Flunarizine for Treatment Resistant Absence Epilepsy

This is an open-label, single-centre study to evaluate the clinical efficacy, safety and tolerability of Flunarizine administered as adjunctive treatment in participants diagnosed with treatment resistant absence epilepsy. The study goal is to see how efficient and safe flunarizine is at decreasing the frequency of absence seizures in children with treatment-resistant refractory epilepsy at doses of 5mg and 10mg once daily.

Study Overview

• Status: Terminated
• Conditions: Juvenile Myoclonic Epilepsy; Childhood Absence Epilepsy; Juvenile Absence Epilepsy
• Intervention / Treatment: Drug: Flunarizine Hydrochloride

Detailed Description

Flunarizine (flunarizine hydrochloride) is indicated for prophylaxis of migraine (with and without aura) in patients with frequent and severe attacks, who have not responded to other treatment and/or in whom other therapy has resulted in unacceptable side effects. Flunarizine readily crosses the blood brain barrier and its primary mechanism of action is to preferentially block the entry of calcium under pathophysiological conditions preventing cellular calcium overload by reducing excessive transmembrane calcium influx.

Flunarizine has been used successfully for many years in children with migraines and is a firstline, though off-label, treatment for alternating hemiplegia of childhood. It is not labeled for the control of seizures, but has been safely trialed as an anti-seizure medication with promising results.

The primary objective is to assess the efficacy, safety and tolerability of flunarizine compared to a baseline period on absence seizures in patients with treatment refractory epilepsy taking a minimum of one anti-seizure medication (ASM). The primary outcome measure is median percent change in weekly absence seizure frequency in patients treated with flunarizine compared with the baseline period.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • BC Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant is 4 to 18 years of age
• Participant has treatment resistant absence seizures. Treatment resistant absence seizures are defined as failure to respond to 2 or more appropriate anti-seizure medications (ASMs). The potential participant must have failed to respond to or tolerate appropriate doses of two of the following: ethosuximide (>/= 20 mg/kg/day), Valproic acid/divalproex sodium (>/= 15 mg/kg/day) or lamotrigine, (>/= 5 mg/kg/day).
• Participant must currently be taking a minimum of one ASM
• Normal development (may have specific learning disabilities and/or attention deficit hyperactivity disorder/attention deficit disorder (ADHD/ADD))
• EEG confirmation of absence seizures and EEG within 2 months of screening visit
• Absence seizures reported at least 10 times per week
• Participants must have no changes in baseline ASMs for 1 month prior to screening period
• Participant or caregiver can maintain a seizure diary
• Participant is able to swallow capsules
• Written informed consent must be provided. Legal guardians of the participants must be able to understand and provide written consent on behalf of the participant, since study participants may be too young to provide informed consent. For participants 7-18 years of age, assent will be required along with written informed consent of the caregiver.
• The participant is willing and able to attend all study visits at British Columbia (BC) Children's Hospital
• Participant has the ability to speak and read in English
• Females of child bearing potential who are sexually active must be willing to use contraceptive methods for the duration of the study and 6 months post last dose of study drug.
• Males who are sexually active with females of child bearing potential must be willing to use contraception for the duration of the study and 3 months post last dose of study drug.

Exclusion Criteria:

• Age < 4 years, > 18 years
• Participant has uncontrolled myoclonic or generalized tonic clonic seizures
• Psychogenic non-epileptic seizures
• Known diagnosis of intellectual disability
• Autism spectrum disorder
• Participant is taking carbamazepine, oxcarbazepine, phenytoin, eslicarbazepine, or vigabatrin
• History of poor compliance with medication
• Inability of parent or caregiver to maintain a seizure diary
• History of depression or psychosis
• Participant has previously taken flunarizine and has had an adverse reaction to treatment
• Participants who are pregnant or breastfeeding,
• Presence of extrapyramidal symptoms
• Participants who have clinically significant hepatic impairment as assessed by the investigator
• Participants with known hypersensitivity to flunarizine or any of its ingredients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Flunarizine; Flunarizine 5 mg capsules will be administered once a day at night. If the 5mg/day dose is tolerated by any given participant, the dose will be escalated to 10mg/day taken as two 5mg capsules at night	Drug: Flunarizine Hydrochloride; Flunarizine tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Percent Change in Weekly absence seizure frequency	Measuring the median percent change in weekly absence seizure frequency in patients treated with flunarizine compared with the baseline period. This will be measured by evaluating patient seizure diaries at baseline and at the end of the treatment period	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluating EEG changes in patients with absence epilepsy	Median percent change in the number of absence seizures captured on EEG, and bursts of spike/wave lasting 2 or more seconds in patients treated with flunarizine compared with the baseline period	12 weeks

Collaborators and Investigators

• Sponsor: University of British Columbia

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2019
• Primary Completion (Actual): May 26, 2023
• Study Completion (Actual): May 26, 2023

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: November 29, 2023
• First Posted (Estimated): December 1, 2023

Study Record Updates

• Last Update Posted (Estimated): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epileptic Syndromes; Epilepsy; Epilepsies, Myoclonic; Myoclonic Epilepsy, Juvenile; Epilepsy, Absence; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Membrane Transport Modulators; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Flunarizine
• Other Study ID Numbers: H19-00185

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No