Efficacy of Fluoxetine Against Seizure-induced Central Apneas (FLUOXETINE)

Efficacy of Fluoxetine Against Seizure-induced Central Apneas : a Randomized Placebo-controled Double-blind Trial.

Sudden unexpected death in epilepsy (SUDEP) is a tragic outcome of seizure disorders that primarily affect young adults suffering from refractory epilepsy. In this population, SUDEP incidence is estimated at 0.5%. While the mechanisms of SUDEP are not completely understood, it appears that the majority of such death occurs in the immediate aftermath of a general tonic-clonic seizure.

There is currently no validated preventive treatment for SUDEP. Some evidence suggest that modulation of the serotoninergic tone, and more specifically selective serotonin recapture inhibitor (SSRI) such as fluoxetine, might prevent SUDEP. Indeed, fluoxetine prevents seizure-induced lethal central apneas in DBA/2 and DBA/1 mice, one of the few animal models of SUDEP. Furthermore, serotoninergic bulbar nuclei are known to play a major role in the control of breathing, especially during sleep and in response to repeated hypoxia.

In patients with epilepsy undergoing in-hospital video-EEG monitoring, about one third of seizures are associated with decrease in SpO2 <90%, an abnormality suspected to represent a risk factor of SUDEP. In a retrospective uncontrolled study, patients treated with SSRIs displayed less frequent ictal/post-ictal hypoxemia than patients not taking SSRIs.

The investigators project aimed at testing whether fluoxetine can reduce the risk of ictal/post-ictal hypoxemia by performing a double-blind, randomized, placebo-controlled trial in patients undergoing video-EEG monitoring as part of the pre-surgical evaluation of their focal drug-resistant epilepsy.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Ictal/Post-ictal Hypoxemia
• Intervention / Treatment: Drug: fluoxetine 20 mg; Drug: placebo 20 mg

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Service de Neurologie Fonctionnelle et d'Epileptologie, Hôpital Neurologique

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patient suffering from drug-resistant focal epilepsy

• Age ≥ 18 years
• Patient for whom a video-EEG monitoring of their seizures was scheduled as part of a pre-surgical assessment
• For women of childbearing age, a method of contraception considered effective by the investigator
• Patient who have given their written informed consent
• Patient accepting an interview with a psychologist and to be refered to a psychiatrist in the event that mood disorders were detected on mood scores and considered severe by the investigator and / or psychologist, leading to require psychiatric care or immediate antidepressant treatment
• Patient with a social security number

Exclusion Criteria:

• Age < 18 years

  • Patient under legal protection
  • Pregnant or breastfeeding women
  • Hypersensitivity to fluoxetine or its excipients
  • History of other serious side effects related to an earlier prescription of fluoxetine;
  • Current suicidal ideation or history of suicide attempt
  • Manic episode
  • Disruption of liver enzymes considered material by the investigator using the following criteria:

transaminases (ALT and AST)> 2N alkaline phosphatase (ALP)> 2N gamma glutamyl transpeptidase (GGT)> 5N (performed as part of routine monitoring of epileptic patients on antiepileptic treatment. Patients often exhibit changed deemed clinically insignificant due to the enzyme-inducing effect of these drugs)

• Renal failure with creatinine clearance <30 ml / min
• Acute heart disease
• Antidepressant treatment
• Other prohibited treatment (see detailed list in protocol).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FLUOXETINE; 4 weeks of treatment before video-EEG monitoring	Drug: fluoxetine 20 mg; Fluoxetine 20 mg per day during 4 weeks prior to video-EEG, then continued during video-EEG. At the end of video-EEG, and according to patient's decision, treatment was either progressively withdrawn (1 week at 10 mg per day and then 1 week at 5 mg per day), or replaced by fluoxetine 20 mg open-label.
Placebo Comparator: PLACEBO; 1 month of treatment before EEG video.	Drug: placebo 20 mg; Placebo 20 mg per day during 4 weeks prior to video-EEG, then continued during video-EEG. At the end of video-EEG, and according to patient's decision, treatment was either progressively withdrawn (1 week at 10 mg per day and then 1 week at 5 mg per day), or replaced by fluoxetine 20 mg open-label.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ictal/post-ictal hypoxemia	Percentage of patients with at least one seizure associated with ictal/post-ictal SpO2 <90% in the group treated with fluoxetine compared to that receiving placebo.	Duration of video-EEG following 4 weeks of fluoxetine treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mood score with BDI-II score	Changes in score of BDI-II after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo	After four weeks of treatment as compared to baseline
Change in mood score with NDDIE score	Changes in score of NDDIE after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo	After four weeks of treatment as compared to baseline
Change in seizure frequency	Changes in seizure frequency after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo	After four weeks of treatment as compared to baseline
Change in sleep disorders score with SASDQ score	Changes in score of SASDQ after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo	After four weeks of treatment as compared to baseline
Change in sleep disorders score with EPWORTH score	Changes in score of EPWORTH after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo	After four weeks of treatment as compared to baseline
Change in score of quality of life	Change in score of QOLIE-89 after four weeks of treatment as compared to baseline in the group treated with fluoxetine compared to that receiving placebo	After four weeks of treatment as compared to baseline

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Study Director: Philippe RYVLIN, Professor, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: September 24, 2015
• First Submitted That Met QC Criteria: October 6, 2015
• First Posted (Estimate): October 7, 2015

Study Record Updates

• Last Update Posted (Estimate): October 5, 2016
• Last Update Submitted That Met QC Criteria: October 4, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Epilepsy; placebo; fluoxetine; SUDEP; SpO2
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Epilepsy; Seizures; Hypoxia; Sleep Apnea, Central; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Fluoxetine
• Other Study ID Numbers: 2009-562