Ensayos clínicos

Inclusion Criteria:

• Age ≥2 to ≤8 years, inclusive as of the day of the Screening Visit.
• Documented medical history to support a clinical diagnosis of EMAS, where convulsive or drop seizures are not completely controlled by current antiseizure therapies:
  • Received therapeutic trials of 2 or more of the following: benzodiazepine (clonazepam, clorazepate, or clobazam), ethosuximide, felbamate, lamotrigine, levetiracetam, rufinamide, topiramate, valproic acid, zonisamide, perampanel, dietary therapy (ketogenic diet or modified Atkins diet);
  • Failed therapy was due to lack of efficacy.
• Seizure onset age 2 to 8 years, inclusive, in an otherwise healthy child.
• Myoclonic atonic seizures, either by history or recorded on EEG.
• Initial development is normal.
• History of normal brain MRI without cortical brain malformation.
• History of EEG demonstrating generalized 2-3 Hz slow spike and wave.
• Lack of alternative diagnosis.
• Had ≥6 convulsive seizures (tonic-clonic, tonic, atonic, clonic) or drop seizures (tonic, atonic, myoclonic atonic) per 6 week period for the past 12 weeks prior to screening, by parent/guardian report to investigator or investigator medical notes.
• All medications or interventions for epilepsy (including ketogenic diet [KD] or modified Atkins diet [MAD] and vagal nerve stimulation [VNS] have been stable for at least 4 weeks prior to screening and are expected to remain stable throughout the study.
• Given information regarding the nature of the study and informed consent legally obtained from the responsible parent/guardian.
• Provided assent in accordance with Institutional Review Board (IRB) requirements, if capable.
• Parent/caregiver is willing and able to be compliant with diary completion, visit schedule, and study drug accountability.
• No cardiovascular abnormality on echocardiogram, including trace mitral or aortic regurgitation or signs of pulmonary hypertension.  If abnormalities are identified during the phase 1 study then continued participation must be granted by the DSMB.
• ≥90% compliance with seizure diary.

Exclusion Criteria:

• History of epileptic or infantile spasms.
• History of developmental delay prior to onset of seizures.
• MRI abnormalities felt to be causative of seizures.
• Diagnosis of glucose transporter deficiency (GLUT-1 deficiency).
• Clinical history and findings most consistent with Lennox Gastaut syndrome.
• Known hypersensitivity to fenfluramine or any of the excipients in the study medication.
• Current pulmonary arterial hypertension.
• Current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarctions, or stroke.
• Current or recent history of Anorexia Nervosa, bulimia, or depression within the prior year that required medical treatment or psychological treatment for a duration greater than 1 month.
• At imminent risk of self-harm or harm to others, in the investigator’s opinion, based on clinical interview and responses provide on the Columbia-Suicide Severity Rating Scale (C-SSRS).Subjects must be excluded if they report suicidal behavior in the past 6 months as measured by the C-SSRS at Screening or Baseline, which includes suicidal ideation with intent or plan (Item #5).If a subject reports suicidal ideation on Item 4 without specific plan, and the investigator feels that the subject is appropriate for the study considering the potential risks, the investigator must document appropriateness for inclusion, and discuss with the parent/caregiver to be alert to mood or behavioral changes, especially around times of dose adjustment.
• Current or past history of glaucoma.
• Moderate or severe hepatic impairment. NOTE: Asymptomatic subjects with mild hepatic impairment (Elevated liver enzymes <3x ULN and/or elevated bilirubin <2x ULN) may be entered into the study after review and approval by the Independent Data Safety Committee, in consideration of comorbidities and concomitant medications.
• Currently receiving concomitant therapy with any of the following: centrally-acting anorectic agents; monamine 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.
• Currently taking carbamazepine, oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
• 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.
• Positive result on urine tetrahydrocannabinol (THC) Panel.
• Participated in another clinical trial within the past 30 days.
• Currently receiving an investigational product.
• Unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
• Has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the past 4 weeks prior to the Screening Visit, other than epilepsy, that would negatively impact study participation, collection of study data, or post a risk to the subject.