UMIN-CTR Clinical Trial

Basic information
Public title	An uncontrolled open-label study on the efficacy and safety of sirolimus for epileptic seizures associated with focal cortical dysplasia type-II
Acronym	An investigator-initiated clinical trial on the efficacy and safety of sirolimus for epileptic seizures associated with FCD type-II
Scientific Title	An uncontrolled open-label study on the efficacy and safety of sirolimus for epileptic seizures associated with focal cortical dysplasia type-II
Scientific Title:Acronym	An investigator-initiated clinical trial on the efficacy and safety of sirolimus for epileptic seizures associated with FCD type-II
Region	Japan

Condition
Condition	focal cortical dysplasia (type-II)
Classification by specialty	Neurology Pediatrics
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	To assess the efficacy, safety, and pharmacokinetics of sirolimus against epileptic seizures in focal cortical dysplasia type-II
Basic objectives2	Efficacy
Basic objectives -Others
Trial characteristics_1	Exploratory
Trial characteristics_2
Developmental phase	Phase II

Assessment
Primary outcomes	A reduction rate of incidence of partial seizures (including secondarily generalized seizures) per 28 days during maintenance therapy from the observation period
Key secondary outcomes	- Change in incidence of general seizures per 28 days during maintenance therapy from the observation period - Change in incidence epileptic spasm per 28 days during maintenance therapy from the observation period - Change in incidence of heavy-weight attacks per 28 days during maintenance period from the observation period - A response rate (proportion of cases in which incidence of seizures during maintenance therapy decreased by 50% or more from the observation period) - Proportion of resolution of partial seizures during maintenance therapy - A decrease rate and a response rate of incidence of partial seizures at 4 weeks, 8 weeks, and 12 weeks in the maintenance therapy from the observation period - Adverse events

Base
Study type	Interventional

Study design
Basic design	Single arm
Randomization	Non-randomized
Randomization unit
Blinding	Open -no one is blinded
Control	Uncontrolled
Stratification	NO
Dynamic allocation	NO
Institution consideration	Institution is not considered as adjustment factor.
Blocking	NO
Concealment	No need to know

Intervention
No. of arms	1
Purpose of intervention	Treatment
Type of intervention	Medicine
Interventions/Control_1	The investigational drug (sirolimus) is orally administered once a day with the following doses: <Dose adjustment period> Initial amount: 1 mg/day for body weight of less than 40 kg, and 2 mg/day for 40 kg or more. Dose adjustment: to increase as necessary to adjust the trough concentration of sirolimus to the range of 5-15 ng/ml, and then, to shift to the maintenance therapy period. <Maintenance therapy period> To adopt dosage regimen and dose of sirolimus at trough concentration of 5-15 ng/ml.
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	6 years-old <=
Age-upper limit	65 years-old >=
Gender	Male and Female
Key inclusion criteria	1. Diagnosed with pathologically localized cortical dysplasia type-II by neuroimaging findings in head MRI within 156 weeks prior to enrollment or brain pathology examination before enrollment. 2. Aged 6 to 65 years at the time of informed consent. 3. Diagnosed with a partial seizure (a simple partial seizure with motor signs which can be objectively diagnosed, a complex partial seizure, or a secondarily generalized seizure) based on the 1981 epileptic seizure type international classification of the International League Against Epilepsy (ILAE). 4. Having treated for at least 52 weeks with two or more antiepileptic drugs after diagnosis with epilepsy. 5. Under treatment with 1 to 4 antiepileptic drugs. 6. Whose dose and regimen of antiepileptic drug are constant from the 8th week before enrollment, or whose stimulation condition is constant from the 8th week before enrollment in case of performing vagus nerve stimulation therapy. 7. With two or more partial seizures (including secondarily generalized seizures) during the baseline observation period of 28 days. 8. Provided written consent by themselves/parent or legal representatives.
Key exclusion criteria	1. Those participated in other trials within 12 weeks before the time of consent. 2. Having used sirolimus or everolimus within 52 weeks before enrollment. 3. Who cannot accurately record the number and time of epileptic seizures by themselves/representatives. 4. Suspected of progressive lesions in CT or MRI. 5. Having underwent cerebral surgery for epilepsy within 28 weeks prior to enrollment. 6. Taking Felbamate or Vigabatrine or having taken it within 28 weeks before enrollment. 7. Under ketogenic diet therapy. 8. Having suicide attempts in the past. 9. With a history or complications of substance abuse including alcohol abuse. 10. Those possibly pregnant and cannot perform contraception during the study period (including partners), pregnant or lactating. 11. Falling under any of the following in clinical examination during baseline observation period: - At least 2.5 times the reference value of AST or ALT - WBC count of less than 3,000/micro L, Ht of less than 30%, platelets of less than 80,000/micro L, or neutrophil counts of less than 1,000/ micro L - Ccr of less than 50 ml/min - HBs antigen-positive, HBs antibody-positive except after vaccination with hepatitis B vaccine, or HBc antibody-positive. Or active hepatitis C excluding inactive cases with normal liver function. - In poor control of dyslipidemia with serum triglycerides of 500 mg/dL or more, or LDL cholesterol of 190 mg/dL or more despite being treated for dyslipidaemia. - With renal dysfunction. (eGFR of less than 30 ml/min/1.73 m2) 12. With complications of arrhythmia requiring treatment. 13. With complications of heart/renal failure that may affect hemodynamics. 14. With immunodeficiency complications. 15. Having underwent surgery (surgery requiring invasion into a body cavity or surgery requiring suture of three or more needles including biopsy) within 12 weeks before enrollment. 16. Judged inappropriate for participating in this study by the principal investigator/sub-investigators.
Target sample size	15

Research contact person
Name of lead principal investigator	1st name Mitsuhiro Middle name Last name Kato
Organization	Showa University Hospital
Division name	Pediatrics
Zip code	142-8555
Address	1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
TEL	03-3784-8000
Email	ktmt-hro@umin.ac.jp

Public contact
Name of contact person	1st name Kenji Middle name Last name Nagaya
Organization	National Hospital Organization Nagoya Medical Center
Division name	Department of Clinical Research Planning and Management, Clinical Research Center
Zip code	460-0001
Address	4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi 460-0001, Japan
TEL	052-951-1111
Homepage URL
Email	study.office@nnh.go.jp

Sponsor
Institute	Hokkaido University Hospital Nishi-Niigata Chuo National Hospital National Center Hospital, NCNP Shizuoka Institute of Epilepsy and Neurological Disorders Okayama University Hospital
Institute
Department

Funding Source
Organization	AMED
Organization
Division
Category of Funding Organization	Government offices of other countries
Nationality of Funding Organization	Japan

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Address	Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan
Tel	054-245-5680
Email	yamamoty@shizuokamind.org

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions	北海道大学病院(北海道) 国立病院機構西新潟中央病院(新潟県) 国立精神・神経医療研究センター病院(東京都) 国立病院機構静岡てんかん・神経医療センター(静岡県) 岡山大学病院(岡山県)

Other administrative information
Date of disclosure of the study information	2018 Year 07 Month 25 Day

Related information
URL releasing protocol
Publication of results	Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled	16
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Completed
Date of protocol fixation	2018 Year 07 Month 13 Day
Date of IRB	2018 Year 08 Month 24 Day
Anticipated trial start date	2018 Year 10 Month 01 Day
Last follow-up date	2020 Year 09 Month 30 Day
Date of closure to data entry	2020 Year 10 Month 30 Day
Date trial data considered complete	2020 Year 12 Month 15 Day
Date analysis concluded	2021 Year 03 Month 12 Day

Other
Other related information

Management information
Registered date	2018 Year 07 Month 25 Day
Last modified on	2021 Year 08 Month 11 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000038203