TABLE 3.
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:
Secondary outcomes:
|
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:
|
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:
Patients who were LEV‐prior compared to others had the best results among BRV 20 mg:
|
Borges Pereira et al. (1996) 13 Brazil Non‐RCT, Cohort |
48 | Range: 18–51 | CBZ only | 33 on monotherapy, 15 on polytherapy |
|
|
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:
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:
|
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:
Secondary:
|
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:
Secondary:
|
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
|
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%) |
|
|
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:
|
|
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) |
|
|
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):
Discontinued TPM (n = 90):
|
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:
Secondary:
|
|
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
|
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:
Secondary:
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
|
Kusznir Vitturi et al. (2019) 34 Brazil Non‐RCT, Cohort |
82 | 24.5 ± 5.5 | N/A |
|
|
|
|
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:
Safety
|
|
|
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%) |
|
|
|
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 |
|
|
|
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 |
|
|
|
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:
Secondary:
|
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:
Secondary:
|
There was a statistically significant difference in median percent reduction in seizure frequency for all seizure groups among ZNS vs. placebo, respectively.
|
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:
Secondary:
|
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 |
|
|
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:
Secondary:
|
|
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):
Additional outcomes:
|
Over the 6‐month timeframe:
|
No statistical analyses were conducted based on monotherapy vs. polytherapy. Of the patients who were seizure‐free (n = 39): TPM and
Of the patients who were responders (n = 80): TPM and
Of the patients for who TPM was withdrawn (n = 12): TPM and
|
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):
Additional outcomes:
|
Over the ≥6‐month timeframe:
|
|
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):
Secondary:
|
At 12 months:
|
|
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
|
|
|
Independent predictor of seizure freedom included:
|
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%) |
|
|
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.