Study for Verification of Efficacy and Safety for Perampanel Monotherapy in Untreated Participants With Partial Onset Seizures (Including Secondarily Generalized Seizures (FREEDOM Study)

Conditions

Partial Onset Seizures

Keywords

perampanel

Brief summary

This study is conducted to evaluate the seizure-free rate of the 26-week Maintenance Period in untreated participants with partial onset seizures (POS).

Yamamoto T, Lim SC, Ninomiya H, Kubota Y, Shin WC, Kim DW, Shin DJ, Iida K, Ochiai T, Matsunaga R, Hiramatsu H, Kim JH.

2024-12-201 citations

10.1016/j.eplepsyres.2024.107494

Perampanel as monotherapy or first adjunctive therapy in pediatric and adult patients with epilepsy: the first United States-based phase IV open-label ELEVATE study.

Punia V, Klein P, Mihaylova T, Biton V, Samad O, Ngo LY, Kumar D, Malhotra M.

2024-05-102 citations

10.1007/s00415-024-12399-w

Long-Term Efficacy of Perampanel Monotherapy in Patients with Newly Diagnosed/Currently Untreated Recurrent Focal-Onset Seizures: FREEDOM Study 342 Extension Phase Analysis by Seizure Type (P11-1.005)

Sung Chul Lim, Anna Patten, Marcia Morita‐Sherman, Stella Ngo, Takamichi Yamamoto

Neurology2023-04-25

10.1212/wnl.0000000000202573

2248 Perampanel monotherapy for focal-onset seizures (FOS): post hoc analysis of treatment-emergent adverse events (TEAEs) by treatment period during FREEDOM study 342

Manoj Malhotra, Ji Hyun Kim, Sung Chul Lim, Hirotomo Ninomiya, Takamichi Yamamoto et al. (8 authors)

Abstracts2022-08-01

10.1136/bmjno-2022-anzan.58

Experience of perampanel monotherapy beyond initial titration to achieve seizure freedom in patients with focal‐onset seizures with newly diagnosed or currently untreated recurrent epilepsy: A post hoc analysis of the open‐label Study 342 (FREEDOM)

Ryan Edbert Husni, Leock Y. Ngo, Hirofumi Senokuchi, Anna Patten, Hidetaka Hiramatsu et al. (7 authors)

Epilepsia Open2021-10-1921 citations

10.1002/epi4.12551

Efficacy and safety of perampanel monotherapy in patients with focal‐onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open‐label Study 342 (FREEDOM Study)

Takamichi Yamamoto, Sung Chul Lim, Hirotomo Ninomiya, Yuichi Kubota, Won Chul Shin et al. (14 authors)

Epilepsia Open2020-05-0644 citations

10.1002/epi4.12398

Efficacy and Safety of Perampanel Monotherapy in Patients with Newly Diagnosed or Currently Untreated Recurrent Partial-Onset Seizures (POS): Final Analysis of Study 342 (FREEDOM) 4 and 8 mg/day Core Data (833)

Takamichi Yamamoto, Ji Hyun Kim, Sung Chul Lim, Hirotomo Ninomiya, Yuichi Kubota et al. (7 authors)

Neurology2020-04-14

10.1212/wnl.94.15_supplement.833

Interventions

DRUGE2007

Oral tablet

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Years to 74 Years

Healthy volunteers

No

Inclusion criteria

* Be considered reliable and willing to be available for the study period and are able to record seizures and report adverse events (AEs) himself/herself or have a caregiver who can record seizures and report AEs for them * Participants who are newly diagnosed or recurrent epilepsy and have experienced at least 2 unprovoked seizures separated by a minimum of 24 hours in the 1 year prior to the Pretreatment Phase * Participants who have excluded the progressive central nervous system (CNS) abnormality occurring seizures by computed tomography (CT) or magnetic resonance imaging (MRI) * Participants who have had a diagnosis of epilepsy with partial seizures with or without secondarily generalized seizures according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures (1981). Diagnosis should have been established by clinical history and an electroencephalogram (EEG) that is consistent with localization-related epilepsy; normal interictal EEGs will be allowed provided that the participant meets the other diagnosis criterion (ie, clinical history)

Exclusion criteria

* Participants who present only simple partial seizures without motor signs * Participants who have seizure clusters where individual seizures cannot be counted * Participants who present or have a history of Lennox-Gastaut syndrome * Participants who have a history of status epilepticus * Participants who have a history of psychogenic non-epileptic seizures * Participants who have a history of suicidal ideation/attempt * Participants who present clinically problematic psychological or neurological disorder(s) * Evidence of clinically significant disease * Evidence of clinically significant active hepatic disease * A prolonged time from the beginning of the QRS complex to the end of the T wave (QT) interval corrected for heart rate * Participants who have a history of receiving any AEDs (except for AEDs used as rescue treatment), antipsychotics or anti-anxiety drugs within 12 weeks prior to the Pretreatment Phase * Participants who have not used a stable dose of antidepressant in the 12 weeks * Participants who have a history of any type of surgery for brain or central nervous system within 1 year * Participants who have a history of receiving any AED (including AED used as rescue treatment) for more than 2 weeks * Participants who have used intermittent rescue benzodiazepines on 2 or more occasions within 4 weeks * Participants who have a history of receiving any AED polytherapy * Participants who experienced treatment with perampanel * Participants who have had non-constant ketogenic diet within 4 weeks * Participants who have a history of drug or alcohol dependency or abuse * Participants who have had multiple drug allergies or a severe drug reaction to an AED(s) * Females who are breastfeeding or pregnant in the Pretreatment Phase (as documented by a positive beta-human chorionic gonadotropin \[β-hCG\] test) * Females of childbearing potential who: * Within 28 days before the start of the Pretreatment Phase, did not use a highly effective method of contraception, which includes any of the following: * total abstinence (if it is their preferred and usual lifestyle); * an intrauterine device or intrauterine hormone-releasing system (IUS); * a contraceptive implant; * an oral contraceptive (with additional barrier method) (Participant must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation); * have a vasectomized partner with confirmed azoospermia * Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation * Participants who have participated in a study involving administration of an investigational drug or device within 4 weeks before Visit 1, or within approximately 5 half-lives of the previous investigational compound, whichever is longer

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Partial-onset Seizures (POS) Who Achieved Seizure-free Status During the 26-week Maintenance Period of 4 mg Perampanel	26 weeks in Maintenance Period of 4 mg perampanel	A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. POS was a seizure that starts in one area of the brain that may or may not associated with loss of awareness and consciousness. Seizure-free status was defined as no incidence of seizure during 26-week Maintenance Period of 4 mg perampanel.

Secondary

Measure	Time frame	Description
Percentage of Participants With POS Who Achieved Seizure-free Status During the 52-week Treatment Phase (26-week Maintenance Period Plus 26-week Extension Phase) of 4 mg of Perampanel	52-week (Maintenance Period of 4 mg perampanel + Extension Phase of 4 mg perampanel)	A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. POS was a seizure that starts in one area of the brain that may or may not associated with loss of awareness and consciousness. Seizure-free status was defined as no incidence of seizure during 52-weeks treatment of 4 mg perampanel.
Percentage of Participants With POS Who Achieved Seizure-free Status During the 52-week of Treatment Phase (26-week Maintenance Period Plus 26-week Extension Phase) of Last Evaluated Dose of 4 or 8 mg Perampanel	52-week (Maintenance Period of last evaluated dose of 4 or 8 mg perampanel + Extension Phase of 4 or 8 mg perampanel)	A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. POS was a seizure that starts in one area of the brain that may or may not associated with loss of awareness and consciousness. Seizure-free status was defined as no incidence of seizure during the 52-week treatment of last evaluated dose of 4 or 8 mg perampanel.
Time to Onset of First Seizure From the First Dose of Study Drug in the Maintenance Period of 4 mg Perampanel	From the first dose of study drug in the Maintenance Period (Week 6) up to the first seizure onset (up to 150 weeks)	Time to onset of first seizure was defined as the period from the first dose of study drug in the 4 mg Maintenance Period to the onset of first seizure. A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Percentage of Participants With POS Who Achieved Seizure-free Status During the 26-week Maintenance Period of Last Evaluated Dose of 4 or 8 mg Perampanel	26 weeks in Maintenance Period of 4 or 8 mg perampanel	A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. POS was a seizure that starts in one area of the brain that may or may not associated with loss of awareness and consciousness. Seizure-free status was defined as no incidence of seizure during the 26-week Maintenance Period of last evaluated dose of 4 or 8 mg perampanel.
Time to Withdrawal From the First Dose of Study Drug in the Maintenance Period of 4 mg Perampanel	From the first dose of study drug in the Maintenance Period (Week 6) up to the date of first withdrawal, regardless of reason (up to 150 weeks)	Time to withdrawal from the study was defined as the period from the first dose of study drug in the 4 mg Maintenance Period to the date of withdrawal from study, regardless of reason.
Time to Withdrawal From the First Dose of Study Drug in the Maintenance Period of Last Evaluated Dose of 4 or 8 mg Perampanel	From the first dose of study drug in the Maintenance Period (Week 6) up to the date of first withdrawal, regardless of reason (up to 150 weeks)	Time to withdrawal from the study was defined as the period from the first dose of study drug in the 4 mg or 8 mg Maintenance Period to the date of withdrawal from study, regardless of reason.
Number of Participants With Any Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Event (TESAEs), and TEAEs Leading to Discontinuation of the Study Drug	From baseline up to 28 days after last dose of study drug (up to 160 weeks)	—
Time to Onset of First Seizure From the First Dose of Study Drug in the Maintenance Period of Last Evaluated Dose of 4 or 8 mg Perampanel	From the first dose of study drug in the Maintenance Period (Week 6) up to the first seizure onset (up to 150 weeks)	Time to onset of first seizure was defined as the period from the first dose of study drug in the 4 mg or 8 mg Maintenance Period to the onset of first seizure. A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

Countries

Japan, South Korea

Participant flow

Recruitment details

Participants took part in the study at 38 investigative sites in Japan and Korea from 28 Jun 2017 to 27 Jul 2020. A total of 98 participants were screened, of which 07 were screen failures and 91 entered Treatment Phase. Of these, 89 participants received the study treatment.

Pre-assignment details

Study consisted of 2 main phases: Treatment Phase (consisted of a 4 milligram \[mg\] Treatment Phase \[Titration Period {6 weeks} and Maintenance Period {26 weeks}\], and for those participants who need a higher dose, the 8 mg Treatment Phase \[Titration Period {4 weeks} and Maintenance Period {26 weeks}\]) and Extension Phase.

Participants by arm

Arm	Count
Perampanel Participants received 2 mg of perampanel tablets orally QD for up to 2 weeks, then dose was up-titrated to 4 mg QD for 4 weeks in 4-mg Titration Period (6 Weeks) followed by 4 mg of perampanel tablets orally QD in Maintenance Period (26 weeks). If a participant experienced seizures during 4-mg Maintenance Period, the participant was transitioned to 8-mg Titration Period based on the participant's safety and tolerability. In 8-mg Titration Period (4 weeks), participants received 6 mg of perampanel tablets orally QD for 2 weeks and up-titrated to 8 mg QD for 2 weeks followed by 8 mg of perampanel tablets orally QD in Maintenance Period (26 weeks). Participants who completed Treatment Phase or who ended Maintenance Period of Treatment Phase due to insufficient efficacy or intolerability, and who agreed to continue perampanel monotherapy entered Extension Phase and received perampanel tablets in 2 mg to 8 mg dose range at the discretion of the investigator based on the participants clinical response and/or tolerability until insufficient seizure control or lack of tolerability, or initiation of AEDs.	89
Total	89

Arm

Count

Perampanel

Participants received 2 mg of perampanel tablets orally QD for up to 2 weeks, then dose was up-titrated to 4 mg QD for 4 weeks in 4-mg Titration Period (6 Weeks) followed by 4 mg of perampanel tablets orally QD in Maintenance Period (26 weeks). If a participant experienced seizures during 4-mg Maintenance Period, the participant was transitioned to 8-mg Titration Period based on the participant's safety and tolerability. In 8-mg Titration Period (4 weeks), participants received 6 mg of perampanel tablets orally QD for 2 weeks and up-titrated to 8 mg QD for 2 weeks followed by 8 mg of perampanel tablets orally QD in Maintenance Period (26 weeks). Participants who completed Treatment Phase or who ended Maintenance Period of Treatment Phase due to insufficient efficacy or intolerability, and who agreed to continue perampanel monotherapy entered Extension Phase and received perampanel tablets in 2 mg to 8 mg dose range at the discretion of the investigator based on the participants clinical response and/or tolerability until insufficient seizure control or lack of tolerability, or initiation of AEDs.

89

Total

89

Withdrawals & dropouts

Period	Reason	FG000
Extension Phase (From Week 63 to 156)	Inadequate therapeutic effect	1
Extension Phase (From Week 63 to 156)	Lost to Follow-up	1
Extension Phase (From Week 63 to 156)	Other	1
Extension Phase (From Week 63 to 156)	Pregnancy	1
Extension Phase (From Week 63 to 156)	Subject choice	1
Extension Phase (From Week 63 to 156)	Withdrawal of consent	3
Treatment Phase (Up to 62 Weeks)	Adverse Event	9
Treatment Phase (Up to 62 Weeks)	Inadequate therapeutic effect	6
Treatment Phase (Up to 62 Weeks)	Lost to Follow-up	2
Treatment Phase (Up to 62 Weeks)	Not treated	2
Treatment Phase (Up to 62 Weeks)	Other than specified	11
Treatment Phase (Up to 62 Weeks)	Subject Choice	1
Treatment Phase (Up to 62 Weeks)	Withdrawal of consent	6

Baseline characteristics

Characteristic	Perampanel
Age, Continuous	42.1 years STANDARD_DEVIATION 18.19
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	89 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	89 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	0 Participants
Sex: Female, Male Female	44 Participants
Sex: Female, Male Male	45 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 89
other Total, other adverse events	73 / 89
serious Total, serious adverse events	13 / 89

Outcome results

Primary

Percentage of Participants With Partial-onset Seizures (POS) Who Achieved Seizure-free Status During the 26-week Maintenance Period of 4 mg Perampanel

A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. POS was a seizure that starts in one area of the brain that may or may not associated with loss of awareness and consciousness. Seizure-free status was defined as no incidence of seizure during 26-week Maintenance Period of 4 mg perampanel.

Time frame: 26 weeks in Maintenance Period of 4 mg perampanel

Population: Modified intent to treat (mITT) set: group of participants who signed informed consent, received at least 1 dose of study drug, who entered the 4-mg Maintenance Period and had at least 1 postdose primary efficacy measurement in the 26-week Maintenance Period.

Arm	Measure	Value (NUMBER)
Perampanel	Percentage of Participants With Partial-onset Seizures (POS) Who Achieved Seizure-free Status During the 26-week Maintenance Period of 4 mg Perampanel	63.0 percentage of participants

Secondary

Number of Participants With Any Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Event (TESAEs), and TEAEs Leading to Discontinuation of the Study Drug

Time frame: From baseline up to 28 days after last dose of study drug (up to 160 weeks)

Population: The safety analysis set was the group of participants who signed informed consent, received at least one dose of study drug and had at least one postdose safety assessment.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Perampanel	Number of Participants With Any Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Event (TESAEs), and TEAEs Leading to Discontinuation of the Study Drug	TEAEs	74 Participants
Perampanel	Number of Participants With Any Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Event (TESAEs), and TEAEs Leading to Discontinuation of the Study Drug	TESAEs	13 Participants
Perampanel	Number of Participants With Any Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Event (TESAEs), and TEAEs Leading to Discontinuation of the Study Drug	TEAEs leading to discontinuation of study drug	9 Participants

Secondary

Percentage of Participants With POS Who Achieved Seizure-free Status During the 26-week Maintenance Period of Last Evaluated Dose of 4 or 8 mg Perampanel

A seizure was a brief episode of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. POS was a seizure that starts in one area of the brain that may or may not associated with loss of awareness and consciousness. Seizure-free status was defined as no incidence of seizure during the 26-week Maintenance Period of last evaluated dose of 4 or 8 mg perampanel.

Time frame: 26 weeks in Maintenance Period of 4 or 8 mg perampanel