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. 2022 Dec 20;43(1):53–84. doi: 10.1002/phar.2748

TABLE 3.

Summary of studies reporting clinical outcomes

Author (year) Country, Study design Total number of participants Age (mean ± SD and/or median, range), in years Intervention and control groups (if applicable) Number of ASMs at baseline Clinical outcome(s) evaluated Summary of results Results based on polytherapy

Azar et al. (2010) 18

US, Non‐RCT, cohort

43 33.3 ± 11.8 (range 18–59) LEV, LTG, OXC

Monotherapy: 15

Polytherapy: 28

Association of seizure interval prolongation (SIP) with additional metrics

SIP was not difference between LEV, LTG, and OXC (p‐value not reported)

Mean SIP was higher in patients with a history of ASM tolerance vs. no reported history (23.9 ± 35.9 days vs. 13.5 ± 16.2 days, p = 0.34)

SIP was greater in monotherapy vs. polytherapy group (25.6 ± 23.7 vs. 13.9 ± 28.0 days, p = 0.02)

Biton et al. (2014) 23

Multinational

RCT

400 randomized

396 ITT

Placebo: 37.5 ± 12.6

BRV 5: 38.9 ± 11.6

BRV 20: 37.3 ± 13.3

BRV 50: 38.9 ± 12.3

Placebo vs. BRV (5, 20, or 50 mg/day)

Placebo:

monotherapy 13 (13.3%)

polytherapy 84 (85.7%)

BRV 5:

monotherapy

14 (14.4%)

Polytherapy 83 (85.6%)

BRV 20:

monotherapy

16 (16%)

polytherapy

84 (84%)

BRV 50:

monotherapy

13 (12.9%)

polytherapy 88 (86.1%)

Primary outcome:
  • Percent reduction over placebo in focal seizure frequency
Secondary outcomes:
  • Median percent reduction from baseline in partial‐onset seizure frequency
  • ≥50% responder rate
  • Seizure freedom from all seizure types
  • Safety

Significant difference in the percent reduction of focal seizure frequency with BRV 50 mg/day compared to placebo (12.8, p = 0.025).

Treatment‐emergent adverse events:
  • BRV 5 mg/day: 69 (71.1%) of 97
  • BRV 20 mg/day: 79 (79.0%) of 100
  • BRV 50 mg/day: 76 (75.2%) of 101

Subgroup analysis of LEV‐naive vs. prior LEV use vs. concomitant LEV (no statistical analysis)

Responder rate based on LEV exposure (found in table S1) 11 :

Patients who were LEV‐naive had the best results among BRV 50 mg compared to prior or concomitant LEV use:
  • Naive: n = 62, 25 (40.3%)
  • Prior: n = 20, 7 (35.0%)
  • Concomitant LEV: n = 19, 1 (5.3%)
Patients who were LEV‐prior compared to others had the best results among BRV 20 mg:
  • Naive: n = 57, 14 (24.6%)
  • Prior: n = 23, 7 (30.4%)
  • Concomitant: n = 19, 2 (10.5%)

Borges Pereira et al. (1996) 13

Brazil

Non‐RCT, Cohort

48 Range: 18–51 CBZ only 33 on monotherapy, 15 on polytherapy
  • Clinical response among patients treated with high‐dose CBZ

  • PK analysis (CBZ plasma level)

  • Seizure control was achieved in 7 patients (14.5%) using 1200 mg/day, and 2 patients (4.2%) using 1400 mg/day but not higher doses.

  • No clinical improvement was seen in 39 patients (81.2%)

No statistical analyses were conducted based on monotherapy vs. polytherapy.

Among the 9 patients who achieved seizure freedom, 3 were prescribed polytherapy. In addition to CBZ, these patients were prescribed:
  • PHB 50 mg/day and PTH 600 mg/day (n = 1)
  • PHB <100 mg/day (n = 2)

Patients taking monotherapy had a higher number of average plasma levels outside of the therapeutic range compared to polytherapy regimens (see figure 3). 15

Brahmbhatt et al. (2021) 15

US

Non‐RCT, Case series

33 43.5 ± 15 (range: 21.8–76.8) CLB only 2 on monotherapy, 31 on polytherapy Demographic information, clinical response, and safety

28 (80%) started CLB due to refractory seizures, and seven (20%) started CLB due to experiencing side effects of other ASMs.

Two patients did not tolerate CLB due to side effects (i.e., tolerability), but one of these patients reported CLB was effective

No statistical analyses were conducted based on monotherapy vs. polytherapy.

At the last study visit, patients were taking CLB and:
  • One other ASM (n = 11)
  • Two other ASMs (n = 19)
  • Three other ASMs (n = 2)

Elger et al. (2009) 16

Multinational, RCT

468 (402 randomized)

Placebo: 37.0 ± 11.93

ESL 400: 37.8 ± 11.43

ESL 800: 41.3 ± 12.04

ESL 1200: 38.4 ± 11.71

Placebo vs. ESL (400, 800, or 1200 mg/day)

Placebo: 33.3% monotherapy, 66.7% polytherapy (defined as 2 or 3 ASMs)

ESL 400: 39.0% monotherapy, 61.0% polytherapy

ESL 800: 31.6% monotherapy, 68.4% polytherapy

ESL 1200: 38.2% monotherapy, 61.8% polytherapy

Primary:
  • Change in seizure frequency compared to baseline
Secondary:
  • Responder rate (≤50% decrease in seizure frequency)
  • Reduction in standardized seizure frequency
  • Number of days with seizures
  • Proportion of seizure‐free patients
  • Proportion of patients with a greater than or equal to 25% exacerbation in standardized seizure frequency compared to baseline
  • Safety
Seizure frequency was significantly lower with ESL 800 mg (LS Mean 5.66, p = 0.0028 mg) and ESL 1200 mg (LS Mean 5.35, p = 0.0003) compared to placebo (LS Mean 7.64), but not ESL 400 mg (LS Mean 6.73, not significant) All patients were taking multiple ASMs

French et al. (2014) 27

Multinational, RCT

366

Placebo: 39.1 ± 12.5

OXC 1200: 39.1 ± 11.5

OXC 2400: 38.5 ± 11.6

Placebo vs. OXC (1200 or 2400 mg/day)

1 ASM Placebo: 43 (35.5%)

OXC 1200: 36 (29.5%)

OXC 2400: 40 (32.5%)

2 ASMs Placebo: 61 (50.4%)

OXC 1200: 68 (55.7%)

OXC 2400: 67 (54.5%)

3 ASMs Placebo: 17 (14.0%)

OXC 1200: 18 (14.8%)

OXC 2400: 16 (13.0%)

(1 patient received 4 ASMs)

Primary:
  • Median percent change from baseline in monthly seizure frequency
Secondary:
  • Responder rate (≥50% seizure frequency reduction)
  • Proportion of seizure‐free patients
  • Safety
  • PK analysis (OXC and MHD concentrations)
Percent change in seizure frequency was significantly lower with OXC 2400 mg (−42.9%) compared with placebo (−28.7%, p < 0.05), but OXC 1200 mg (−38.2%) compared to placebo All patients were taking multiple ASMs
  • Clearance was increased 31% in patients taking certain concomitant ASMs (i.e., CBZ, PTH, PHB, or VPA) but taking multiple of these agents did not increase clearance of MHD any further

French et al. (2021) 14

Multinational

Non‐RCT, Cohort

149 37.6 ± 10.9 Cenobamate only

1 ASM: 13 (8.7%)

2 ASM: 70 (47.0%)

3 ASM: 62 (41.6%)

>3 ASM: 4 (2.7%)

  • Demographic data

  • Safety information, including frequency of TEAEs and serious TEAEs, severity of TEAEs, and TEAEs leading to discontinuation

  • At the end of the study period, 85 (57.0%) were still taking cenobamate. Median duration of treatment was 6.8 years (mean ± SD: 6.9 ± 0.3, range: 6.4–7.8 years)

  • Median duration of treatment for the entire cohort was 6.25 years (median weeks: 325, range in weeks: 1–407).

  • Frequent reasons for discontinuation: withdrawal by patient (19.5%), AE (10.1%), and lack of efficacy (5.4%)

Over 50% (53.7%) of patients were able to discontinue one or more concomitant ASMs, while 26.2% of patients required the addition of one or more concomitant ASMs during the study period

Harden et al. (1993) 21

US

Non‐RCT, Patient‐controlled

18 43 (26–61) CBZ‐VPA bitherapy vs. CBZ monotherapy NA Seizure frequency compared to CBZ monotherapy, categorized as:
  • ≥50%

  • <50%

  • Unchanged

  • Increased

  • Three patients had ≥50% decrease in seizure frequency, while 6 patients had a moderate decrease (<50%) in seizure frequency

  • Nine (50%) patients had unchanged or increased seizure frequency (3 with no change and 6 with increased seizure frequency)

All patients received the same treatment

Kellet et al. (1999) 30

UK

Non‐RCT, Cohort

174 Not reported TPM Not reported (119/174 patients were taking two or more ASMs at baseline)
  • Demographic characteristics of patients taking vs. discontinuing TPM

  • Time to discontinuation

  • Retention rate

  • Factors associated with discontinuation

  • At the end of the study period, 90 (51.7%) patients stopped taking TPM.

  • Median survival (i.e., time to TPM discontinuation): 427 days (95% CI 362.9–491.1)

  • Cumulative survival at 1 year (retention rate) was 54.9% (95% CI 47.5–62.3)

  • Only two factors that were statistically significantly associated with shorter time‐to‐stop TPM were
    1. The escalation regimen (standard vs. faster vs. slower; χ2 4.06, p = 0.44) and
    2. Add‐on (vs. substitution for another ASM; χ2 = 3.88, p = 0.49)

Taking other ASMs at baseline was not associated with time‐to‐stop TPM (χ2 0.62, p = 0.733)

Monotherapy or polytherapy:

Continued TPM (n = 84):
  • 28 (33.3%) on monotherapy
  • 56 (66.7%) on two or more ASMs
Discontinued TPM (n = 90):
  • 27 (30%) on monotherapy
  • 63 (70%) on two or more ASMs

Klein et al. (2015) 24

Multinational

RCT

768

Placebo: 39.8 ± 12.5

BRV 100: 39.1 ± 13.4

BRV 200: 39.8 ± 12.8

Placebo vs. BRV (100 or 200 mg/day)

1 ASM: Placebo: 75 (29.0%)

BRV 100: 70 (27.8%)

BRV 200: 69 (27.7%)

2 ASMs:

Placebo: 181 (35.5%)

BRV 100: 182 (72.2%)

BRV 200: 179 (71.9%)

≥3 ASMs: Placebo: 3 (1.2%)

BRV 100: 0 BRV 200: 1 (0.4%)

Co‐primary:
  • Percent reduction in POS frequency vs. placebo
  • ≥50% responder rate
Secondary:
  • Median percent reduction in seizure frequency from baseline to the treatment period
  • Categorized percent reduction from baseline in seizure frequency over the treatment period
  • Seizure freedom rate (all seizures)
  • Safety
  • PK analysis: BRV plasma concentration
  • Percent reduction in seizure frequency was 22.8% (95% CI 13.3–31.2) for BRV 100 mg/day and 23.2% (95% CI 13.8–31.6) for BRV 200 mg/day compared to placebo (p < 0.05).

  • The ≥50% responder rate was 38.9% (OR 2.39 [95% 1.6–3.6]) for BRV 100 mg/day, and 37.8% (OR 2.19 [1.5–3.3]) for BRV 200 mg/day, compared to placebo (21.6%, p < 0.05 for both comparisons)

Patients taking ≤2 ASMs had better outcomes than >2 ASMs in both BRV 100 and 200 mg/day compared to placebo (p‐values not reported).

Based on LEV exposure
  • A total of 412 patients had previously tried and discontinued LEV due to insufficient efficacy (278, 67.5%), AEs (77, 18.7%), other reason (31, 7.5%), or unknown reason (26, 6.3%).
  • LEV‐naive patients had better outcomes than Prior LEV patients in both BRV 100 and 200 mg/day compared to placebo (p < 0.05; see figure 4A,B) 21

Kraiprab et al. (2005) 26

Thailand

RCT

39

Total: 31.6 ± 7.1 (range 18–44)

OXC 600: 30.4 ± 7.3

OXC 1200: 31.7 ± 6.9

OXC 600 vs. 1200 mg/day

1 ASM: 20 (51%)

2 ASM: 10 (26%)

3 ASM: 9 (23%)

Primary:
  • Percent reduction in seizure frequency
Secondary:
  • ≥50% reduction in seizure frequency
  • Seizure freedom
  • Safety
  • PK analysis:

MHD plasma concentration

Median percent reduction was −47% for OXC 600 mg/day compared with −58% for OXC 1200 mg/day (p = 0.729) Based on CBZ exposure
  • Among patients taking concomitant CBZ, median percent reduction was −47% for OXC 600 mg/day compared with −58% for OXC 1200 mg/day (p = 0.587)

Kusznir Vitturi et al. (2019) 34

Brazil

Non‐RCT, Cohort

82 24.5 ± 5.5 N/A
  • 41 on monotherapy, 40 on polytherapy

  • Seizure frequency

  • Seizure control

  • Adjustment to ASM therapy

  • At the end of the study period, 4% were seizure‐free and 12% experienced decreased seizure frequency, while 33% had unchanged frequency and 51% had an increase in seizure frequency.

  • Seizure control was obtained for 55 (67.1%) patients and was associated with good adherence, no dose adjustment, and withdrawal of one ASM (p < 0.05)

  • Polytherapy was not significantly associated with seizure control, increased seizure frequency, or same seizure frequency (all p < 0.05); however, the addition of an ASM was significantly associated with increased seizure frequency (OR 4.3 (95% CI 1.1–17.1), p = 0.01)

Lattanzi et al. (2021) 19

Italy

Non‐RCT, Cohort

92 69 (range 66–73) PER All patients were taking 1 or 2 concomitant ASMs
Effectiveness:
  • Rates of seizure response (≥50% reduction in baseline monthly seizure frequency)
  • Seizure freedom
  • Seizure worsening (>25% increase in monthly seizure frequency relative to baseline)
  • Treatment discontinuation at 12 months
Safety
  • Rate of treatment discontinuation due to AEs
  • Incidence of PER‐related AEs determined by physicians
  • Seizure response was achieved in 53 (57.6%).

  • Seizure freedom was achieved in 22 (23.9%).

  • 32 (34.8%) experienced at least one AE.

  • By the end of the study, 20 (21.7%) participants discontinued PER

  • At 12 months, there was a numerically higher number of responders to PER in patients on concomitant non‐EiASMs vs. patients on EiASMs (80.0% vs. 52.0%; p = 0.012)

  • More patients taking non‐EiASMs were free from seizures than patients on EiASMs (36.0% vs. 16.0%; p = 0.073).

  • Participants experienced similar rates of behavioral and psychiatric AEs irrespective of concomitant treatment with LEV (p = 0.776)

Lee et al. (2013) 35

Korea

Non‐RCT, Cohort

95 39.1 ± 10.8 N/A

1 ASM – 9 (9.5%)

2 ASMs – 43 (45.3%)

3 ASMs – 21 (22.1%)

4 or more ASMs – 22 (23.2%)

  • Seizure frequency (average monthly number of seizures during each 3‐month interval)

  • Responder (≥50% reduction in seizure frequency from baseline)

  • Seizure freedom

  • Loss in initial efficacy of LEV (shift from responder status during the first 3 months to non‐responder status)

  • During the first 3 months of LEV treatment, 50 (52.6%) participants were responders. By the end of the study period, 21 (42.0%) switched to the non‐responder status.

  • Seizure freedom was achieved in 29 (30.5%) participants in the first 3 months. By the end of the study, 7 (7.4%) participants remained seizure free

  • Those who achieved responder status in the first 3 months had a lower number of concomitant ASMs compared to non‐responders (2.4 ± 1.0 vs. 3.0 ± 1.1, p = 0.004).

  • The number of concomitant ASMs, among other factors, did not differ between those were maintained responder status compared to those who became non‐responders (p‐value not reported)

Pirio Richardson et al. (2004) 38

US

Non‐RCT, Cohort

35 39.8 (range 20–63) N/A All were on polytherapy at the start of the study were converted to monotherapy, and followed for 12 months
  • Seizure frequency (during 2‐month window prior to monotherapy conversion and after 12 months)

  • The average seizure frequency was 9.14 seizures per month after conversion to monotherapy.

  • None of the 35 patients had worsening of seizure frequency after conversion completed

  • 14 (40%) patients became seizure‐free after conversion to monotherapy

  • 28 (80%) patients had a 50% or greater reduction in seizure frequency with conversion to monotherapy and maintained that reduction for at least 12 months

  • No statistical analyses were conducted.

  • The most common polytherapy combinations included CBZ and PTH (11, 31%) and PHB and PTH (7, 20%). Only two patients were taking three ASMs – CBZ/TPM/GBP and CBZ/PTH/PHB.

  • Monotherapy regimens were not part of the initial polytherapy regimen. At the end of the study, the most common monotherapy ASMs included LEV (13, 37%), LTG (12, 34%), and ZNS (7, 20%).

Pisani et al. (1999) 22

Italy

Non‐RCT, Response‐conditional crossover

20 Range: 19–51 VPA vs. LTG vs. combo VPA/LTG

15 patients were on monotherapy

5 were on polytherapy

  • Responder status (≥50% reduction in seizure frequency)

  • Adverse effects

  • ASM dosages

  • PK analysis: serum ASM levels

  • When VPA was introduced, three patients were considered responders and continued treatment with VPA.

  • Of the 17 patients who switched to LTG, 4 patients were considered responders.

  • Of the remaining 13 patients, 4 patients became seizure‐free after receiving VPA and LTG, and 4 were responders

  • No statistical analyses were conducted based on monotherapy vs. polytherapy.

  • Of the three patients who responded to VPA, two were on CBZ monotherapy.

  • Of the four patients who responded to LTG, three were on CBZ monotherapy

Ryvlin et al. (2014) 25

Multinational

RCT

398

Total population: 37.2 ± 13.1

Placebo: 36.4 ± 13.0

BRV 20: 35.7 ± 12.5

BRV 50: 38.9 ± 13.6

BRV 100: 38.0 ± 13.1

Placebo vs. BRV (20, 50, or 100 mg/day)

1 ASM: 68 (17.1%)

2 ASMs: 314 (78.9%)

≥3 ASMs: 16 (4.0%)

Primary:
  • Percent reduction in seizure frequency/week of BRV 50 mg compared to placebo
Secondary:
  • Median percent reduction from baseline; responder rate (≥50% from baseline in seizure frequency); and seizure freedom (no seizures of any type with all seizure diary recorded for treatment period)
  • Safety
The percent reduction of focal seizure frequency/week was 6.5% for BRV 50 mg compared to placebo and was not statistically significant (p = 0.261) Patients taking concomitant LEV did not benefit as much as LEV‐naive patients or those with prior LEV use regarding primary efficacy outcome or response rate (no p‐values reported)

Sackellarres et al. (2004) 31

US

RCT

152

Placebo: 36.4 ± 11.3

ZNS: 35.6 ± 12.1

Placebo vs. ZNS Not reported
Primary:
  • Median percentage reduction in seizure frequency from baseline
Secondary:
  • Responder rate (≥50% reduction in seizure frequency from baseline)
  • Safety
There was a statistically significant difference in median percent reduction in seizure frequency for all seizure groups among ZNS vs. placebo, respectively.
  • All partial seizures: 28.9% vs. −4.7% (p = 0.0009)

  • Complex partial: 27.4% vs. 0.5% (p = 0.0007)

  • All seizures: 25.5% vs. −6.6% (p = 0.0005)

Not reported

Schmidt et al. (1993) 32

Europe

RCT

139 Range: 18–59 Placebo vs. ZNS Up to three concomitant ASMs (with therapeutic levels prior to study start)
Primary:
  • Reduction in seizure frequency based on % change from baseline for complex partial seizures
Secondary:
  • Reduction in seizure frequency for other seizure types
  • Responder rate ≥50% reduction in frequency of seizures, % of seizure‐free days
There was a statistically significant reduction in the medial percent change in complex partial seizure frequency from baseline with ZNS compared to placebo (−27.7% vs. 3.9%, p < 0.05) Not reported

Senadim et al. (2018) 39

Turkey

Non‐RCT, Cohort

39 34.3 ± 9.3 (range: 19–56) ZNS ZNS was started as the second drug in 12.8% (n = 5) of patients, the third in 61.5% (n = 24), the fourth in 23.1% (n = 9) and the fifth drug in 2.6% (n = 1) Demographic information, clinical response, and safety
  • Twelve patients experienced ≥50% reduction in seizure frequency, and seven (19.4%) experienced ≥75% reduction.

  • Three patients (8.3%) achieved seizure freedom.

  • Four patients, who were taking three or four concomitant ASMs, experienced an increase in seizure frequency, and ZNS was discontinued

  • Among 20 patients who continued ZNS, the most frequent ASM combination was CBZ and LEV (n = 8).

  • ASM combinations for patients who achieved seizure freedom included: ZNS/VPA/CBZ, ZNS/LEV/LTG, and ZNS/VPA/LEV

Shorvon et al. (2000) 36

Multinational

Non‐RCT, Cohort

324 37 ± 11 Placebo vs. LEV

60 (19%) were on monotherapy

264 (81%) were on polytherapy (2 or 3 ASMs)

Primary:
  • Mean seizure frequency/week
Secondary:
  • Seizure frequency by seizure type
  • Responder rate (≥50% reduction in seizure frequency from baseline)
  • Incidence of seizure‐free patients
  • Safety
  • PK analysis: plasma concentrations of all ASMs
  • Reduction in seizure frequency from baseline experienced in both LEV 1000 mg and LEV 2000 mg and were statistically significant (See table 3) 17

Not reported

Stephen et al. (2000) 28

Scotland

Non‐RCT, Prospective observational

170 18–75 TPM only

93 patients were on monotherapy

67 taking two ASMs

10 taking three ASMs

Co‐primary (at 6 months):
  • Seizure freedom
  • Responder (≥50% seizure reduction)
  • Discontinuation of TPM for any reason
Additional outcomes:
  • PK analysis: plasma concentrations of all ASMs
  • Effect of withdrawing concomitant ASMs after achieving response
  • Safety
Over the 6‐month timeframe:
  • 39 (23%) became seizure‐free

  • 80 (47%) reported ≥50% reduction in monthly seizure frequency

  • 51 (30%) discontinued TPM, due to side effects (n = 15) and/or lack of efficacy (n = 24). Specifically, seizure control got worse when TPM was introduced (n = 12)

No statistical analyses were conducted based on monotherapy vs. polytherapy.

Of the patients who were seizure‐free (n = 39): TPM and
  • Monotherapy n = 8
  • 1 ASM n = 12
  • 2 ASMs n = 9
  • 3 ASMs n = 2
Of the patients who were responders (n = 80): TPM and
  • Monotherapy n = 3
  • 1 ASM n = 34
  • 2 ASMs n = 37
  • 3 ASMs n = 6
Of the patients for who TPM was withdrawn (n = 12): TPM and
  • Monotherapy n = 1
  • 1 ASM n = 31
  • 2 ASMs n = 17
  • 3 ASMs n = 2

Stephen et al. (2011) 20

Scotland

Non‐RCT, Cohort

135 44 (18–76) PGB only

1 ASM – 93 patients

2 ASMs – 67

3 ASMs – 10

Co‐primary (at ≥6 months):
  • Seizure freedom
  • Responder (≥50% reduction from baseline) or marginal improvement (<50% reduction in seizure frequency from baseline)
  • Discontinuation of PGB for any reason
Additional outcomes:
  • Safety
Over the ≥6‐month timeframe:
  • 14 (10.4%) became seizure‐free

  • 33 (24.4%) achieved responder status

  • 20 (14.8%) achieved marginal improvement

  • 68 (50.4%) discontinued PGB, due to side effects (n = 40), lack of efficacy (n = 7), or both (n = 21)

  • No association between seizure status/frequency and previous or concomitant ASMs regimens.

  • Evidence of weight gain increased as the number of concomitant ASMs increased (reported as weight gain in kg and percentage of patients with weight gain, no p‐values reported)

Villanueva et al. (2012) 17

Spain

Non‐RCT, Cohort

158 42.1 ± 15.3 LCS only All but five patients were taking at least one ASM at baseline
Co‐primary (at 12 months):
  • Proportion of patients who were seizure free
  • Proportion of responders (≥50% reduction in seizure frequency from baseline)
  • Retention rate
Secondary:
  • Primary outcomes at 3‐ and 6‐months
  • Outcomes according to baseline characteristics and concomitant ASMs
  • Safety (at 3, 6, and 12 months)
At 12 months:
  • 24.1% of the population became seizure‐free

  • 46.8% were responders

  • Retention rate was 69.9%

  • A higher percentage of patients taking non‐sodium channel blockers were seizure free vs. not (p = 0.001) and responders vs. non‐responders (p = 0.017) compared to those taking other sodium channel blockers.

  • Significantly more patients taking sodium channel blockers experienced AEs compared to non‐sodium channel blockers (p = 0.004).

  • No associated between specific baseline ASM combinations and seizure freedom (no data shown)

Wezyk et al. (2020) 37

Poland

Non‐RCT, Cohort

530 36.1 ± 12.6 NA

292 (55.1%) on monotherapy

238 (44.9%) on polytherapy
  • 2 ASMs: 173
  • 3 ASMs: 58
  • ≥4 ASMs: 7
  • Seizure freedom or remission (at 12 months)

  • Correlation between number of ASMs and seizure freedom

  • 246 (46.4%) achieved seizure freedom

  • Of these patients, 191 (77.6%) took 1 ASM.

  • Among patients taking ≥3 ASMs, 5 (7.7%) achieved seizure freedom

Independent predictor of seizure freedom included:
  • Lower number of ASMs (OR 0.22, 95% CI 0.10–0.47, p = 0.001)

  • VPA/LTG (OR 2.51, 95% CI 1.1–5.55, p = 0.024)

Zhang et al. (2011) 29

China

RCT

86 73.4 ± 8.5 Placebo vs. TPM

1 ASM: 8 (9.3%)

2 ASMs: 37 (43.0%)

3 ASMs: 41 (47.7%)

  • Percentage seizure reduction: (1) ≥50% seizure reduction, (2) 25%–50% reduction, (3) 0%–25%, (4) worsening (≥25% seizure increase), or (5) withdrawal

  • Responder rate (≥50% seizure reduction) vs. non‐responder (<50% seizure reduction)

  • Safety

  • There were 22 and 3 patients who were classified as responders in the TPM and placebo groups, respectively (p < 0.005).

  • Three patients in the placebo group experienced an increase in seizure frequency; none were reported in the TPM group

Not reported

Abbreviations: AEs, adverse effects; ASM, antiseizure medication; EEG, electroencephalogram; Ei‐ASM, enzyme‐inducing antiseizure medication; EMU, epilepsy monitoring unit; ITT, intention to treat; LS, least square; MHD, monohydroxycarbazepine; PK, pharmacokinetics; POS, partial‐onset seizures; TEAEs, Treatment‐emergent adverse events; US, United States.

Abbreviations for ASMs: BRV, brivaracetam; CBZ, carbamazepine; CLB, clobazam; ESL, eslicarbazepine acetate; GBP, gabapentin; LCS, lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PER, perampanel; PGB, pregabalin; PHB, phenobarbital; PTH, phenytoin; TPM, topiramate; VGB, vigabatrin; VPA, valproate; ZNS, zonisamide.

HHS Vulnerability Disclosure