a. Seizure frequency i. Seizure freedom
Both studies of newer drugs versus placebo
(monotherapy) reported the proportion of seizure- free participants. A summary of the main
characteristics of these studies is presented in Table 10.
No studies examined the use of LTG or TPM, and evidence for OXC was limited to only two
relatively small trials (169 participants in total). Both trials considered participants with partial seizures; however, one trial looked at newly diagnosed participants whereas the other examined refractory patients. The two trials also used different doses of drug (1200 and
2400 mg/day) and neither trial examined effects over a long period of time. In particular, the trial
of refractory partial patients only considered 27
TABLE 9 Number of monotherapy studies assessing each comparison and outcome
No. of studies reporting outcome measures
Comparison N Seizure free 50% Time to Time to
responders 1st seizure exit Cognitive QoL
New vs placebo 2 (OXC) 2 (OXC) 0 1 (OXC) 1(OXC) 0 0 New vs old 12 (LTG) 10 (LTG) 3 (LTG) 4 (LTG) 5 (LTG) 1 (LTG) 6 (LTG)
6 (OXC) 4 (OXC) 2 (OXC) 1 (TPM) 2 (OXC) 1 (OXC) 1 (OXC)
1 (TPM) 1 (TPM) 1 (TPM)
New vs new 1 (LTG) 1 (LTG) 0 1 (LTG) 1 (LTG) 0 0
N, total number of studies.
TABLE 10 Summary of studies (monotherapy, newer drugs vs placebo) assessing the proportion of seizure-free participants
Study characteristicsa
Drug Refractory/ Seizure type Dose Comments Study details
newly diagnosed Follow-up
N
LTG No studies
OXC Refractory Partial 2400 mg/day Specifically includes Schachter, 199978
10 days patients under
N= 102 evaluation for surgery
Newly diagnosed Partial 1200 mg/day Sachdeo, 1998111
90 days
N= 67
TPM No studies
N, total number of randomised participants.
treatment over a 10-day period and was carried out in a specific group of patients who were undergoing evaluation for possible surgery. Therefore, the findings of this trial have limited applicability to the general population of patients with partial seizures. In view of the clinical heterogeneity between the studies it was not appropriate to combine the individual RRs (see Figure 2).
The unpooled RRs show that monotherapy OXC is favoured over placebo, but only the data from the larger trial proved to be statistically significant. In addition, these findings must be viewed in the context of their short duration and relatively small population sizes. Taking these factors into
consideration along with the relatively limited applicability of the larger study of potential candidates for surgery, there is very little evidence on which to base an assessment of the effectiveness of monotherapy OXC, LTG or TPM versus
placebo.
ii. 50% reduction in seizure frequency No studies of newer drugs versus placebo (monotherapy) reported the proportion of participants who experienced at least a 50% decrease in seizure frequency.
b. Time to first seizure
One of the two studies of newer drugs versus placebo (monotherapy) reported time to first
seizure. A summary of the main characteristics of this study is presented in Table 11.
The study examined the use of OXC in 67 newly diagnosed patients with partial seizures over a relatively short 90-day period. The study reported the median time to first seizure for each of the treatment arms (OXC, 11.67 days; placebo,
3.23 days; p= 0.0457), but failed to report an HR. The reported data appear to favour OXC over placebo, but this finding must be considered in the context of the relatively small population size and treatment period.
c. Time to withdrawal/exit
One of the two studies of newer drugs versus placebo (monotherapy) reported the time to withdrawal/exit. A summary of the main characteristics of this study is presented in Table 12.
The study examined the use of 2400 mg/day OXC in 102 patients with refractory partial seizures over a 10-day period, during which the patients were evaluated as potential candidates for surgery. Such patients represent a very specific group for whom drug treatment has proved particularly ineffective and problematic. The aetiology of their seizures is also very specific and hence findings from such a group of patients are unlikely to be applicable to the general population of patients with epilepsy. The log-rank test significantly favoured OXC over 28 0.5 1 2 5 10 100 2.406 (95% CI: 0.986 to 6.096) 13.000 (95% CI: 2.333 to 76.368) RR (95% CI) (unpooled) Study details Favours OXC Favours placebo Sachdeo 1998 1200 mg/d (N = 67) (90 days) Schachter 1999 2400 mg/d (N = 102) (10 days)
placebo (p= 0.0001) and similarly the Cox’s proportional hazards regression model also showed significance in favour of OXC
(p= 0.0001). However, this apparent evidence in favour of OXC should be considered with caution in the light of the limited data, the short
treatment period and the lack of generalisability of the results.
d. Quality of life
No studies of newer drugs versus placebo (monotherapy) reported QoL outcomes. e. Cognitive function
No studies of newer drugs versus placebo (monotherapy) reported cognitive function outcomes.
29
TABLE 11 Summary of studies (monotherapy, newer drugs vs placebo) assessing time to first seizure
Study characteristicsa
Drug Refractory/ Seizure type Dose/ Comments Study details
newly diagnosed Follow-up
N
LTG No studies
OXC Newly diagnosed Partial 1200 mg/day Sachdeo, 1998111
90 days
N= 67
TPM No studies
N, total number of participants randomised.
aParallel, superiority trial.
TABLE 12 Summary of studies (monotherapy, newer drugs vs placebo) assessing time to withdrawal/exit
Study characteristicsa
Drug Refractory/ Seizure type Dose Comments Study details
newly diagnosed Follow-up
N
LTG No studies
OXC Refractory Partial 2400 mg/day Specifically includes Schachter, 199978
10 days potential candidates
N= 102 for surgery
TPM No studies
N, total number of participants randomised.
aParallel, superiority trial.
Summary statement for monotherapy newer AEDs versus placebo
Data were only available for proportion of seizure-free participants and the time to event outcomes (first seizure and exit/withdrawal). There were no data for LTG or TPM
monotherapy versus placebo, and only two trials compared OXC with placebo. Both OXC trials included only two patients with partial seizures (refractory in one case and newly diagnosed patients in the other).
In conclusion, there is no evidence on which to base an assessment of LTG and TPM. The evidence to support OXC in favour of placebo was also very limited. The data come from small trials conducted over short treatment durations and one trial relates specifically to patients undergoing evaluation for surgery, limiting its applicability. Considering all of these factors, the statistically significant differences observed in the proportion of seizure-free participants and the time to event outcomes in favour of OXC versus placebo should be regarded with caution.