Add-on Therapy With Low Dose Fenfluramine in Lennox Gastaut Epilepsy

Study Overview
=================
Brief Summary
-----------------
In this trial, the potential anti-epileptic effect of low dose fenfluramine in Lennox Gastaut epilepsy will be studied. An exploratory dose finding add-on trial is proposed. At baseline and at the end of the study, ECG and ultrasound of the heart will be performed as part of the safety follow up.

Official Title
-----------------
Add-on Therapy With Low Dose Fenfluramine in Lennox Gastaut Epilepsy

Conditions
-----------------
Epilepsy, Lennox Gastaut Syndrome

Intervention / Treatment
-----------------
* Drug: Fenfluramine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria Electro-clinical epilepsy syndrome compatible with Lennox Gastaut syndrome: Minimum requirements (based on ILAE epilepsydiagnosis.org): Multiple seizure types including in any case tonic seizures EEG shows slow spike waves and abnormal background Abnormal cognitive development MRI compatible with Lennox Gastaut epilepsy : no progressive disease Drug resistant: at least 4 documented seizures in the last 4 weeks before inclusion (minimum 4 seizures in at least 2 separate weeks) Seizure types eligible for inclusion are : generalized tonic-clonic seizures GTC , tonic seizures TS , atonic seizures AS or clearly recognizable focal seizures FS. on >= 2 AEDs (including VNS) during the 4 weeks before inclusion (no changes in treatment before inclusion and during the trial) Age between 3 and 18 years Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing potential must not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative urine pregnancy test. Subjects of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control, which includes abstinence, while being treated on this study and for 90 days after the last dose of study drug. Exclusion Criteria Known clinical cardiovascular abnormalities (including valvular problems, shunts, pulmonary hypertension, exercise intolerance) Any cardiac ultrasound/ECG abnormalities at baseline Weight below percentile 3 for age at baseline Subject is receiving concomitant therapy with: centrally-acting anorectic agents; monoamine oxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville oranges, and their juices beginning with the Baseline Period and throughout the study.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 18 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: fenfluramine<br>Experimental : one armed open label study : Add-on fenfluramine in refractory Lennox Gastaut patients. Starting dose 0.2mg/kg/day. In non-responders (<50% seizure frequency decrease), dose will be uptitrated every 4 weeks from 0,2 to 0,4 and max 0,8 mg/kg/day (max 30 mg). Total duration study and max exposure to the drug 20 weeks | Drug: Fenfluramine<br>* study of efficacy and safety of add-on fenfluramine at different dosages in refractory Lennox Gastaut patients : 0.2 - 0.4 and 0.8 mg/kg/day (max 30 mg).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of add-on FFA in Lennox Gastaut epilepsy: Number of responders and seizure free patients at each FFA dosage (0,2 or 0,4 or 0,8 mg/kg/day) |  | up to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure frequency change per patient and per major seizure type (Tonic Clonic Seizures (TCS), Tonic Seizures (TS), Atonic Seizures (AS), Focal Seizures (FS)) |  | 20 weeks | 
| Adverse events (cardiac and general) |  | 20 weeks | 
| Sleep quality : 10 point scale instrument to score sleep quality |  | 20 weeks | 
| CGI (clinical global impression) scale at last visit , by patient/caregiver and treating physician |  | 20 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
refractory childhood epilepsy, Lennox Gastaut syndrome, fenfluramine, anti-epileptic treatment