Epileptic Disorders
MENUPreliminary efficacy of levetiracetam in monotherapy Volume 5, supplément 1, Supplement, May 2003
Illustrations
Auteur(s) : Elinor Ben-Menachem
University of Göteborg, Sahlgren Hospital, Göteborg, Sweden
Introduction
The management of epilepsy has become more sophisticated in
recent years as our understanding of epileptic syndromes and their
classification has improved and the number of effective agents has
increased. The optimal management of the epileptic patient involves
making a precise diagnosis—based on precipitating factors, seizure
type, age at onset, family history, and interictal EEG
abnormalities—and using that information to choose a rational
treatment plan [1].
Historically, patients with epilepsy were treated with multiple
agents from the outset. This approach was based on the belief that
two agents worked synergistically, resulting in better seizure
control with fewer side effects, since lower doses of each drug
were necessary [2]. This approach, which lacked a scientific
rationale and was not based upon empirical evidence, has been
superceded in recent decades by a strong preference for
monotherapy. It appears in a large number of patients that
monotherapy is as effective as polytherapy but with fewer side
effects and drug interactions. When two drugs with similar
dose-related side-effect profiles are taken at therapeutic doses,
drug-drug interactions may magnify the risk for side effects [3].
Studies have shown that in up to 70% of patients with new-onset
seizures, monotherapy with any one of the standard or new
antiepileptic drugs (AEDs) will result in adequate seizure control
[1]. For those who do not achieve adequate control on a single
drug, rationally chosen polypharmacy may be necessary and
beneficial [3].
The six classic AEDs—phenobarbital, primidone, phenytoin,
carbamazepine, ethosuximide, and valproate—are still often used as
the drugs of first choice for the initiation of epilepsy therapy.
However, up to 30% of patients may not respond adequately
regardless of drug choice [1]. Newer drugs approved for clinical
use in recent years can complement the older AEDs when used in
combination [1, 2]. The newer drugs have proven to be effective as
add-on therapy. Their adverse event profiles, particularly with
regard to somnolence, have frequently been more favorable than
those of the classic AEDs, suggesting that some patients may do
better on monotherapy with a newer agent than with a classic agent
[1]. In fact, their tolerability and ease of use suggest that many
of the newer AEDs are attractive candidates for monotherapy even at
the start of therapy.
The new-generation AEDs may be effective as monotherapy even in
patients who have been refractory to therapy with classic agents
[4-7]. Data are accumulating from a variety of clinical trials
suggesting that levetiracetam, currently approved for clinical use
as an adjuvant AED for the treatment of partial-onset seizures with
and without secondary generalization, may soon join those new AEDs
effective in monotherapy.
Mechanism of action of levetiracetam
The mechanism of action of levetiracetam is not related to that
of any of the AEDs currently in use [8]. The precise mechanism of
antiepileptic action for levetiracetam is still unclear. Unlike
most other AEDs, levetiracetam is without significant activity in
several animal models involving acute single seizures induced in
normal animals by maximal stimulation with electrical current or
different chemoconvulsants but has demonstrated seizure protection
in animals with genetic or kindled epilepsy, and in models in which
chemical convulsants were used to produce seizures mimicking
partial epileptic seizures in man [9]. Moreover, in these animal
studies, levetiracetam demonstrated an unusually high safety
margin.
Other studies have shown that levetiracetam lacks any effect on
neuronal Na+ channels, low voltage-activated T-type
Ca2+ channels, or ionotropic excitatory glutamate
receptors and any direct effect on GABA or glycine-dependent
inhibitory currents [10-12]. These targets account for most of the
known mechanisms of action of both the classic and newer
anticonvulsants. (For a more complete discussion of the mechanism
of action of levetiracetam, see the article by Drs. Klitgaard and
Pitkänen in this supplement.)
Levetiracetam as add-on therapy
Levetiracetam administered as adjunctive therapy to patients
with refractory partial-onset seizures who have failed at least two
other AEDs has been evaluated in three placebo-controlled, pivotal
trials with double-blind evaluation periods ranging from 12 to
14 weeks [13-15]. In one multicenter study conducted in the
United States, 294 patients were randomized to receive
placebo, levetiracetam 1000 mg/day, or levetiracetam
3000 mg/day [13]. Patients receiving both levetiracetam doses
had a significantly better reduction in partial seizure frequency
compared with placebo and a significantly better responder rate.
Seizure reduction was observed for all seizure sub-types. The other
two studies were conducted in Europe. In one, 324 patients
were randomized to receive placebo, levetiracetam 1000 mg/day,
or levetiracetam 2000 mg/day [14]. Here too, the groups
treated with levetiracetam responded significantly better than
those receiving placebo in seizure frequency and responder rate. In
the second European study, 286 patients were randomized to
receive placebo or 3000 mg/day of levetiracetam [15]. The
patients receiving levetiracetam had significantly fewer seizures
than patients receiving placebo. In all three studies,
statistically significant seizure freedom rates were observed with
levetiracetam at the 3000 mg dose level. Moreover,
levetiracetam was well tolerated in all three studies. The most
common adverse events considered drug-related by the investigators
were somnolence, asthenia, headache, and dizziness.
A pooled analysis of the efficacy data from these three pivotal
trials included data from 559 patients who completed titration
and were evaluated on a stable dose of levetiracetam and from
301 placebo-treated patients [16]. Overall, patients receiving
levetiracetam had a 32.5% median decrease in the number of partial
seizures per week, compared with a 7.0% decrease in the
placebo-treated group (P < 0.001).
The percentage of patients who responded increased with increasing
dose. Of patients receiving 1000, 2000, or 3000 mg/day,
respectively, 27.7%, 31.6%, and 41.3%, had a 50% or greater
reduction in seizures from baseline, compared with 12.6% of
placebo-treated patients (P < 0.001 for
each dose versus placebo). Only two (0.6%) patients in the placebo
group became seizure-free, compared with 32 (5.7%) of those on
levetiracetam (P < 0.001).
Levetiracetam as monotherapy
Success with an AED as add-on therapy is not considered
sufficient to support its use as monotherapy. It is necessary to
demonstrate that the drug is safe and effective when used as
monotherapy in adequate and well-controlled clinical trials. The
design and conduct of such trials is not a simple matter, however.
The Food and Drug Administration recommends comparison of the study
drug to placebo in a randomized, double-blind clinical trial
without the use of other, potentially confounding AEDs. However,
according to the Committee for Proprietary Medicinal Products Note
for Guidance on the clinical investigation of medicinal products in
the treatment of epileptic disorders, therapeutic confirmatory
monotherapy studies should always be randomized, double-blind,
positive-controlled trials aiming to demonstrate at least a similar
benefit/risk balance of the test product as compared with an
acknowledged standard product at its optimal use.
The withdrawal from add-on therapy to monotherapy design is the
first step recommended before conducting a confirmatory study in
monotherapy. In this design, baseline AEDs are gradually withdrawn
from patients selected at the end of the add-on period because
their seizures were brought under adequate control in the course of
the add-on trial [15]. If the frequency of seizures increases, or
if adverse events become intolerable, patients are removed from the
study. The primary efficacy outcome measure is time to exit or the
percentage of patients who complete the monotherapy phase.
An early study making use of this design to evaluate levetiracetam
as monotherapy for the treatment of patients with refractory
partial seizures was the second European double-blind
placebo-controlled trial discussed above [15]. Patients in this
trial who had a reduction in partial seizure frequency of 50% or
more in the 12-week add-on therapy phase were entered into an
extension phase. In this phase of the study, patients were tapered
off the baseline AED over a maximum of 12 weeks, after which
they received 12 weeks of levetiracetam alone at the original
dosage. At the conclusion of the add-on phase, 17 placebo
patients and 69 levetiracetam patients were found to be
eligible for the monotherapy phase. Of these 69 patients,
49 were successfully converted to monotherapy. Of these,
36 patients completed the study. Nine patients on
levetiracetam monotherapy were seizure-free throughout the 12-week
monotherapy period. The median percent reduction in partial seizure
frequency compared with baseline was 73.8%. This study suggested
that in patients with partial seizures not responding to standard
AED treatment, levetiracetam can be successfully converted to
monotherapy if the patient responds to levetiracetam as add-on
therapy.
Several other reports of clinical success with levetiracetam as
monotherapy have appeared as abstracts in the literature. Hovinga
et al. [17] reported a retrospective review of the records
of 77 adult and 27 pediatric patients treated with
levetiracetam as add-on therapy. Eight adult patients and four
children were converted to monotherapy. Seven of the adults and two
of the children became seizure-free. In an open-treatment series
reported by Krauss et al. [18], seven of 36 adult
patients treated with levetiracetam achieved monotherapy. A chart
review by Gustafson et al. found that of 50 children
treated with levetiracetam for refractory epilepsy, eight became
seizure-free, and four of these were successfully converted to
monotherapy [19]. In another pediatric study, Mandelbaum et
al. report that of 26 children with refractory seizures
treated with levetiracetam, 24 remained on therapy at
3 months [20]. Of these, 12 had a greater than 50%
reduction in seizure frequency, and six were seizure-free. Of the
three on monotherapy, one was seizure-free.
Long-term experience
A review of long-term data on patients treated with
levetiracetam showed that 54.1% were male and 86.5% were white
[21]. The mean age was 37.9 years. The median daily dose was
3000 mg, and the mean duration of exposure to levetiracetam
was 1044.9 days.
Few restrictions were placed on the antiepileptic management of
these patients. Patients could be converted to monotherapy,
additional AEDs could be added and subsequently removed, and the
dose could be changed, all according to the clinical judgment of
the investigators. Therefore, the data should be interpreted with
caution, due to the limitation of selection bias. These data are
however of clinical interest.
Sixty-seven patients were on monotherapy for at least
3 months at any given time during treatment with
levetiracetam. Of these 67 patients, 49 were still on
monotherapy at the end of the study. The analyses presented here
are on these 49 patients. The demographic characteristics of
this group are shown in table
1.
Table 1. Long-term experience with levetiracetam in subjects on monotherapy for at least 3 months at study end (N = 49)
Demographic characteristics | |
Mean (SD) age, y | 41.0 (14.4) |
Male, n (%) | 22 (44.9%) |
White, n (%) | 44 (89.8%) |
Mean (SD) weight, kg | 71.4 (17.9) |
Mean (SD) body mass index, kg/m2 | 24.7 (4.9) |
Disposition of subjects | |
ITT population | 49 (100%) |
Completed study | 33 (67.3%) |
Discontinued study | 16 (32.7%) |
Adverse event | 1 (2%) |
Lack/loss of efficacy | 3 (6.1%) |
Lost to follow-up | 2 (4.1%) |
Withdrawal of consent | 5 (10.2%) |
Other reason | 5 (10.2%) |
Adverse events | |
Total no. of adverse events | 365 |
Subjects with at least 1 adverse event | 36 (73.5%) |
Subjects with adverse events that led to discontinuation or dose reduction | 3 (6.1%) |
Subjects with treatment-related adverse events | 15 (30.6%) |
Subjects with serious adverse events | 13 (26.5%) |
Subjects with treatment-related serious adverse events | 2 (4.1%) |
No. of deaths | 0 |
The duration of monotherapy ranged from 132 to 1968 days; 67.3% were on monotherapy for 18 months to 4 years.
In this analysis, 67.3% of patients on monotherapy for at least
3 months completed the study. As shown in table 1, 2% discontinued due to adverse events and
6.1% discontinued due to lack or loss of efficacy.
Over the course of the long-term study, subjects in the
monotherapy group had a very low seizure frequency per week and had
a high likelihood of being seizure-free (figure 1). This is
consistent with clinical practice, where patients responding well
to polytherapy will be selected for withdrawal to monotherapy.
Seizure frequency remained stable in all cohorts, an indication of
the sustained efficacy of levetiracetam.
Using survival analysis techniques, the probability of being
seizure-free for at least 12 weeks was 64.2%. The probability
of having a seizure-free period of at least 24 weeks (almost
6 months), at least 48 weeks (almost 1 year), and at
least 156 weeks (almost 3 years) was 57.5%, 54.8%, and
52.2%, respectively. One subject was seizure-free for
276 weeks (about 5.3 years) when the study was
terminated.
In general, levetiracetam was very well tolerated. The types of
adverse events were consistent with the known adverse event profile
of levetiracetam.
The long-term database also included 456 patients who were
not on monotherapy for at least 3 months at the end of the
study. The demographic characteristics of this group were similar
to those of the monotherapy group (table
2), and 52.9% of patients completed the study.
Table 2. Long-term experience with levetiracetam in subjects not on monotherapy for at least 3 months at study end (N = 456)
Demographic characteristics | |
Mean (SD) age, y | 37.7 (12.5) |
Male, n (%) | 251 (55%) |
White, n (%) | 393 (86.2%) |
Mean (SD) weight, kg | 72.8 (15.2) |
Mean (SD) body mass index, kg/m2 | 25.3 (4.5) |
Disposition of subjects | |
ITT population | 456 (100%) |
Completed study | 241 (52.9%) |
Discontinued study | 215 (47.1%) |
Adverse event | 38 (8.3%) |
Lack/loss of efficacy | 135 (29.6%) |
Lost to follow-up | 8 (1.8%) |
Withdrawal of consent | 24 (5.3%) |
Other reason | 10 (2.2%) |
Adverse events | |
Total no. of adverse events | 4169 |
Subjects with at least one adverse event | 394 (86.4%) |
Subjects with adverse events that led to discontinuation or dose reduction | 95 (20.8%) |
Subjects with treatment-related adverse events | 228 (50%) |
Subjects with serious adverse events | 154 (33.8%) |
Subjects with treatment-related serious adverse events | 15 (3.3%) |
No. of deaths | 11 (2.4%) |
As in the monotherapy group, seizure frequency remained stable
over time (figure
2), an indication of the sustained efficacy of
levetiracetam in this group as well.
The probability of being seizure-free for at least 12 weeks
was 24.8%. The probability of having a seizure-free period of at
least 24 weeks (almost 6 months), at least 48 weeks
(almost 1 year), and at least 156 weeks (almost
3 years) was 20.1%, 17.6%, and 16.2% respectively. Two
subjects were seizure-free for at least 300 weeks (about
5.8 years) and then left the study.
The adverse event profile in this group was also consistent with
the known adverse event profile of levetiracetam.
Conclusions
The discovery and approval of many new AEDs in recent years has
greatly increased the treatment options available to patients with
refractory epilepsy. Most of the newer agents have been used as
add-on drugs in clinical trials and medical practice. It has become
clear, however, that monotherapy may be the treatment of choice for
new-onset and refractory epilepsy, given the lower risk of adverse
events and drug interactions [2].
The key difference between levetiracetam and other AEDs is its
combination of efficacy, excellent tolerability, and ease of use.
Recent studies have shown that levetiracetam demonstrates efficacy
in many patients with refractory epilepsy as add-on therapy, and
there is preliminary evidence for efficacy as monotherapy.
Experience with levetiracetam monotherapy (up to 7 years)
lends supportive evidence that levetiracetam monotherapy may be a
safe, effective, and rational choice for the treatment of partial
seizures.