Eslicarbazepine acetate add‐on for drug‐resistant partial epilepsy

Xian‐Chao Chang; Hai Yuan; Yi Wang; Hui‐Qin Xu; Rong‐Yuan Zheng

doi:10.1002/14651858.CD008907.pub2

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Analysis 1.1

Comparison 1 Proportion of responders, Outcome 1 Primary analysis.

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Analysis 1.2

Comparison 1 Proportion of responders, Outcome 2 Worst case scenario.

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Analysis 1.3

Comparison 1 Proportion of responders, Outcome 3 Best case scenario.

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Analysis 2.1

Comparison 2 Seizure free, Outcome 1 Eslicarbazepine acetate 400 mg/day versus placebo.

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Analysis 2.2

Comparison 2 Seizure free, Outcome 2 Eslicarbazepine acetate 800 mg/day versus placebo.

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Analysis 2.3

Comparison 2 Seizure free, Outcome 3 Eslicarbazepine acetate 1200 mg/day versus placebo.

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Analysis 2.4

Comparison 2 Seizure free, Outcome 4 Eslicarbazepine acetate any dose versus placebo.

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Analysis 3.1

Comparison 3 Treatment withdrawal, Outcome 1 Treatment withdrawal (any reason).

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Analysis 3.2

Comparison 3 Treatment withdrawal, Outcome 2 Treatment withdrawal(adverse effect).

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Analysis 4.1

Comparison 4 Adverse effects, Outcome 1 ataxia.

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Analysis 4.2

Comparison 4 Adverse effects, Outcome 2 dizziness.

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Analysis 4.3

Comparison 4 Adverse effects, Outcome 3 fatigue.

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Analysis 4.4

Comparison 4 Adverse effects, Outcome 4 nausea.

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Analysis 4.5

Comparison 4 Adverse effects, Outcome 5 somnolence.

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Analysis 4.6

Comparison 4 Adverse effects, Outcome 6 rash.

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Analysis 4.7

Comparison 4 Adverse effects, Outcome 7 headache.

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Analysis 4.8

Comparison 4 Adverse effects, Outcome 8 diplopia.

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Analysis 4.9

Comparison 4 Adverse effects, Outcome 9 vomiting.

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Summary of findings for the main comparison. Eslicarbazepine acetate compared to placebo for drug‐resistant partial epilepsy

Eslicarbazepine acetate compared to placebo for drug‐resistant partial epilepsy
Patient or population: patients with drug‐resistant partial epilepsy Settings: Intervention: eslicarbazepine acetate Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Eslicarbazepine acetate
People who had 50% reduction in seizures patient diaries Follow‐up: 12‐18 weeks	193 per 1000¹	360 per 1000 (282 to 457)	RR 1.86 (1.46 to 2.36)	1146 (4 studies)	⊕⊕⊕⊕ high^2,3
Treatment withdrawal (any reason) clinical observation Follow‐up: 12‐18 weeks	208 per 1000¹	223 per 1000 (152 to 327)	RR 1.07 (0.73 to 1.57)	1146 (4 studies)	⊕⊕⊝⊝ low^2,4
Treatment withdrawal(adverse effect) Clinical oberservation Follow‐up: 12‐18 weeks	48 per 1000¹	108 per 1000 (47 to 248)	RR 2.26 (0.98 to 5.21)	1146 (4 studies)	⊕⊕⊝⊝ low^2,5
Seizure free Patient diary Follow‐up: 12‐18 weeks	24 per 1000¹	72 per 1000 (34 to 153)	RR 3.04 (1.44 to 6.42)	1146 (4 studies)	⊕⊕⊝⊝ low^2,5
dizziness Patient reports and Clinical observation Follow‐up: 12‐18 weeks	62 per 1000¹	193 per 1000 (126 to 297)	RR 3.09 (2.01 to 4.75)	1146 (4 studies)	⊕⊕⊕⊝ moderate²	Dizziness, nausea and diplopia are three significant adverse effects.
nausea Patient reports and Clinical observation Follow‐up: 12‐18 weeks	30 per 1000¹	92 per 1000 (41 to 204)	RR 3.06 (1.38 to 6.81)	744 (3 studies)	⊕⊕⊝⊝ low^2,5
diplopia Patient reports and Clinical observation Follow‐up: 12‐18	17 per 1000¹	65 per 1000 (27 to 153)	RR 3.73 (1.57 to 8.86)	1049 (3 studies)	⊕⊕⊝⊝ low^2,5
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ As there is little variation in baseline risk, the median control group risk across studies was used. ² These study were funded by BIAL ‐ Portela & Co, SA. ³ Dose response analysis indicate an increase in effect with increasing dose. ⁴ Ben‐Menachem 2010 study shows people in ESL group are significantly more likely to have treatment withdrawn, but there were no significant difference between placebo and ESL group in other three study. ⁵ There was serious imprecision about RRs.

Summary of findings for the main comparison. Eslicarbazepine acetate compared to placebo for drug‐resistant partial epilepsy

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Table 1. Estimated percentage responders per dose

Dose	Responders %	95% CIs
0	18	14‐22
400	24	18‐30
800	32	26‐38
1200	40	34‐46

Table 1. Estimated percentage responders per dose

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Table 2. Percentage difference in responders per dose compared to placebo

Dose	Difference	95% CIs
400	6	‐2‐14
800	14	6‐22
1200	22	14‐30

Table 2. Percentage difference in responders per dose compared to placebo

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Comparison 1. Proportion of responders

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary analysis Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Eslicarbazepine acetate 400 mg/day versus placebo	2	398	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.80, 1.85]
1.2 Eslicarbazepine acetate 800 mg/day versus placebo	3	573	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [1.49, 2.68]
1.3 Eslicarbazepine acetate 1200 mg/day versus placebo	3	569	Risk Ratio (M‐H, Fixed, 95% CI)	2.13 [1.59, 2.84]
1.4 Eslicarbazepine acetate any dose versus placebo	4	1146	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [1.46, 2.36]
2 Worst case scenario Show forest plot	4	1146	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.75, 1.05]

3 Best case scenario Show forest plot	4	1146	Risk Ratio (M‐H, Fixed, 95% CI)	3.09 [2.45, 3.89]

Comparison 1. Proportion of responders

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Comparison 2. Seizure free

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Eslicarbazepine acetate 400 mg/day versus placebo Show forest plot	2	398	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.21, 5.02]

2 Eslicarbazepine acetate 800 mg/day versus placebo Show forest plot	3	573	Risk Ratio (M‐H, Fixed, 95% CI)	4.07 [1.37, 12.07]

3 Eslicarbazepine acetate 1200 mg/day versus placebo Show forest plot	3	569	Risk Ratio (M‐H, Fixed, 95% CI)	3.84 [1.29, 11.43]

4 Eslicarbazepine acetate any dose versus placebo Show forest plot	4	1146	Risk Ratio (M‐H, Fixed, 95% CI)	3.04 [1.44, 6.42]

Comparison 2. Seizure free

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Comparison 3. Treatment withdrawal

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment withdrawal (any reason) Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Eslicarbazepine acetate 400 mg/day versus placebo	2	398	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.38, 2.30]
1.2 Eslicarbazepine acetate 800 mg/day versus placebo	3	573	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.59, 1.42]
1.3 Eslicarbazepine acetate 1200 mg/day versus placebo	3	569	Risk Ratio (M‐H, Random, 95% CI)	1.63 [1.02, 2.62]
1.4 Eslicarbazepine acetate any dose versus placebo	4	1146	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.73, 1.57]
2 Treatment withdrawal(adverse effect) Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Eslicarbazepine acetate 400 mg/day versus placebo	2	398	Risk Ratio (M‐H, Random, 95% CI)	2.12 [0.53, 8.48]
2.2 Eslicarbazepine acetate 800 mg/day versus placebo	3	573	Risk Ratio (M‐H, Random, 95% CI)	2.61 [1.08, 6.27]
2.3 Eslicarbazepine acetate 1200 mg/day versus placebo	3	569	Risk Ratio (M‐H, Random, 95% CI)	4.32 [1.82, 10.26]
2.4 Eslicarbazepine acetate any dose versus placebo	4	1146	Risk Ratio (M‐H, Random, 95% CI)	2.26 [0.98, 5.21]

Comparison 3. Treatment withdrawal

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Comparison 4. Adverse effects

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ataxia Show forest plot	2		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

1.1 Eslicarbazepine acetate 400 mg/day versus placebo	1	196	Risk Ratio (M‐H, Fixed, 99% CI)	1.04 [0.21, 5.09]
1.2 Eslicarbazepine acetate 800 mg/day versus placebo	2	373	Risk Ratio (M‐H, Fixed, 99% CI)	2.49 [0.75, 8.29]
1.3 Eslicarbazepine acetate 1200 mg/day versus placebo	2	365	Risk Ratio (M‐H, Fixed, 99% CI)	2.59 [0.77, 8.64]
1.4 Eslicarbazepine acetate any dose versus placebo	2	647	Risk Ratio (M‐H, Fixed, 99% CI)	2.14 [0.71, 6.48]
2 dizziness Show forest plot	4		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

2.1 Eslicarbazepine acetate 400 mg/day versus placebo	2	398	Risk Ratio (M‐H, Fixed, 99% CI)	2.25 [0.97, 5.22]
2.2 Eslicarbazepine acetate 800 mg/day versus placebo	3	573	Risk Ratio (M‐H, Fixed, 99% CI)	2.89 [1.57, 5.32]
2.3 Eslicarbazepine acetate 1200 mg/day versus placebo	3	569	Risk Ratio (M‐H, Fixed, 99% CI)	4.02 [2.24, 7.22]
2.4 Eslicarbazepine acetate any dose versus placebo	4	1146	Risk Ratio (M‐H, Fixed, 99% CI)	3.09 [1.76, 5.43]
3 fatigue Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

3.1 Eslicarbazepine acetate 400 mg/day versus placebo	1	196	Risk Ratio (M‐H, Fixed, 99% CI)	0.83 [0.15, 4.51]
3.2 Eslicarbazepine acetate 800 mg/day versus placebo	1	201	Risk Ratio (M‐H, Fixed, 99% CI)	0.99 [0.20, 4.85]
3.3 Eslicarbazepine acetate 1200 mg/day versus placebo	1	198	Risk Ratio (M‐H, Fixed, 99% CI)	1.43 [0.33, 6.17]
3.4 Eslicarbazepine acetate any dose versus placebo	1	395	Risk Ratio (M‐H, Fixed, 99% CI)	1.08 [0.30, 3.92]
4 nausea Show forest plot	3		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

4.1 Eslicarbazepine acetate 400 mg/day versus placebo	1	196	Risk Ratio (M‐H, Fixed, 99% CI)	2.08 [0.45, 9.66]
4.2 Eslicarbazepine acetate 800 mg/day versus placebo	2	373	Risk Ratio (M‐H, Fixed, 99% CI)	3.39 [0.95, 12.17]
4.3 Eslicarbazepine acetate 1200 mg/day versus placebo	2	365	Risk Ratio (M‐H, Fixed, 99% CI)	4.78 [1.39, 16.43]
4.4 Eslicarbazepine acetate any dose versus placebo	3	744	Risk Ratio (M‐H, Fixed, 99% CI)	3.06 [1.07, 8.74]
5 somnolence Show forest plot	4		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

5.1 Eslicarbazepine acetate 400 mg/day versus placebo	2	398	Risk Ratio (M‐H, Fixed, 99% CI)	1.15 [0.54, 2.45]
5.2 Eslicarbazepine acetate 800 mg/day versus placebo	3	573	Risk Ratio (M‐H, Fixed, 99% CI)	1.38 [0.75, 2.54]
5.3 Eslicarbazepine acetate 1200 mg/day versus placebo	3	569	Risk Ratio (M‐H, Fixed, 99% CI)	1.61 [0.89, 2.90]
5.4 Eslicarbazepine acetate any dose versus placebo	4	1146	Risk Ratio (M‐H, Fixed, 99% CI)	1.48 [0.88, 2.47]
6 rash Show forest plot	3		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

6.1 Eslicarbazepine acetate any dose versus placebo	3	1049	Risk Ratio (M‐H, Fixed, 99% CI)	1.50 [0.25, 8.98]
7 headache Show forest plot	4		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

7.1 Eslicarbazepine acetate 400 mg/day versus placebo	2	398	Risk Ratio (M‐H, Fixed, 99% CI)	1.17 [0.49, 2.80]
7.2 Eslicarbazepine acetate 800 mg/day versus placebo	3	573	Risk Ratio (M‐H, Fixed, 99% CI)	1.18 [0.60, 2.30]
7.3 Eslicarbazepine acetate 1200 mg/day versus placebo	3	569	Risk Ratio (M‐H, Fixed, 99% CI)	1.57 [0.84, 2.95]
7.4 Eslicarbazepine acetate any dose versus placebo	4	1146	Risk Ratio (M‐H, Fixed, 99% CI)	1.26 [0.72, 2.21]
8 diplopia Show forest plot	3		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

8.1 Eslicarbazepine acetate 400 mg/day versus placebo	2	398	Risk Ratio (M‐H, Fixed, 99% CI)	2.42 [0.59, 10.01]
8.2 Eslicarbazepine acetate 800 mg/day versus placebo	3	573	Risk Ratio (M‐H, Fixed, 99% CI)	4.29 [1.30, 14.11]
8.3 Eslicarbazepine acetate 1200 mg/day versus placebo	3	569	Risk Ratio (M‐H, Fixed, 99% CI)	4.56 [1.38, 15.13]
8.4 Eslicarbazepine acetate any dose versus placebo	3	1049	Risk Ratio (M‐H, Fixed, 99% CI)	3.73 [1.19, 11.64]
9 vomiting Show forest plot	3		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

9.1 Eslicarbazepine acetate 400 mg/day versus placebo	1	196	Risk Ratio (M‐H, Fixed, 99% CI)	1.39 [0.20, 9.59]
9.2 Eslicarbazepine acetate 800 mg/day versus placebo	2	373	Risk Ratio (M‐H, Fixed, 99% CI)	2.84 [0.86, 9.40]
9.3 Eslicarbazepine acetate 1200 mg/day versus placebo	2	365	Risk Ratio (M‐H, Fixed, 99% CI)	2.80 [0.84, 9.35]
9.4 Eslicarbazepine acetate any dose versus placebo	3	744	Risk Ratio (M‐H, Fixed, 99% CI)	2.45 [0.79, 7.55]

Comparison 4. Adverse effects

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