Table 3.
Clinical studies with the mTOR inhibitors for the anti-epileptic effects
| Type of study | Disease | Drug and dose | Number and age of patient(s) | Duration of treatment | Anti-epileptic effect | Refs |
|---|---|---|---|---|---|---|
| Prospective, open-label, phase I/II clinical trial | TSC | Everolimus | 16 patients; 3 year-old or older | Median duration : 21.5 months (range, 4.7–34.4) | Reduction in seizure frequency in 9/16 patients | [11] |
| 4.7–5.6 mg/m2/day | ||||||
| Case report | TSC | Everolimus | 1 patient; 10-year-old man | 12 months | Cessation of seizure | [20] |
| 4.5 mg/m2/day | ||||||
| Prospective, multicenter, openlabel, phase I/II clinical trial | TSC | Everolimus | 20 patients; median age : 8 years (age range, 2–21) | 12 weeks | Reduction in seizure frequency in 17/20 patients, 4 ofthese patients were seizure-free at 12 weeks | [24] |
| 5 mg/m2/day | ||||||
| Prospective, double-blind, parallel-group, placebo-controlled, multicenter phase III | TSC | Everolimus | 8 patients, children under the age of 3 | 35 months (range, 33–38) | Cessation of seizures in 1 patient, significant (at least a 50%) reduction in the number of seizures in 2 patients | [10] |
| 4.5 mg/m2/day | ||||||
| Case study series | TSC | Everolimus | 6 patients; median age : 5 years (age range, 2–12) | 36 weeks | Reduction in seizure frequency in 4/6 patients | [29] |
| 5–7 mg/day | ||||||
| Open-label, single center case series | TSC | Everolimus | 1 patients; 14-year-old female | 18 months | 25-50% seizure reduction | [3] |
| 5 mg/day | ||||||
| Case study | TSC | Everolimus | 1 patient; 13.5-year-old female | 12 days | Seizure aggravation | [30] |
| 5 mg/m2/day | ||||||
| Case study | TSC | Everolimus | 1 patient; 13-year-old female | 1.5 year | Reduction in seizure frequency | [28] |
| 5 mg/day | ||||||
| Prospective, open-label, phase I/II clinical trial | TSC | Everolimus | 14 patients; median age : 8 years (age range, 2.0–21.3) | 48 months | Reduction in seizure frequency in 13/14 patients (over 50% seizure reduction) | [12] |
| 5 mg/m2/day | ||||||
| Core phase, phase III, randomized, double-blind, placebo-controlled | TSC | Everolimus | 366 patients (including placebo group); median age; 10.1 years (age range, 2.2–56.3) | 18 weeks | Response rate; 15.1% with placebo 28.2% with low-exposure everolimus 40.0% with high-exposure everolimus | [7] |
| Low exposure group; 5.2 mg/m2/day (range, 1.3–14.5) | ||||||
| High exposure group; 7.5 mg/m2/day (range, 1.4–24.4) | ||||||
| Extension phase, phase III, randomized, double-blind, placebo-controlled | TSC | Everolimus | 294 patients; median age : 8.7 years (age range, 2.2–18.0) | 1 year | Sustained seizure reduction in 48.05%； Median percentage reduction in seizure frequency: 48.2% | [5] |
| 5–9 mg/m2/day | ||||||
| Case study series | TSC | Sirolimus | 3 patients; 15 years (age range, 5.5–21 years) | Median 4 months (range, 3–5) | Reduction in seizure frequency in 2/3 patients | [6] |
| 1.5 mg/kg/day | ||||||
| Case report | TSC | Sirolimus | 1 patient; 9-year-old female | 10 months | Reduction in seizure frequency | [18] |
| 0.15 mg/kg/day | ||||||
| Case study series | PMSE | Sirolimus | 6 patients; median age : 3 years (age range, 5 months–5 year) | 6 months | Reduction in seizure frequency | [19] |
| 1-5 mg/m2/day | ||||||
| Open-label, single center case | TSC | Sirolimus | 6 patients; median age : 6 years (age range, 3–17) | Median duration : 18 months (range, 6–36) | Over 50% reduction in seizure frequency in 5/6 patients | [3] |
| 1 mg/m2/day | ||||||
| Case report | HME | Sirolimus | 1 patient; 3-month-old man | 3 months | Seizure reduction (over 50%) | [31] |
| 1 mg/m2/day |
mTOR : mechanistic target of rapamycin, TSC : tuberous sclerosis, PMSE : polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome, HME : hemimegalencephaly