Meta-analysis of study-reported tolerability and safety
| End points Subgroup analysis | #RCTs | #RCT participants | RCT pooled relative risk (95% CI)* | I2 | GRADE (RCTs) | #Non-RCTs | #Non-RCT participants | Non-RCT pooled estimate (95% CI)† | I2 | GRADE (non-RCTs) |
| 4. Withdrawals | 3 | 306 | 2.96 (0.64 to 13.78) | 55.2 | ⨁⨁◯◯ LOW | 4 | 486 | 28.0% (5.2 to 59.5) | 98.0 | ⨁◯◯◯ VERY LOW |
| Age group | ||||||||||
| Paediatric | 1 | 120 | 2.90 (0.83 to 10.20) | ⨁⨁◯◯ LOW | 2 | 194 | 47.9% (40.9 to 55.0) | 0.0 | ⨁◯◯◯ VERY LOW | |
| Adult | 1 | 15 | 0.57 (0.06 to 5.03) | ⨁⨁◯◯ LOW | ||||||
| Paediatric and adult | 1 | 171 | 13.84 (1.86 to 102.91) | ⨁⨁◯◯ LOW | 2 | 292 | 15.2% (11.3 to 19.6) | 0.0 | ⨁◯◯◯ VERY LOW | |
| Epilepsy type | ||||||||||
| Dravet syndrome | 1 | 120 | 2.90 (0.83 to 10.120) | ⨁⨁◯◯ LOW | ||||||
| Lennox-Gastaut syndrome | 1 | 171 | 13.84 (1.86 to 102.91) | ⨁⨁◯◯ LOW | ||||||
| Secondary generalised epilepsy | 1 | 15 | 0.57 (0.06 to 5.03) | ⨁⨁◯◯ LOW | ||||||
| 5. Withdrawals due to adverse events | 3 | 345 | 4.87 (1.10 to 21.68) | 0.0 | ⨁⨁◯◯ LOW | 6 | 521 | 4.1% (0.9 to 8.8) | 72.3 | ⨁⨁◯◯ LOW |
| Age group | ||||||||||
| Paediatric | 1 | 120 | 7.74 (1.00 to 59.97) | ⨁⨁◯◯ LOW | 3 | 211 | 6.7 (2.2 to 12.9) | 0.0 | ⨁⨁◯◯ LOW | |
| Adult | ||||||||||
| Paediatric and adult | 2 | 225 | 2.88 (0.33 to 25.53) | 0.0 | ⨁⨁◯◯ LOW | 3 | 310 | 2.2% (0.0 to 6.8) | 0.0 | ⨁⨁◯◯ LOW |
| Epilepsy type | ||||||||||
| Dravet syndrome | 1 | 120 | 7.74 (1.00 to 59.97) | ⨁⨁◯◯ LOW | ||||||
| Lennox-Gastaut syndrome | 2 | 225 | 2.88 (0.33 to 25.53) | ⨁⨁◯◯ LOW | ||||||
| Mixed epilepsy syndromes | 5 | 503 | 3.7% (0.7 to 8.4) | 75.5 | ⨁⨁◯◯ LOW | |||||
| Tuberous sclerosis complex | 1 | 18 | 11.1% (3.1 to 32.8) | ⨁⨁◯◯ LOW | ||||||
| 6. Adverse events—all cause | 5 | 531 | 1.24 (1.13 to 1.36) | 0.0 | ⨁⨁◯◯ LOW | 12 | 651 | 50.6% (31.7 to 69.4) | 94.4 | ⨁◯◯◯ VERY LOW |
| Age group | ||||||||||
| Paediatric | 1 | 120 | 1.25 (1.06 to 1.48) | ⨁⨁◯◯ LOW | 8 | 353 | 47.7% (32.4 to 63.3) | 82.7 | ⨁◯◯◯ VERY LOW | |
| Adult | 1 | 15 | 5.71 (0.86 to 37.91) | ⨁⨁◯◯ LOW | 3 | 132 | 27.6% (4.0 to 59.8) | 0.0 | ⨁◯◯◯ VERY LOW | |
| Paediatric and adult | 3 | 396 | 1.23 (1.10 to 1.38) | 0.0 | ⨁⨁◯◯ LOW | 2 | 166 | 82.8% (75.6 to 89.1) | 0.0 | ⨁◯◯◯ VERY LOW |
| Epilepsy type | ||||||||||
| Dravet syndrome | 1 | 120 | 1.25 (1.06; to 1.48) | ⨁⨁◯◯ LOW | 1 | 3 | 100.0% (43.9 to 100.0) | ⨁⨁◯◯ LOW | ||
| Lennox-Gastaut syndrome | 3 | 396 | 1.23 (1.10 to 1.38) | 0.0 | ⨁⨁◯◯ LOW | 1 | 1 | 100.0% (20.7 to 100.0) | ⨁⨁◯◯ LOW | |
| Secondary generalised epilepsy | 1 | 15 | 5.71 (0.86 to 37.91) | ⨁⨁◯◯ LOW | ||||||
| Mixed epilepsy syndromes | 4 | 216 | 74.3% (41.0 to 98.0) | 89.1 | ⨁⨁◯◯ LOW | |||||
| Tuberous sclerosis complex | 1 | 18 | 66.7% (43.7 to 83.7) | ⨁⨁◯◯ LOW | ||||||
| Specific event† | ||||||||||
| Drowsiness | 3 | 306 | 2.53 (1.40 to 4.57) | 7.0 | ⨁⨁◯◯ LOW | 15 | 897 | 22.6% (15.3 to 30.7) | 84.4 | ⨁⨁◯◯ LOW |
| Diarrhoea | 2 | 291 | 2.63 (1.45 to 4.76) | 0.0 | ⨁⨁◯◯ LOW | 9 | 209 | 11.3% (2.8 to 23.0) | 85.2 | ⨁⨁◯◯ LOW |
| Vomiting | 2 | 291 | 1.25 (0.28 to 5.49) | 75.3 | ⨁⨁◯◯ LOW | 7 | 333 | 2.6% (0.8 to 5.1) | 0.0 | ⨁⨁◯◯ LOW |
| Fatigue | 1 | 120 | 5.80 (1.36 to 24.83) | ⨁⨁◯◯ LOW | ||||||
| Fever | 2 | 291 | 1.63 (0.83 to 3.21) | 0.0 | ⨁⨁◯◯ LOW | |||||
| Upper respiratory tract infection | 1 | 120 | 1.35 (0.46 to 4.03) | ⨁⨁◯◯ LOW | 4 | 108 | 2.1% (0.0 to 6.5) | 0.0 | ⨁⨁◯◯ LOW | |
| Change in appetite | 2 | 291 | 5.46 (2.18 to 13.69) | 0.0 | ⨁⨁◯◯ LOW | 12 | 613 | 7.2% (3.1 to 12.5) | 67.8 | ⨁⨁◯◯ LOW |
| Convulsion | 1 | 120 | 2.26 (0.61 to 8.32) | ⨁⨁◯◯ LOW | 1 | 162 | 11.1% (7.1 to 16.9) | ⨁⨁◯◯ LOW | ||
| Lethargy | 1 | 120 | 2.58 (0.72 to 9.26) | ⨁⨁◯◯ LOW | 4 | 223 | 3.6% (0.6 to 8.3) | 21.6 | ⨁⨁◯◯ LOW | |
| Gastrointestinal symptoms | 1 | 15 | 3.38 (0.16 to 71.67) | ⨁⨁◯◯ LOW | 3 | 268 | 6.9% (4.0 to 10.5) | 0.0 | ⨁⨁◯◯ LOW | |
| Ataxia | 7 | 94 | 17.1% (1.1 to 41.7) | 79.9 | ⨁⨁◯◯ LOW | |||||
| Change in weight | 5 | 340 | 5.7% (1.6 to 11.5) | 79.7 | ⨁⨁◯◯ LOW | |||||
| Confusion | 2 | 135 | 0.6% (0.0 to 3.4) | 0.0 | ⨁⨁◯◯ LOW | |||||
| Insomnia | 6 | 221 | 2.6% (0.8 to 5.1) | 0.0 | ⨁⨁◯◯ LOW | |||||
| 7. Serious adverse events | 4 | 516 | 2.55 (1.48 to 4.38) | 0.0 | ⨁⨁◯◯ LOW | 7 | 201 | 2.2% (0.0 to 7.9) | 94.2 | ⨁⨁◯◯ LOW |
| Age group | ||||||||||
| Paediatric | 1 | 120 | 3.22 (0.93 to 11.14) | ⨁⨁◯◯ LOW | 5 | 179 | 3.9% (0.0 to 11.4) | 64.9 | ⨁⨁◯◯ LOW | |
| Adult | ||||||||||
| Paediatric and adult | 3 | 396 | 2.40 (1.17 to 4.93) | 29.6 | ⨁⨁◯◯ LOW | 2 | 22 | 0.0% (0.0 to 6.4) | ⨁◯◯◯ VERY LOW | |
| Epilepsy type | ||||||||||
| Dravet syndrome | 1 | 120 | 3.22 (0.93 to 11.14) | ⨁⨁◯◯ LOW | ||||||
| Lennox-Gastaut syndrome | 3 | 396 | 2.40 (1.17 to 4.93) | 29.6 | ⨁⨁◯◯ LOW | |||||
| Mixed epilepsy syndromes | 6 | 183 | 2.7% (0.0 to 9.5) | 56.1 | ⨁⨁◯◯ LOW | |||||
| Tuberous sclerosis complex | 1 | 18 | 0.0% (0.0 to 17.6) | ⨁◯◯◯ VERY LOW | ||||||
| Treatment-related serious adverse events | 3 | 396 | 5.93 (1.38 to 25.46) | 0.0 | ⨁⨁◯◯ LOW | 1 | 162 | 1.1% (0.6 to 1.8) | ⨁⨁◯◯ LOW | |
| Specific event† | ||||||||||
| Status epilepticus | 1 | 120 | 0.97 (0.20 to 4.60) | ⨁⨁◯◯ LOW | 1 | 162 | 5.6% (3.0 to 10.2) | ⨁⨁◯◯ LOW | ||
| Elevated aminotransferase levels | 1 | 120 | 11.61 (1.56 to 86.48) | ⨁⨁◯◯ LOW | ||||||
| Severe diarrhoea | 1 | 162 | 1.9% (0.6 to 5.3) | ⨁⨁◯◯ LOW | ||||||
| Appetite loss | 1 | 162 | 0.6% (0.1 to 3.4) | ⨁⨁◯◯ LOW | ||||||
| Death | 1 | 162 | 0.6% (0.1 to 3.4) | ⨁⨁◯◯ LOW |
*Significant results indicate a greater likelihood of the event in the intervention group relative to controls, and are highlighted bold.
†See online supplementary materials for full list of reported adverse events.
GRADE, Grades of Recommendation, Assessment, Development and Evaluation; RCT, randomised controlled trial.