Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to assess the long-term safety, tolerability, and efficacy of adjunctive therapy of LP352 in subjects with developmental and epileptic encephalopathies who completed participation in Study LP352-201.

Detailed Description
-----------------
This Phase 2, multicenter, open-label, multiple-dose extension clinical study is designed to evaluate long-term safety of LP352 in subjects with developmental and epileptic encephalopathy who completed Study LP352-201. The study consists of a Screening Period (Day -1) and a 50-week open-label Treatment Period that includes a 15-day Up-titration Period (during which time subjects will titrate up to their highest tolerated doses) and an open-label Maintenance Period (48 weeks). The Treatment Period will be followed by a Down-titration/Taper Period (up to 15 days) and Follow-up Period (14 days after completion of down-titration). The starting dose of up-titration will be 6 mg TID. The target final maintenance doses are 6 mg TID, 9 mg TID, and 12 mg TID after a 15-day up-titration period, if tolerated.

Official Title
-----------------
A Phase 2, Multicenter, Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy Who Completed Study LP352-201 and Are Candidates for Continuous Treatment for Up to 52 Weeks

Conditions
-----------------
Dravet Syndrome, Developmental and Epileptic Encephalopathy, Lennox-Gastaut Syndrome

Intervention / Treatment
-----------------
* Drug: LP352


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or non-pregnant, non-lactating female, age 12 to 65 years who have satisfactorily completed study LP352-201 Diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or other developmental and epileptic encephalopathy The patient/parent/caregiver is able and willing to attend study visits, complete the diary and take study drug as instructed Exclusion Criteria: Had an SAE in Study LP352-201 that was definitely, probably, or possibly related to exposure to study drug Current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, stroke, pulmonary arterial hypertension or abnormal blood pressure Has glaucoma, renal impairment, liver disease or any other medical condition that would affect study participation or pose a risk to the subject Current or recent history of moderate or severe depression, anorexia nervosa, bulimia or at risk of suicidal behavior Currently taking anorectic agents, monoamine oxidase inhibitors; serotonin agonists or antagonists including fenfluramine, atomoxetine, vortioxetine, or other medications for weight loss Positive test result on the drug screen, except tetrahydrocannabinol (THC) for patients taking prescribed cannabidiol

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LP352<br>Subjects will be titrated up to highest tolerated dose of LP352 during a 15-day period, followed by a 48-week maintenance period and a 15-day taper/down titration period. | Drug: LP352<br>* LP352 6 mg, 9 mg or 12 mg administered three times daily, orally or through G-tube<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent Adverse Events | Incidence and severity of treatment-emergent adverse events, including serious adverse events and adverse events leading to study discontinuation and clinically significant changes in vital signs, physical examination endpoints, clinical safety laboratory values and ECGs | Baseline up to Week 52 | 
| Columbia-Suicide Severity Rating Scale (C-SSRS) Response | Type of Suicidal Ideation, Intensity (1 - 5, with 5 being most severe), Suicidal Behavior | Baseline up to Week 52 | 
| Patient Health Questionnaire-9 Total Score and Question 9 Score | Severity Rating Scale: 0 - 27; higher scores indicate greater severity of depressive disorder | Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in Observed Countable Motor Seizure Frequency During the Treatment Period | Baseline Used for Seizure Frequency = Baseline from Study LP352-201 and Baseline from Study LP352-202 | Baseline to Week 50 | 
| Proportion of Subjects with > 50% Reduction in Total Seizures During the Treatment Period |  | Baseline to Week 50 | 
| Percent Reduction in Individual Seizure Type During the Treatment Period |  | Baseline to Week 50 | 
| Proportion of Subjects Requiring Rescue Medication During the Treatment Period |  | Baseline to Week 50 | 
| Percent Change from Baseline in the Number of Episodes of Status Epilepticus During the Treatment Period |  | Baseline to Week 50 | 
| Percent of Subjects with Countable Motor Seizure-free Days During the Treatment Period |  | Baseline to Week 50 | 
| Percentage Change from Baseline in Non-motor and Difficult to Count Seizures |  | Baseline to Week 50 | 
| LGS: Percentage Change from Baseline in the Frequency of Observed Drop Seizures Over the Treatment Period |  | Baseline to Week 50 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CDKL5 deficiency disorder, developmental and epileptic encephalopathy, Dravet Syndrome, epilepsy, Lennox-Gastaut Syndrome, treatment resistant epilepsy, tuberous sclerosis complex