Ignite Creation Date:
2025-12-25 @ 12:37 AM
Ignite Modification Date:
2026-03-09 @ 10:50 AM
Study NCT ID:
NCT02929667
Status:
COMPLETED
Last Update Posted:
2020-05-04
First Post:
2016-07-26
Is Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Abnormal Ventilatory Response to Carbon Dioxide: a Potential Biomarker for Seizure Induced Respiratory Depression & Modification by SSRI
Sponsor:
Rup Kamal Sainju
Organization:
Study Overview
Official Title:
Abnormal Ventilatory Response to Carbon Dioxide: a Potential Biomarker for Seizure Induced Respiratory Depression & Modification by SSRI
Status:
COMPLETED
Status Verified Date:
2020-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Sudden unexpected death in epilepsy patients (SUDEP) is devastating outcome for some patients with epilepsy. It ranks second only to stroke among neurological diseases in years of potential life lost. Patho-mechanisms of SUDEP remain not well understood, however peri-ictal respiratory dysfunction likely plays an important role in many cases.
Literature supports a critical role for the serotonergic system in central control of ventilation. Serotonin neurons in the raphe nuclei of the brainstem sense rising carbon dioxide and low pH, thereby stimulating breathing and arousal. These responses may serve as mechanisms that protect against asphyxia, particularly during sleep or the post-ictal state. In mouse models of seizure-induced sudden death, pre-treatment with selective serotonin reuptake inhibitor (SSRI) agents prevents death following seizures. Hence, the investigators hypothesize that a subset of drug resistant epilepsy patients who have impaired central chemo-responsiveness have a greater degree of peri-ictal respiratory depression, therefore a higher risk of SUDEP. The investigators further hypothesize that fluoxetine will improve central chemo-responsiveness and therefore will reduce peri-ictal respiratory depression.
Literature supports a critical role for the serotonergic system in central control of ventilation. Serotonin neurons in the raphe nuclei of the brainstem sense rising carbon dioxide and low pH, thereby stimulating breathing and arousal. These responses may serve as mechanisms that protect against asphyxia, particularly during sleep or the post-ictal state. In mouse models of seizure-induced sudden death, pre-treatment with selective serotonin reuptake inhibitor (SSRI) agents prevents death following seizures. Hence, the investigators hypothesize that a subset of drug resistant epilepsy patients who have impaired central chemo-responsiveness have a greater degree of peri-ictal respiratory depression, therefore a higher risk of SUDEP. The investigators further hypothesize that fluoxetine will improve central chemo-responsiveness and therefore will reduce peri-ictal respiratory depression.
Detailed Description:
Sudden unexpected death in epilepsy (SUDEP) refers to the sudden, unexpected, nontraumatic, non-drowning, witnessed or unwitnessed death of an individual with epilepsy. Postmortem examination in such cases fails to reveal an obvious medical or toxicologic cause for the death, and patients who die from SUDEP are typically healthy apart from their epilepsy. The incidence of SUDEP in epilepsy patients is estimated to be 0.1 in 1000 patient years, and this rate increases to \>9.3 per 1000 for those with durg resistant epilepsy (DRE) who are candidates for epilepsy surgery. Although thought to be rare, SUDEP is estimated to be responsible for 17% of all deaths in patients with epilepsy, and approximately 50% of all deaths in patients with DRE. It is second only to stroke among neurological diseases in YPLL because many who die of SUDEP are relatively young and therefore it is a major public health concern. While there are some acknowledged risk factors for SUDEP, the actual cause, or causes, of SUDEP is not known. Seizure induced respiratory depression is likely to be a major contributor in SUDEP in many cases.
Preliminary results from the ventilatory response to CO2 or hypercapnic ventilatory response (HCVR) study of patient with epilepsy in epilepsy monitoring unit (EMU) suggests prolonged period of CO2 elevation after seizures correlating with low HCVR. These findings suggest a defect in CO2 responsiveness in this high-risk population that may predispose to SUDEP. Serotonin nerve cells in the brain stem are responsible for detecting increases in CO2, and in response stimulating breathing and arousal from sleep. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) drug that increases availability of serotonin in the brain. As such, it may serve to stimulate breathing after seizures in patients with epilepsy who exhibit low CO2 sensitivity at baseline and this may alter SUDEP risk.
This study consists of a double blind randomized controlled clinical trial with a 6-week titration of an intervention. It is designed to evaluate primarily feasibility of a larger clinical trial testing efficacy of fluoxetine in modifying HCVR in patients with epilepsy while also collecting important secondary and exploratory outcomes that would be valuable for designing future larger studies.
We will evaluate challenges in screening, enrollment, randomization, and completion of study-related procedures by quantifying the numbers of subjects eligible for screening, the number of subjects enrolled in the study per month, the proportion of patients successfully completing the study, and the specific challenges at each step. We will also assess challenges in setting up and performing outpatient HCVR testing.
Preliminary results from the ventilatory response to CO2 or hypercapnic ventilatory response (HCVR) study of patient with epilepsy in epilepsy monitoring unit (EMU) suggests prolonged period of CO2 elevation after seizures correlating with low HCVR. These findings suggest a defect in CO2 responsiveness in this high-risk population that may predispose to SUDEP. Serotonin nerve cells in the brain stem are responsible for detecting increases in CO2, and in response stimulating breathing and arousal from sleep. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) drug that increases availability of serotonin in the brain. As such, it may serve to stimulate breathing after seizures in patients with epilepsy who exhibit low CO2 sensitivity at baseline and this may alter SUDEP risk.
This study consists of a double blind randomized controlled clinical trial with a 6-week titration of an intervention. It is designed to evaluate primarily feasibility of a larger clinical trial testing efficacy of fluoxetine in modifying HCVR in patients with epilepsy while also collecting important secondary and exploratory outcomes that would be valuable for designing future larger studies.
We will evaluate challenges in screening, enrollment, randomization, and completion of study-related procedures by quantifying the numbers of subjects eligible for screening, the number of subjects enrolled in the study per month, the proportion of patients successfully completing the study, and the specific challenges at each step. We will also assess challenges in setting up and performing outpatient HCVR testing.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: