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Reporting and analysis of open-label extension studies of anti-epileptic drugs

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DOI: 10.1016/j.eplepsyres.2008.04.007 · Source: PubMed

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Epilepsy Research (2008) 81, 24—29

journal homepage: www.elsevier.com/locate/epilepsyres

Reporting and analysis of open-label extension

studies of anti-epileptic drugs
M.J. Maguire a,∗, K. Hemming b, J.L. Hutton b, A.G. Marson a

a
The Department of Neuroscience, University of Liverpool, Liverpool, UK
b
The Department of Statistics, University of Warwick, Coventry, UK

Received 16 October 2007; received in revised form 6 April 2008; accepted 13 April 2008
Available online 2 June 2008

KEYWORDS Summary
Open-label extension; Purpose: Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are
Anti-epileptic drugs; widely believed to be prone to patient selection biases which may inflate effect estimates.
Efficacy; This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically
ITT analysis evaluates the associated underlying assumptions. We propose an alternative method of analysis,
in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach,
in which it is assumed that all patients who discontinue treatment are non-responders.
Methods: A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate,
levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted.
Sample sizes and numbers of responders, along with reported outcomes were extracted. To
evaluate the feasibility of the assumptions underlying the various methods of analysis, the
most common causes of discontinuation were evaluated. For each FORCT, we compared the
reported outcome to the proposed ITT analysis.
Results: The 10 FORCT reports identified all excluded from the analysis patients who dropped
out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinu-
ation. Analysis based on the ITT method, led to smaller effect estimates than those reported.
For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to
28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT.
Conclusions: FORCTs can provide important information about long-term efficacy and tolera-
bility of newer therapies. However, current reporting methods are likely to be misleading as
outcomes are reported for the subset of patients continuing with treatment at the end of the
FORCT. Since the majority of patients who discontinue treatment do so for reasons associated
with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of
the patients.
© 2008 Elsevier B.V. All rights reserved.

∗ Corresponding author. Present address: The Department of Neurology, Sunderland Royal Hospital, Kayll Road, Sunderland, SR4 7TP, UK.

Tel.: +44 191 565258.

E-mail address: melissa.maguire@liv.ac.uk (M.J. Maguire).

0920-1211/$ — see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2008.04.007
Reporting and analysis of open-label extension studies of anti-epileptic drugs
Introduction
Randomised placebo-controlled trials (RCTs) are the gold
standard study design for assessing the efficacy of newer
drugs. However, longer term observational studies also have
a crucial role to play. Following completion of a RCT, patients
may be invited to participate in an open-label (unblinded)
extension study, or follow-on RCT (FORCT). During the
FORCT, patients are given the active treatment regardless
of whether they were originally randomised to placebo or
treatment. These extension studies vary in length from a
few weeks to up to several years, and they can therefore
provide information on the longer term efficacy and safety
of newer AEDs beyond the usual 12—20 weeks of a typi-
cal regulatory RCT. This information is crucial in epilepsy
where treatment is required in the long term and often for
life. However, FORCTs are also less prescriptive in design
than the parent RCT, with both investigator and participant
unblinded to treatment and the dose or titration of medica-
tion can be altered by the investigator according to clinical
response.
Due to the uncontrolled and unblinded setting of FORCTs
they are prone to various biases. In particular, they are prone
to patient selection biases, as participants who have not
responded in the original RCT, or who have experienced mod-
erate or severe side effects are less likely to persist with
treatment. It is widely believed that these selection biases
result in over optimistic estimates of treatment efficacy,
since FORCTs often report higher effect estimates compared
to RCTs of the same drug. For example, a FORCT study of
gabapentin reported responder rates of 35—71% (The US
Gabapentin Study Group, 1994) compared to just 19% for
the parent RCT (The US Gabapentin Study Group No 5, 1993)
and a pooled responder rate of 23% in a meta-analysis of four
gabapentin RCTs (Marson et al., 1997).
The usual method of analysis of a FORCT is to carry out
what is termed an ‘‘evaluable case analysis’’ (ECA) An ECA
is carried out on the subset of patients who did not drop
out of the study and therefore have outcome data avail-
able. Underlying this method is the assumption that any
patients discontinuing treatment are representative of those
who remain in the trial (Hemming et al., 2008). However, in
trials of AEDs, the majority of those who dropout do so for
reasons of lack of efficacy or adverse events. Rather than
assuming that these patients are representative of those
who remain in the trial, these patients should be considered
as non-responders.
An alternative approach is to treat all patients discon-
tinuing treatment as non-responders. This is a reasonable
assumption for those who discontinue for reasons of lack
of efficacy or intolerability. For the smaller subset who
dropout for other unclear reasons or ‘protocol violations’,
such an approach may be less obvious, but at the very
least represents an intention to treat (ITT) approach, as
is recommended in the analysis of RCTs, providing a more
conservative estimate of treatment effects.
We describe a systematic review of reporting practices,
effect estimates and the statistical analyses used in FORCTs
of three newer anti-epileptic drugs; gabapentin, topiramate
and levetiracetam used in refractory adult epilepsy. We
aim to compare statistical methods used within published
reports and compare recalculated results based on both the
25
commonly used method of the evaluable case analysis and
the proposed ITT approach.
Methods
Eligibility criteria and search strategy
Reports had to satisfy the following criteria:
1. Fully published or in abstract form in any language.
2. Randomised placebo-controlled trials or FORCTs recruiting
patients that had previously participated in an RCT of topira-
mate, levetiracetam, or gabapentin as add-on therapy in adults
with refractory epilepsy.
Duplicate reports were identified and excluded, as were studies
which recruited additional patients at the start of the FORCT.
Search strategies
To identify completely published studies, electronic searches of
the following databases were carried out: MEDLINE (1966—2006),
EMBASE (1974—2006), CINAHL (1982—2006), the Cochrane database
of systematic reviews, the Cochrane Controlled Trials register and
the DARE database. RCTs were identified using the Cochrane RCT
search strategy (Dickersin et al., 1994). Reports were identified
using the keyword searches ‘open-label study’, ‘follow-on RCT’
or ‘extension study’ and relevant text words for each interven-
tion. Abstracts were identified by searching the ZETOC database
(1993—2006), the ISI PROCEEDINGS (1990—2006), the International
Bureau for Epilepsy (IBE) congress proceedings database, the
International League Against Epilepsy (ILAE) congress proceedings
database, and by hand searching abstract books of symposia con-
gresses, meeting abstracts and research reports.
All non-English language articles were included and translated.
Any additional studies identified from reference lists of study arti-
cles which fulfilled the eligibility criteria were included. The search
was censored to include all studies published before 31st December
2006. Each FORCT was linked to its parent RCT, either through the
use of direct reference within the FORCT paper, or in the case of
abstracts (where no such citations were available) by delineation
using a search of the author’s names, location and medical institute
to match to the identified RCTs.
Extraction of data
For each FORCT report, trial and patient characteristics were
extracted. This consisted of information on reported responder
rates, numbers of cases entering into the studies, numbers of cases
dropping out of the studies, along with mean study dosage, age,
number of concomitant AEDs and type of epilepsy.
Statistical analysis
Reported responder proportions were compared to recalculated
responder proportions based on an ITT analysis. Estimates based
on an ITT analysis use the number entering into the RCT as the
denominator in calculations. This ITT analysis has been called a
‘‘full case analysis’’ to distinguish it from what we have called an
‘‘eligible case analysis’’ where only those entering into the FORCT
are included within an ITT inference. As an ITT approach includes
all patients entering into the trial, for those who discontinue treat-
ment an outcome must be assumed: responder or non-responder.
As the great majority of those who discontinue treatment in short-
term regulatory RCTs of AEDs do so for lack of efficacy, it is assumed
26
that those who discontinue treatment are non-responders. In con-
trast, the evaluable case analysis uses only patients who have
completed the FORCT with available data in the denominator. An
implicit assumption underlying an evaluable case analysis is that all
those who discontinue treatment are representative, in terms of
responder status, to those who remain in the trial.
In order to quantify long-term effects, all patients included
within the analysis should have been exposed to treatment for the
duration of the study. In FORCTs, those patients initially randomised
to placebo have less exposure compared to those initially ran-
domised to the treatment. To accommodate this, an ITT sub-analysis
of responder proportions was carried out for patients entering the
FORCT who were originally assigned to the active treatment arm
in the RCT, excluding patients who were originally assigned to the
placebo arm. An example calculation demonstrating the various
analyses can be found in Appendix 1.
Some FORCTs reported from a single centre, participating within
a multi-centre RCT but with no information on the selection pro-
portion from RCT to FORCT. For these studies, the dropout rate for
the original multi-centre RCT was used as an approximate selection
proportion for the single centre: this assumes that the single centre
population was typical of the study population.
Results
Identified studies
Sixteen FORCT studies were identified through the search
methods with six studies excluded as they did not meet the
inclusion criteria (Privitera, 1995; Abou-khalil and Schaich,
2005; Handforth and Treiman, 1994; Schear et al., 1991;
Ojemann et al., 1992; Anhut et al., 1995).
Six FORCTs of topiramate (Ben-Menachem, 1995;
Engelskjon et al., 1993; Mikkelsen et al., 1993; Michelucci
et al., 1996; Fincham and Schottelius, 1995; Sharief et al.,
1993), two FORCTs of levetiracetam (Cameron et al., 1996;
Betts et al., 2000) and two FORCTs of gabapentin (The
US Gabapentin Study Group, 1994; Sivenius et al., 1991)
were included in the review. All FORCTs of topiramate were
reports from single centres that had participated in multi-
centre RCTs. Three topiramate FORCTs (Ben-Menachem,
1995; Engelskjon et al., 1993; Mikkelsen et al., 1993) were
reports from three separate centres that had participated
in a single RCT (Ben-Menachem et al., 1996) while a fur-
ther three (Michelucci et al., 1996; Fincham and Schottelius,
1995; Sharief et al., 1993) were from single centres partic-
ipating in three other RCTs (Tassinari et al., 1996; Privitera
et al., 1996; Sharief et al., 1996). For levetiracetam, one
FORCT (Betts et al., 2000) reported on the entirety of
patients from a single RCT (Betts et al., 2000), while another
FORCT (Cameron et al., 1996) reported a subpopulation from
a single RCT (Cereghino et al., 2000). For gabapentin, two
FORCTs (The US Gabapentin Study Group, 1994; Sivenius et
al., 1994) reported on all patients who had entered long-
term follow-up from two separate RCTs (The US Gabapentin
Study Group No 5, 1993; Sivenius et al., 1991).
Quality of reporting in FORCTs
Information on the original RCT study sample size was
reported in three out of the six topiramate FORCTs
(Michelucci et al., 1996; Fincham and Schottelius, 1995;
Sharief et al., 1993) and all levetiracetam and gabapentin
M.J. Maguire et al.
FORCT reports. It was possible to derive original RCT sam-
ple sizes for a further two topiramate FORCTs (Engelskjon
et al., 1993; Mikkelsen et al., 1993) as the parent RCT gave
information on number of patients recruited according to
centre.
Details on patient selection from the original RCT through
into the FORCT were reported in two topiramate FORCTs
(Michelucci et al., 1996; Fincham and Schottelius, 1995),
one levetiracetam FORCT (Betts et al., 2000), and one
gabapentin FORCT (The US Gabapentin Study Group, 1994).
The levetiracetam FORCT also reported the number entering
the FORCT and responders according to randomised treat-
ment status in the RCT. This was the only FORCT to report
such data.
The length of treatment period and daily dose and the
reporting of patient characteristics were missing in the
majority of reports.
Dropout rates and reasons
The number of patients dropping out during the initial RCT
phase was reported for three FORCT studies (Michelucci et
al., 1996; Fincham and Schottelius, 1995; Sharief et al.,
1993). Dropouts occurring during the RCT phase for two
FORCTs were extracted from the parent RCTs (Betts et al.,
2000; The US Gabapentin Study Group No 5, 1993). The pro-
portions dropping out during the RCT ranged between 6% and
38%. Adverse events accounted for the majority of dropouts
in two studies (Betts et al., 2000; The US Gabapentin Study
Group, 1994) and inefficacy in the other study (Michelucci
et al., 1996).
The number of patients dropping out during the FORCT
phase was reported in all FORCT studies. The proportion
of dropouts ranged between 0% and 72%, with inefficacy
accounting for the majority of dropouts in three studies (The
US Gabapentin Study Group, 1994; Engelskjon et al., 1993;
Sivenius et al., 1994) adverse events in two studies (Ben-
Menachem, 1995; Betts et al., 2000) and equally attributed
to the two reasons in another study (Michelucci et al., 1996).
Statistical methods used in reporting outcomes in
FORCTs and parent RCTs
Five FORCTs reported the proportion of 50% responders.
Of these five studies, one used an eligible case analysis
(Sivenius et al., 1994) three reported outcomes based on
an evaluable case analysis (Engelskjon et al., 1993; Betts
et al., 2000; The US Gabapentin Study Group, 1994) and
one an analysis that could not be determined (Mikkelsen et
al., 1993). All but one parent RCT reported outcomes based
on an ITT analysis, which reported outcomes based on an
evaluable case analysis (Betts et al., 2000).
Proportion 50% responders according to a full case
analysis, eligible case analysis and an evaluable
case analysis
Six FORCTs (Engelskjon et al., 1993; Sharief et al., 1993;
Cameron et al., 1996; Betts et al., 2000; The US Gabapentin
Study Group, 1994; Sivenius et al., 1991) reported the num-
 Reporting and analysis of open-label extension studies of anti-epileptic drugs
Table 1 Summary of efficacy data available for all FORCTs investigating add-on topiramate, levetiracetam or gabapentin in refractory epilepsy (n = 10)
Drug FORCT study Numbers of patients Proportion 50% responders (FORCT) Proportion 50% responders (RCT)
reference
Number entering Number of Number Number of dropouts during the Number completing No. 50% Full case Eligible Evaluable Reported ITT analysis Reported
into RCT dropouts entering FORCT FORCT responders analysis case case analysis outcome in RCT Rx arm outcome in
during RCT FORCT analysis FORCT RCT Rx arm
AE ISC O Total
Topiramate Ben-Menachem — — 25 8 6 0 14 11 — — — 57(m) 57(m) 43 43
(1995)
Engelskjon et al. 16 — 25 5 10 2 17 13 6 40 46 46 — 43 43
(1993)
Mikkelsen et al. 13 — 9 1 0 1 2 7 — — — — 68(m) 43 43
(1993)
Michelucci et al. 13 5 8 2 2 0 4 4 — — — — — 47 47
(1996)
Fincham and 17 1 16 0 0 3 3 13 — — — — — 41 41
Schottelius
(1995)
Sharief et al. 25 5 18 — — — 5 13 10 40 56 77 — 35 35
(1993)
Levetiracetam Cameron et al. — — 5 0 0 0 0 5 5 91 100 100 — 39 39
(1996)
Betts et al. 119 33 86 5 0 3 8 78 34 29 (29) 39 (40) 43 (43) 43 (43) 26 38
(2000)
Gabapentin The US 306 — 240 10 72 10 92 148 71 23 30 48 35—71 19 19
Gabapentin Study
Group (1994)
Sivenius et al. 43 — 25 0 13 5 18 7 5a 12 20 71 20 20 20
(1994)
AE: adverse events; ISC: inadequate seizure control; O: other reason for dropouts; full case analysis: ITT analysis where patients entering into the RCT are included within an ITT inference; eligible case analysis: ITT analysis where only patients
entering into the FORCT are included within an ITT inference; evaluable case analysis: analysis based on patients who continued with treatment at the end of the FORCT; (m): mean percentage reduction in seizure frequency; ITT analysis RCT
Rx arm: ITT analysis for all patients randomised to treatment in the RCT; values in brackets represent responder proportions for patients initially randomised to active drug only; (—): unknown value.
a At 4 years of follow-up seven patients remained on treatment, of which five were 50% responders.

27
28
ber of patient responders. For these six studies, responder
rates could be recalculated based on a full case analysis
and an eligible case analysis. For these six studies, effect
estimates were smaller based on either a full case analysis
or an eligible case analysis than an evaluable case anal-
ysis. Estimates differed in one study by 37% (Sharief et
al., 1993). Only three of these six FORCT studies reported
responder rates, with the other three studies simply report-
ing the number of responders. For the three studies which
reported responder rates, the full case analysis and the
eligible case analysis gave smaller effect estimates than
outcomes reported (Table 1) (Betts et al., 2000; The US
Gabapentin Study Group, 1994; Sivenius et al., 1991).
Effect estimates for FORCTs based on a full case analysis
were similar to reported estimates for patients randomised
to the treatment arm in the parent RCT (Engelskjon et
al., 1993; Sharief et al., 1993; Betts et al., 2000; The US
Gabapentin Study Group, 1994; Sivenius et al., 1991) (where
the reported responder proportion for the RCTs were in all
but one case based on an ITT analysis). For example, in a
FORCT of topiramate, the recalculated proportion of 50%
responders reduced from 77% according to an evaluable case
analysis to 40% based on full case analysis, which was com-
parable to the 35% reported for patients in the treatment
arm of the parent RCT (Sharief et al., 1996).
Discussion
Reports of FORCTs fail to acknowledge patient selection
through the RCT into the FORCT. Since in the study of AEDs,
the majority of those not continuing into the FORCT do so
for reasons of inefficacy or adverse events, it is preferable
to treat all those who do not enter the FORCT or who drop
out during the RCT, as non-responders, using an intention to
treat analysis. In fact, in the analysis of RCTs investigating
AEDs this is the routine method of analysis. However, cur-
rent methods used in all but one of the FORCTs identified,
used an evaluable case analysis in which it is unreasonably
assumed that those who discontinue treatment are repre-
sentative (in terms of responder status) of those who remain
in the trial. The evaluable case analysis led to over opti-
mistic estimates of efficacy and inferences based on this
method of analysis are likely to be misleading. The alter-
native proposed intention to treat approach better reflects
the responder status of the majority of patients and lim-
its selection biases. This approach however may impact less
on other forms of bias such as unblinding of patients and
investigators to treatment.
The reported estimates of responder rates from the two
FORCTs for topiramate were 57% and 68%. Using an ITT
approach, responder rates for two FORCTs were 40%, similar
to the estimate of 44% from a meta-analysis of six topira-
mate RCTs (Marson et al., 1997). Similarly, results obtained
when recalculating responder rates for levetiracetam based
on an ITT analysis for one FORCT of levetiracetam (Betts
et al., 2000) led to a responder rate of 29% compared to
43% reported by the FORCT. Results from this FORCT were
consistent when calculations were based only on patients
who were initially randomised to active treatment in the
RCT. For gabapentin, the estimated ITT analysis responder
rates were 12% and 23% which are broadly consistent with
M.J. Maguire et al.
reported results for corresponding RCTs of Gabapentin (19%
and 20%).
It might be expected that an analysis based on an ITT
approach would lead to lower estimates of responder pro-
portions, compared to the RCTs, as more patients might be
expected to drop out of the study as duration of exposure to
drug increases. It is possible that increases in responder pro-
portions between RCTs and some of the FORCTs presented
here, are attributed to patients initially randomised to the
placebo arm.
Although FORCTs are increasingly conducted in health-
care research, few appear in the published literature (Taylor
and Wainwright, 2005). The majority of FORCTs identi-
fied were published only as abstracts (70%) and were
reports from single centres with small numbers of patients.
Researchers conducting RCTs with an open-label exten-
sion should make more data available within published
work.
We identified serious inadequacies in the reporting on
FORCTs in particular abstracts and this included lack of
information on the number of patients entering into the
initial parent RCT information should be provided on base-
line characteristics and sample sizes for participants within
the original RCT, dropouts, and those who continue into the
FORCT. The reporting of numbers responding, as opposed to
rates would prevent ambiguity and allow reliable interpre-
tation of results. Retention rates as the primary endpoint in
open-label studies also prevents ambiguity. Guidelines for
the reporting of observational studies have recently been
outlined in the strengthening the reporting of observational
studies in epidemiology (STROBE) statement (Elm et al.,
2007). Reporting standards, however, may have less impact
on the reporting of abstracts. We recommend that submitted
abstracts are more structured and report sufficient detail to
allow the reader to ascertain how the study was designed
and conducted.
Implications for clinical practice
There is a clear need for information on the longer term effi-
cacy of newer add-on anti-epileptic drugs. Ideally this could
be achieved through long-term multi-centre pragmatic RCTs
conducted over a minimum of 12 months. To conduct such
trials would require significant financial and resource input,
which may not be readily available. In addition, the conduct
of such trials may be low on the agenda for pharmaceuti-
cal companies whose prime aim is to gain a drug licence
indication. FORCTs represent a valuable and more practica-
ble alternative to long-term pragmatic RCTs when deriving
information about long-term treatment effects.
This study has highlighted that few FORCTs are reported
in full. Failure to disseminate study findings through full
publication raises ethical considerations as patients who
consent to an extension study may do so, on the premise that
their participation in the study may benefit clinical practice
(Dowd, 2004). Failure to report these studies can also lead
to publication bias or small study effect bias when system-
atic reviews or meta-analyses are conducted. It is therefore
important that results of these studies are made more widely
available. Analysis based on an intention to treat approach
can help limit the impact of patient selection biases.
Reporting and analysis of open-label extension studies of anti-epileptic drugs 29

Acknowledgements
MM has been sponsored to attend conferences by Janssen
Cilag and Pfizer and has received research funds from Pfizer.
AGM has been sponsored to attend conferences by Janssen
Cilag, UCB Pharma and Pfizer, has undertaken consultancy
for UCB Pharma, and has received research funds from Pfizer.
Funding: Dr. M.J. Maguire and Dr. K. Hemming were
employed as research fellows to Dr. A.G. Marson and Prof.
J.L. Hutton for the duration of this work, and funded under
a Medical Research grant (number G0400642) ‘Models for
selection bias, applied to controlled trials and observational
studies of anti-epileptic drugs’.
Appendix A. Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/
j.eplepsyres.2008.04.007.
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