point of

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seizure control, a greater proportion of patients using CBD and CLB have had a 50% or greater reduction in seizure frequency than of those taking only CBD. However, if this difference

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remained significant in both a larger sample size and over a longer time period, this could

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support the idea that CLB and CBD may be a positive combination therapy once optimized. Based on this study, this difference is not considered noteworthy as there was no significant difference in the mean change in weekly seizure frequency based on concomitant CLB use at

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that time point (p=0.3004). The trend is likely due to the smaller sample size and larger spread of the change in weekly seizure frequency data for those taking CBD without CLB as well as

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the greater variability in the first year of treatment data.

4.3 Change in CLB and nCLB Levels At both two months of treatment and the best point of seizure control in the first year of treatment with CBD, generally, CLB serum levels decreased from baseline. However, the mean percentage of change was small (-3.5 ± 50.3%, -9.1 ± 52.8%) and there is notable variability in the changes at both timepoints. This variability is evident graphically when comparing

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change in CLB levels to change in mean weekly seizure frequency as well as in the ranges of the changes in the CLB levels at both timepoints (Figure 3A, -73.6 - 137.0%; Figure 3B, -74.8 – 159.3%). Given that concomitant AEDs were stable and that the CBD dose was standardized at two months of treatment, this range of changes likely reflects variability in hepatic metabolism. There is also no significant relationship between the changes in CLB level and changes in mean weekly seizure frequency at either time point (Figure 3A, p=0.1528; Figure 3B, p=-0.1984), suggesting a lack of causal relationship between seizure control and change in

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CLB serum levels. This is consistent with the results of the UAB CBD program study.11

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CYP2C19 is the major P450 enzyme involved in the nCLB hydroxylation pathway.22 It is

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therefore expected that nCLB levels increase when CLB is used concomitantly with CBD as CBD’s inhibition of CYP2C19 is thought to lead to a buildup of nCLB.17,18 At both two months

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of treatment and the best point of seizure control in the first year of treatment with CBD, nCLB

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serum levels increased, on average, over 200% from baseline (271.3 ± 320.0%, 219.6 ± 241.3%). However, at both timepoints, the mean change in nCLB level also had a standard deviation greater than 240%, indicating a very large spread and variability in the data. This

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variability is further evident in the graphical comparison of the changes in nCLB levels and the changes in mean weekly seizure frequency as well as in the ranges of the changes in the nCLB

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levels at both timepoints (Figure 3C, -17.5 - 1694.8%; Figure 3D, -53.4 – 1137.1%). The variability in how much nCLB levels change could be due to CLB interactions with other concomitant medicines as well as individual liver diversity affecting the metabolism. Specifically, genetic polymorphisms for the expression of CYP2C19 can result in the enzyme being metabolized poorly. In these poor metabolizers, nCLB serum levels have been reported to be fivefold higher than in those with typical metabolisms.16 The nCLB levels in poor metabolizers are also thought to be less influenced by changes in concomitant AEDs, inducers

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or inhibitors of CYP2C19, than in those with typical metabolisms.23,8 These polymorphisms could therefore explain some of the variance in both the CLB and nCLB levels, CLB to nCLB ratios, and responses to CBD.17

While these increases in nCLB levels have been well demonstrated, with the exception of the clinical implications of the drug-drug interaction effects on tolerability previously noted, a clinical correlation with seizure control was not observable.17 When comparing change in

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nCLB levels to reductions in seizure frequency, no strong correlation or relationship is evident

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(Figure 3C, p=-0.1996; Figure 3D, p=-0.2194). This finding suggests that changes in nCLB levels do not play a clinically significant role in the reduction in mean weekly seizure frequency

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seen in those treated with CBD and concomitant CLB. This also weakens the claim that CBD’s efficacy can be explained purely by it potentiating CLB metabolism and increasing nCLB

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levels.8,6,7 Given results suggest that changes in CLB and nCLB levels are not related to

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increased seizure control in those treated with CBD, additional research looking into whether the interaction is instead related to efficacy of CBD in terms of quality of life improvements is

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particularly of interest.12

4.3 Limitations and Improvements

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Data from this and previous studies suggest that CBD is effective with or without concomitant CLB use. They also suggest that when CBD treatment is introduced, concomitant CLB use likely carries greater implications on tolerability than on the efficacy of CBD in controlling seizures.3,4,9,10 This is clinically relevant as a reduction in seizure frequency has been observed.5,17,18,23,11 Given that this study involves human subjects and self-reporting, there could be potential limitations due to noncompliance and misreporting. However, the longer, one-year long observation period of this study, which allows for the evaluation of trends over

T. Savage 24

time, lessens the impact of this limitation. Previous studies investigating the efficacy of CBD and the CBD-CLB interaction have assessed data over much shorter observation periods, 12 and eight weeks respectively.5,17 Meta-analyses investigating the efficacy and safety of CBD in the GWPCARE3 and GWPCARE4 trials were also analyzed data over a 14-week treatment period.3,4 All of these studies are therefore more influenced by biases than our study. The longer observation period also allows subjects more time to reach their optimal dose of CBD and a stable state. This provides additional insight into the roles of the variety of concomitant AEDs

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and their optimization in the clinical context of concomitant CBD use. Approaching the longer

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one year duration of our study, the UAB CBD program did analyze data at 12, 24, and 48 weeks of CBD treatment. However, due to patients withdrawing over time, the number of patients

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decreased sample size at the later time points.11

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included in each analysis were not consistent at each timepoint and resulted in a significantly

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An additional limitation of our study is that the ethnic diversity of the study population was relatively low as participating subjects were predominantly Caucasian (Table 1). Subjects were not excluded from participation on the basis of race or ethnicity so this low level of diversity

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is thought to be representative of the study site’s demographics. While this lack of ethnic diversity may limit the generalizability of this study to the overall population, it does not

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significantly impede comparison to existing research as the proportion of Caucasian subjects is consistent with those found in other recent research publications, including the GWPCARE3 and GWPCARE4 trials.4,11

Analyzing our data at the best point of seizure control within the first year of treatment with CBD instead of at a finite time point may be a limitation of our study. This analysis method was chosen as it best facilitates the evaluation of the primary focus of our research, the

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implications of changes in CLB and nCLB plasma levels on seizure control. If a relationship was present between changes in CLB or nCLB levels and improved seizure control, the relationship would be most evident at this best point of seizure control. This method may however skew reported efficacy measures towards greater reductions in seizure frequencies and responder rates. This limitation of efficacy overestimation is also present using the common alternate method of data analysis, last-observation-carried-forward (LOCF).24,25

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Changes in other AED levels was not addressed in this study as it was considered outside the

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scope of this research. Although the changes to other concomitant AEDs did not significantly differ between CLB usage groups, not incorporating changes in other concomitant AED levels

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is considered a limitation of this study. Comparable research also experienced this limitation.11 A phase 1 pharmacokinetic trial analyzed by Morrison et al. did however suggest that even

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though CLB, STP, and VPA are all metabolized by the same cytochrome P450 (CYP) pathway

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as CBD, only the CBD-CLB was thought to have a clinically significant interaction.21 Further research must be done to more fully investigate other drug-drug interactions with CBD and whether there are any other trends regarding concomitant CLB and CBD usage. Additionally,

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due to the lack of CBD serum levels, this study cannot assess changes in seizure frequency with regards to the level of CBD in the patients’ systems. Given the variance in individual

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metabolisms, this would be important for future studies to investigate whether there is a relationship between CBD serum level and response.

This study allows evaluating the effect of CLB and nCLB serum levels on CBD’s efficacy as we reliably analyzed these levels. The effect is important to understand as it has been theorized that the efficacy of CBD in controlling seizures is due to the CBD-CLB interaction increasing the CLB and nCLB serum levels. However, our study clearly indicates that the change in nCLB

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levels does not strongly correlate with change in mean weekly seizure frequency. Therefore, we conclude that the explanation for the efficacy of CBD is still unknown.

DISCLOSURE Elizabeth A. Thiele, M.D., Ph.D. has served as a paid consultant for GW Pharmaceuticals companies. The remaining authors have no conflict of interest to disclose.

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ACKNOWLEDGMENTS Study drug provided by GW Research Ltd (Cambridge, UK). Funding was provided by GW

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Research Ltd (Cambridge, UK), the Pediatric Epilepsy Program at Massachusetts General

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Hospital, and the Herscot Center for Tuberous Sclerosis Complex.

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3. Lattanzi, S., Brigo, F., Trinka, E., Zaccara, G., Cagnetti, C., Giovane, C. D., & Silvestrini, M. (2018). Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis. Drugs, 78(17), 1791–1804. doi: 10.1007/s40265-0180992-5 4. Lattanzi, S., Brigo, F., Cagnetti, C., Trinka, E., & Silvestrini, M. (2018). Efficacy and Safety of Adjunctive Cannabidiol in Patients with Lennox–Gastaut Syndrome: A

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