JIMMA UNIVERSITY

COLLEGE OF PUBLIC AND HEALTH SCIENCES

DEPARTMENT OF PHARMACY

Drug Information and Literature Evaluation (Phar 651)

Critical Appraisal on Clinical Trial

Ethosuximide, Valproic Acid, and Lamotrigine in Childhood
Absence Epilepsy

Submitted to:Mr. Mulugeta Tarekegn (B.Pharm, MSc)

January, 2016
Jimma,Ethiopia
Title:Ethosuximide, ValproicAcid, and Lamotrigine in Childhood Absence Epilepsy
Citation:Tracy A, Avital C, Shlomo S, etal. Ethosuximide, Valproic Acid, and Lamotrigine in
Childhood Absence Epilepsy. N Engl J Med 2010; 362:790-9.
Journal name:New England journal of medicine
1 by: Ginenus F.
Introduction:
 Childhood absence epilepsy accounts for 10 to 17% of all cases of childhood- onset epilepsy,
making it the most common form of pediatric epilepsy.
 The syndrome is characterized by daily frequent but brief staring spells, typically beginning
at 4 to 8 years of age.
 Often misperceived as a benign form of epilepsy, childhood absence epilepsy is associated
with variable remission rates.
 Three medications are commonly used as initial monotherapy for this condition
Ethosuximide, Valproic acid and Lamotrigine but the most efficacious and tolerable initial
empirical treatment has not been defined.
Objective
To assess the efficacy, tolerability, and neuropsychological effect of three medications
(Ethosuximide, Valproic acid and Lamotrigine) to determine the optimal initial empirical
monotherapy for children with childhood absence epilepsy.
Methods
Recruitment:This trial was conducted at 32 sites across the United States.
Study Design: 16 week ofdouble-blind, randomized, controlled clinical trial
Subjects: 453 children (between 2.5 and 13 years) were enrolled and were randomly assigned to
one of three treatment groups
Patient selection and enrollment (inclusion and Exclusion criteria)
Inclusion criteria
 Children between 2.5 and 13 years of age
 Had childhood absence epilepsy of new onset that was clinically diagnosed according to the
International League against Epilepsy classification of epilepsy syndromes.
 had bilateral synchronous, symmetric spike waves (2.7 to 5 Hz) on a normal
background with at least one electrographically recorded seizure lasting 3 seconds or more on
a 1-hour, awake video EEG
 weighed 10 kg or more
 had a body-mass index below the 99th percentile
 had a normal complete blood count and normal levels of serum alanine aminotransferase,
serum aspartate aminotransferase, and bilirubin
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 The girls had to be premenarchal
Exclusion criteria
 had received antiseizure medication for more than 7 days before randomization
 had a history of non-febrile seizures other than absence seizures (e.g., afebrile generalized
tonic–clonic or myoclonic seizures)
 had a history consistent with juvenile absence epilepsy or juvenile myoclonic epilepsy (e.g.,
generalized tonic– clonic or myoclonic seizures)
 had a history of a severe dermatologic reaction to any medication, or had a history of major
psychiatric disease,
 autistic-spectrum disorder,
 Any clinically significant medical condition.
Intervention

Eligible subjects were randomly assigned to receive one of the three study medications in a 1:1:1
ratio.Subjects were treated withEthosuximide (Zarontin) (250-mg capsules or 250 mg per 5 ml of
syrup), valproic acid (Depakote) (25-mg capsules or 125-mg dose of sprinkles), and lamotrigine
(Lamictal) (5-mg and 25-mg chewable tablets or 25-mg tablets) were provided. Doses were
increased to highest allowable dose every 1 to 2 weeks over a 16-week period until either freedom
from seizures was attained or side effects limited the dose given.

Study Endpoints
 Primary outcome
o Freedom from treatment failureat week 16 or week 20
 Secondary outcome
o Evidence of attentional dysfunction (Confidence Index of 0.60 or higher on the
Conners’ Continuous Performance Test)
Statistical Analysis
 The interim analysis was carried out for both efficacy and futility.
 Outcome analyses were based on a modified intention-to-treat approach, and all analyses were
pre specified.

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 The primary and secondary outcomes were analyzed by means of Fisher’s exact test for the
pairwise comparisons between treatments; a P value of 0.017 was considered to indicate
statistical significance (accounting for a Bonferroni correction).
 An overall exact chi-square test was also performed, as well as an odds-ratio calculation with
a 95% confidence interval.
 Kaplan–Meier curves were constructed to show the time to treatment failure over the 20-week
study period.
 A logrank test of the three pairs of study drugs was performed at week 16 or week 20.
 A post hoc Tukey–Kramer analysis of attentional function at the final visit incorporated
baseline attentional differences.
 All analyses were carried out using SAS software, version 9.1 (SAS Institute), and StatXact
software, version 8.0 (Cytel Software).
Results
Primary Endpoint: Freedom from Treatment Failure
 Overall, 209 of the 446 children (47%) were free from treatment failure at the week 16 or
week 20 visit.
 Those treated with either ethosuximide or valproic acid had higher freedom-from failure
rates (53% and 58%, respectively) than those given lamotrigine (29%; P<0.001 for both
comparisons).
 The two most common reasons for treatment failure at weeks 16 and 20 were lack of seizure
control (in 109 subjects [24%]) and intolerable side effects (in 97 subjects [22%]).
 In eight subjects, treatment was discontinued owing to generalized tonic–clonic seizures:
three subjects in the ethosuximide group, four in the valproic acid group, and one in the
lamotrigine group.
Secondary Endpoints:Evidence of attentional dysfunction (Confidence Index Scores on
ContinuousPerformance Test)
 Confidence Index results from the Conners’ Continuous Performance Test were available for
316 subjects by the week 16 and week 20 visits.
 At these visits, the percentage of subjects with a Confidence Index score of 0.60 or higher was
greater in the valproic acid group than in the ethosuximide group (49% vs. 33%; P=0.03) and
the lamotrigine group (49% vs. 24%; P<0.001).
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 On post hoc analysis, even after adjustment for differences in the baseline Confidence Index
scores, the valproic acid group had significantly worse scores at the week 16 and week 20
visits than did the ethosuximide and lamotrigine groups (P<0.001
for both comparisons).
Conclusions and recommendations

For children with childhood absence epilepsy, ethosuximide and valproic acid were significantly
more effective than was lamotrigine in controlling seizures without intolerable side effects
(primary outcome), and ethosuximide had a significantly smaller negative effect on attentional
measures than did valproic acid (secondary outcome). Even though ethosuximide is a sensible
choice for initial empirical monotherapy in childhood absence epilepsy for it is efficacy and
safety long-term follow-up of this study cohort is needed.

CRITICAL APPRAISAL OF THE CLINICAL TRIAL

Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy
A. JOURNAL, TITLE, AUTHORS AND ABSTRACT
Journal
 New England journal of medicine is a reputablebiomedical journals that publishes quality
articles.
 The journal is peer reviewed and intended primarily for practicing physicians
 It for expanding knowledge, stimulating research, and promoting the practice of evidence
based patient care.
Title
 The title of the study is reflective of the work, unbiased, specific, and concise.
 It would have been more attractive and precise since it contains <=10 words.
 Better if the sensitive and specificword ‘comparison of’ is added before the title to describe
the title better
 Moreover, it is not too general or detailed
 However it hadn’t identified as Randomized clinical trials in the title.
 It does not overemphasize the conclusion and not phrased as a question.
Investigators/authors

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 The members of the writing group are highly professional, experienced researchers on
management of childhood absence seizure, and practicing at internationally familiar
universities.
 Authors are qualified to do the trial with MD, PHD
 The investigators have a good track record of prior research. The group of researchers had
been publishing several articles on the same topic. The lead author (Tracy A. Glauser, M.D)
has published other papers in the area
 The process of data analysis or evaluation was not carried out by statistician (A biostatistician
was not involved as an author)
 All the investigators are from university hospitals and universities and are not from
pharmaceutical industry so that there will be no question for validity of studies authored.

Abstract
 The structured abstract contains objective, research design, clinical setting,
participants,interventions, main outcome measurements, results, and conclusions. But as
deficiencies, in this study the objective is not clearly included in to the abstract and despite the
involvement of many centers; there is no any description about the general status of the
clinical settings.
 All pertinent information is included and it is concise and complete enough for readers to
have a reasonable understanding of the important portions of the article. But the study design
which is available in abstract is not specified in methods

B. INTRODUCTION
 The authors described pertinent previous researches. Moreover, in this study it is not clear
whether the investigators exhaustively searched for published and unpublished studies on the
topic that used the same methods of study design
Study rationale and purpose
 There is clear description of the gap of knowledge to be filled with this RCT, the rationale of
the study.
Objective and hypothesis
 The objective of the trial is clearly stated on the last paragraph of the introduction
appropriately as well as in a way that reflects the methodology.

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 But null hypotheses have not been presented separately and clearly.
 Therefore, this may limit the reader’s ease of understanding the methods to be implemented.

C. METHODS
Study subjects were not clearly shown in methods but under the results Subjects:. From the total
of 453 study participants, after randomization, two subjects never received a study drug. Five
subjects were found to be ineligible on central review: three did not meet EEG criteria, one had an
abnormal neutrophil count, and one had a BMI greater than the 99 th percentile. Thus, 451 subjects
were included in the safety analyses and 446 in the efficacy analyses. Moreover the way the
subjects were recruited is also stated clearly.
Study Design:it is not clearly described in methods being double-blind, randomized, controlled
clinical trial but in abstract and discussion
Patient Inclusion/Exclusion Criteria:There was a clear inclusion criterion which enables the
investigators at all sites to easily identify the eligible subjects
The exclusion criteria were also clearly stated and appropriate. But the reasons behind exclusion
criteria was not clearly indicated. The disease was defined clearly by using the appropriate
diagnostic method.
Intervention and Control Groups:the comparative groups of drugs to be evaluated were clearly
described.Comparison of Relative safety and efficacy of Ethosuximide, Valproic Acid, and
Lamotrigine in Childhood Absence Epilepsy was described.
Institutional Review Board (IRB)/Subject Consent: the trial was approved by the institutional
review boards of each participating site, the coordinating center, and the data and safety
monitoring board appointed by the National Institutes of Health. Written informed consent was
obtained from parents or guardians, and assent was obtained from the subjects when applicable.
Blinding: The other positive thing was that the study was double blinded and both the
investigators and the patients were not aware of the assignment of the subjects to the treatment or
control group.Blinded study medications were prepared at the central pharmacy and were shipped
in prepackaged kits for dispensing. Blinding was maintained with the use of either a double-
dummy approach (for solid and liquid formulations) or over encapsulation.
Randomization: Eligible subjects were randomly assigned to receive one of the three study
medications in a 1:1:1 ratio. The randomization was appropriate and there were no significant
differences between the treatment groups for any variable as presented by table of

7 by: Ginenus F.
baseline.Treatment assignments were performed centrally according to a computer-generated
random schedule in permuted blocks of three within age strata (<6 years and ≥6 years) and within
study site.
Endpoints:the trial clearly shown the primary and secondary end points: The primary outcome
was freedom from treatment failure after 16weeks of therapy; the secondary outcome was
attentional dysfunction.
Follow-Up Schedule/Data Collection/Compliance:Study data were gathered by the
Childhood Absence Epilepsy Study Group. Parallel study design was employed and it is
appropriate because there were enough subjects and since following period was very short no
problem was observed regarding the precise results. Thus the obtained result was appropriate with
appropriate follow-up and compliance.
Sample Size:Calculations of sample size were based on the ability to detect a 20% difference in
freedom-from failure rates (three pairwise comparisons) at 16 weeks with 80% power at a two-
sided P value of 0.017 and one interim analysis, which was planned to be performed when 50% of
subjects reached the primary outcome. The number of subjects to enroll in a clinical trial was
dependent on the expected magnitude of difference in the endpoint effect between the
intervention and control. The calculated would sufficient to detect difference between the primary
endpoint effect between the intervention and control groups. If financially and logistically
possible if more amount of sample would be obtained, gives more generalization
Statistical Analysis:
 The study used type error, 95 CI, power of 0.8 and being two tail was reasonable according to
most studies. However the probability of false significance finding, of 0.017 and being three
pair wise do not comply with many literatures as it is difficult for discussion.
 To protect against increasing a false-positive error rate one interim analysis, which was
planned to be performed when 50% of subjects reached the primary outcome was used..
 Baseline characteristics and safety variables for the three treatments were compared by means
of either an exact chi-square test or a two-way analysis of variance. An overall P value of 0.05
was considered to indicate statistical significance. This comply with other different studies.
 The data for measurement of primary end points were continuous and nominal but the nature
of the data distribution is not stated in the study.

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 Accordingly, it is appropriate that main analyses used were based on standard time-to-event
methods, with each treatment group assessed with the use of the log-rank test and Cox
proportional-hazards models were used to calculate hazard ratios.
 All analyses were carried out using SAS software, version 9.1 (SAS Institute), and StatXact
software, version 8.0 (Cytel Software) which is one of current sophisticated softwares for data
analysis.
Measurements
 The investigators set appropriate primary and secondary end points measurements.
 Baseline neuropsychological testing was performed either before or within 7 days after the
start of the study medication.
 At week 16 (the fourth visit), seizure status was determined by means of clinical report,
bedside hyperventilation testing, and a 1-hour video EEG (primary outcome measurement)
 Pretreatment serum samples for pharmacokinetic analyses were obtained at week 16 or week
20.
 Conners’ Continuous Performance test was repeated before or at the time of the week 16 or
week 20 (which assesses attention; standardized tests of verbal and nonverbal intelligence,
vocabulary, memory, learning skills, vasomotor integration, executive function, and academic
achievement; and questionnaires on behavior and quality of life was carried out during the
trial (secondary end point measurement.
 The subjects were not followed for a sufficient duration (only 16-20 weeks) time to obtain
well generalized and measured result
RESULTS
All relevant results were presented clearly and accurately. The tables and graphs as well as the
statistical presentations were clear and appropriate.
Subject Demographics: In the study all the number of patients eligible, screened, enrolled,
administered treatment, completing and final outcome obtained were reported with the
appropriate reasons. It shows a good matching between three subjects treated with Ethosuximide,
Valproic acid and Lamotrigine. There were no significant differences among the treatment groups
within each age stratum or with respect to overall demographic characteristics and clinical
baseline characteristics like sex, race and BMI. A general overview of the average subjects were
described, in a table of baseline information.

9 by: Ginenus F.
Subject Dropout and Compliance:the study showed that small number dropout and compliance
problem, thus it gives more or less precise result. In eight subjects, treatment was discontinued
owing to generalized tonic–clonic seizures. Intention- to- treat analysis was used and all subjects
who received at least one dose of a study drug were included in the safety analyses. This is
important to represent the actual patient characteristics and ITT analysis better mimic’s real-life
application of an intervention into practice. But it fail to determine the actual effects of the
intervention in subjects that followed the study protocol and completed the entire course of
therapy.
Endpoints and Safety: the study clearly put the primary and secondary end points.The primary
end point revealed that from,overall, 209 of the 446 children (47%) were free from treatment
failure at the week 16 or week 20 visit. Secondary end point result indicated that the percentage of
subjects with a Confidence Index score of 0.60 or higher was greater in the valproic acid group
than in the ethosuximide group (49% vs. 33%; P=0.03) and the lamotrigine group (49% vs. 24%;
P<0.001).An independent data and safety monitoring board appointed by the National Institutes
of Health monitored the trial. The safety and tolerability of subjects were described. In eight
subjects, treatment was discontinued owing to generalized tonic–clonic seizures and seventeen
types of adverse events were reported in 5% or more of the subjects in at least one treatment
group. In addition by the visit at 16 or 20 weeks, eight subjects (2%) had had serious adverse
events that required hospitalization.
Surrogate Endpoints:The criteria for treatment failure were defined in terms of surrogate points
like: platelet count, absolute neutrophil count, alanine aminotransferase or aspartate
aminotransferase level, total bilirubin level, or increase in the body-mass index.
Subgroup Analysis: Subgroup analyses, were not pre-specified, not documented justification for
conducting it and not done with regard to different base lines. If Sub group analysis was
performed it was better to compare and contrast the result.
Ancillary versus Adjunctive Therapies:There was no information whether the patients have
received Ancillary versus Adjunctive Therapies. In addition effect of the ancillary and adjunctive
therapy on the study results hadn’t evaluated. Since another therapy could distort or interfere with
the results, if any therapies were provided to the subjects it should be clearly indicated.
D. DISCUSSION AND CONCLUSION
Investigators began with a summary of the key findings of the study and explanations of the study
results. Then they tried to interpret the trial results in comparison with results of another study
10 by: Ginenus F.
they conducted earlier. They explained the possible causes for differences and the differences of
their study result with the others. However for majority of the results possible causes of
differences haven’t described which may reduce the quality of the result.They have given issues
to be considered in validity of the result regarding to internal validity because quality of study
design itself. No as such issue was described regarding the generalizability of the result external
validity. Because the conclusions of the study may not applied to other practice and there was
difference of results among other articles.
The authors haven’t discussed the limitation and strength of the trial. As a limitation they have
put only that this short-term study was not designed to detect long-term systemic or other
cognitive effects of these three medications.
Valid conclusions were not drawn based on the objective, methods and results. Because on the
methods and results part combination of primary and secondary outcomes suggests that
Ethosuximide is the optimal initial empirical monotherapy for childhood absence epilepsy. No
issue of failurity and less efficacy of ethosuximide was discussed. But it was concluded that
eventhough ethosuximide is the best empirical therapy, however, fails in almost 50% of newly
diagnosed cases and reported lack of effectiveness in preventing such seizures.
The study also addressed unanswered questions. But it have addressed future concerns and
recommendations. Even though ethosuximide is a sensible choice for initial empirical
monotherapy in childhood absence epilepsy for it is efficacy and safety long-term follow-up of
this study cohort is needed.
E. STATISTICAL SIGNIFICANCE VERSUS CLINICAL DIFFERENCE
The investigators calculated a p value for the endpoints using the collected study results and
statistical tests. The p value was compared to the α value established prior to the beginning of the
clinical trial that served as a benchmark against which p values are compared to determine if
statistical significance is present.
Measures of association:Baseline characteristics and safety variables for the three treatments
were compared by means of either an exact chi-square test or a two-way analysis of variance
(with treatment as one factor and age stratum as the other factor). Based on standard time-to-event
methods, with each treatment group assessed with the use of the log-rank test and Cox
proportional-hazards models were used to calculate hazard ratios. This measures of association
accurately revealed to be clinically significant.
F. BIBLIOGRAPHY/REFERENCES
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The authors have listed the materials they used in the manuscript appropriately including their
own but not excessively. The trial was referenced with appropriate literature, but majority of
references were not up-to-date. Example (1982, 1983, 1989, 1987, 1991, 1992, 1993 etc) which
are not update.
G. ACKNOWLEDGMENTS
No individuals contributing to the clinical trial have acknowledged. Better if any individuals or
groups had contributions in the trial have recognized and acknowledged.
H. FUNDING AND STATEMENT OF THE COI
 The study was supported by grants from the National Institutes of Health. The funding source
had no role in the design or conduct of the study, analysis or interpretation of the data, or the
decision to submit the manuscript for publication.
 Study medications were provided free of charge by Pfizer, Abbott Laboratories, and
GlaxoSmithKline. These companies had no role in the design of the study, data accrual, data
analysis, or manuscript preparation.
 Thus there was no potential bias that preclude the use of the study result.
 Since the research site is at hospital, there were no limitations with respect to resources and
technology to conduct the study effectively
 Dr. Glauser reports receiving consulting and lecture fees from Eisai, UCB Pharma, and
Johnson & Johnson; Dr. Shinnar, receiving consulting fees from Eisai, Johnson & Johnson,
and King Pharmaceuticals and lecture fees from Eisai and UCB Pharma, Dr. Capparelli,
receiving consulting fees from Cadence Pharmaceuticals, Bristol-Myers Squibb, and Arpida
Pharmaceuticals; and Dr. Adamson, receiving grant support from Abbott Laboratories. No
other potential conflict of interest relevant to this article was reported.

The end! Thank you!

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