TY - JOUR
T1 - Sirolimus for epileptic seizures associated with focal cortical dysplasia type II
AU - Kato, Mitsuhiro
AU - Kada, Akiko
AU - Shiraishi, Hideaki
AU - Tohyama, Jun
AU - Nakagawa, Eiji
AU - Takahashi, Yukitoshi
AU - Akiyama, Tomoyuki
AU - Kakita, Akiyoshi
AU - Miyake, Noriko
AU - Fujita, Atsushi
AU - Saito, Akiko M.
AU - Inoue, Yushi
N1 - Funding Information:
This study was supported by grants from the Project Promoting Clinical Trials for Development of New Drugs from the Japan Agency for Medical Research and Development (20lk0201069h0004), Grant‐in‐Aid for Scientific Research–KAKENHI (C) from the Japan Society for the Promotion of Science (20K08236) to M. K., and a grant from the Ministry of Health, Labor, and Welfare (JPMH20FC1039) to M. K. and Y. I. Funding Information
Funding Information:
The authors thank the patients and families for their participation in the present clinical trial. The authors also thank Dr. Chizuru Ikeda at NHO Kumamoto Saishun Medical Center and Dr. Tatsuharu Sato at Nagasaki University Hospital for patient recruitment. This study was supported by grants from the Project Promoting Clinical Trials for Development of New Drugs from the Japan Agency for Medical Research and Development (20lk0201069h0004), Grant-in-Aid for Scientific Research–KAKENHI (C) from the Japan Society for the Promotion of Science (20K08236) to M. K., and a grant from the Ministry of Health, Labor, and Welfare (JPMH20FC1039) to M. K. and Y. I. Nobelpharma Co., Ltd. provided the investigational drug and was responsible for the delivery of the drug but had no role in study design or conduct. Other funders, including Nobelpharma Co., Ltd., had no role in data collection, interpretation, and analyses or writing of the manuscript.
Funding Information:
The authors thank the patients and families for their participation in the present clinical trial. The authors also thank Dr. Chizuru Ikeda at NHO Kumamoto Saishun Medical Center and Dr. Tatsuharu Sato at Nagasaki University Hospital for patient recruitment. This study was supported by grants from the Project Promoting Clinical Trials for Development of New Drugs from the Japan Agency for Medical Research and Development (20lk0201069h0004), Grant‐in‐Aid for Scientific Research–KAKENHI (C) from the Japan Society for the Promotion of Science (20K08236) to M. K., and a grant from the Ministry of Health, Labor, and Welfare (JPMH20FC1039) to M. K. and Y. I. Nobelpharma Co., Ltd. provided the investigational drug and was responsible for the delivery of the drug but had no role in study design or conduct. Other funders, including Nobelpharma Co., Ltd., had no role in data collection, interpretation, and analyses or writing of the manuscript.
Publisher Copyright:
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2022/2
Y1 - 2022/2
N2 - Objective: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. Methods: Sixteen patients (aged 6–57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5–15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. Results: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1–4-, 5–8-, and 9–12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. Interpretation: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.
AB - Objective: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. Methods: Sixteen patients (aged 6–57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5–15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. Results: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1–4-, 5–8-, and 9–12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. Interpretation: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.
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U2 - 10.1002/acn3.51505
DO - 10.1002/acn3.51505
M3 - Article
C2 - 35040598
AN - SCOPUS:85122813656
VL - 9
SP - 181
EP - 192
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 2
ER -