A Phase 2 interventional study of Fluoxetine and Placebo in Epilepsy and SUDEP, sponsored by Rup Kamal Sainju. Completed at 2 sites in United States. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2020-05-04.
Sponsored by Rup Kamal Sainju · Phase 2, Interventional, and Prevention
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.
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.
1,650 studies on the registry are indexed under Respiratory Insufficiency; 296 are open to participants now.
This study's enrollment of 30 is below the median of 55 across 1,043 interventional studies indexed under Respiratory Insufficiency.
Browse Respiratory Insufficiency studies →This is the only study on the registry with Rup Kamal Sainju as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Subjects randomized to treatment arm will receive fluoxetine with titration schedule consisting of 10 mg per day for 1 week, 20 mg per day for 1 week, 40 mg per day for 2 weeks, 20 mg per day for 1 week and 10 mg per day for 1 week. Then stop.
Drug: Fluoxetine
Subjects randomized to control arm will receive placebo with titration schedule consisting of 10 mg per day for 1 week, 20 mg per day for 1 week, 40 mg per day for 2 weeks, 20 mg per day for 1 week and 10 mg per day for 1 week. Then stop.
Drug: Placebo
Standard 6 weeks titration, starting 10 mg per day.
Also known as: Prozac
Standard 6 weeks titration.
Study Recruitment Rate
Number of participants enrolled every 3 months.
Time frame: From the date of enrollment every 3 months up to 2 years
Study Retention Rate
Number of participants completing the study every 3 months.
Time frame: From date of enrollment until either completion of study or lost to follow up every 3 months up to 2 years and 3 months
Change in Minute Ventilation During Hypercapnic Ventilatory Response (HCVR) Testing
Minute ventilation was evaluated at baseline HCVR testing and HCVR testing at 4 weeks after receiving an intervention. Change from baseline was calculated.
Time frame: At the end of HCVR testing- at baseline and 4 weeks after receiving an intervention
Change in PHQ-9 Score.
Patient Health Questionnaire (PHQ-9) was used to evaluate mood. Score on PHQ-9 scale ranges from 0-27. Scores corresponding to severity of depression: 0-4: minimal to none ; 5-9: mild; 10-14: moderate; 15-19 moderately severe; 20-27: severe. All subjects in the study were interviewed using standard questions per PHQ-09 questionnaire at baseline and 4 weeks after randomization to an intervention.
Time frame: At baseline and 4 weeks after randomization to an intervention
Change in Slope of HCVR
All the subjects undergo CO2 rebreathing (HCVR) testing at baseline and 4 weeks after receiving an intervention. During CO2 rebreathing (HCVR) testing, CO2 gradually rise in the body that stimulates breathing, which in turn increases minute ventilation (L/min). The rate of this increase in minute ventilation with each mm Hg rise in CO2 is the HCVR slope, which is calculated for baseline testing and 4 weeks after receiving an intervention. HCVR slope at 4 weeks after receiving an intervention compared to the baseline HCVR slope in each group.
Time frame: At baseline and 4 weeks after receiving an intervention
A total of 30 subjects enrolled from February 2017 to February 2019. These 30 subjects underwent further screening before randomization to an intervention. Eight of the subjects failed to meet eligibility for randomization to an intervention, hence only 22 participants were randomized equally (1:1) to one of the treatment arms.
| Milestone | Treatment | Control |
|---|---|---|
| Started | 11 | 11 |
| Completed | 11 | 11 |
| Not completed | 0 | 0 |
Number of participants enrolled every 3 months.
| participants/3 months | Recruitment |
|---|---|
| Study Recruitment Rate | 3.8 (0 to 6) |
Number of participants completing the study every 3 months.
| participants/3 months | Fluoxetine | Placebo |
|---|---|---|
| Study Retention Rate | 1.2 (0 to 4) | 1.1 (0 to 3) |
Minute ventilation was evaluated at baseline HCVR testing and HCVR testing at 4 weeks after receiving an intervention. Change from baseline was calculated.
| Liters/minute (L/min) | Fluoxetine | Placebo |
|---|---|---|
| Change in Minute Ventilation During Hypercapnic Ventilatory Response (HCVR) Testing | 1.739 (-2.991 to 6.469) | 2.758 (-2.955 to 8.470) |
Patient Health Questionnaire (PHQ-9) was used to evaluate mood. Score on PHQ-9 scale ranges from 0-27. Scores corresponding to severity of depression: 0-4: minimal to none ; 5-9: mild; 10-14: moderate; 15-19 moderately severe; 20-27: severe. All subjects in the study were interviewed using standard questions per PHQ-09 questionnaire at baseline and 4 weeks after randomization to an intervention.
| score on a scale | Fluoxetine | Placebo |
|---|---|---|
| Change in PHQ-9 Score. | 0.455 (-4.309 to 5.218) | -1.000 (-4.194 to 2.194) |
All the subjects undergo CO2 rebreathing (HCVR) testing at baseline and 4 weeks after receiving an intervention. During CO2 rebreathing (HCVR) testing, CO2 gradually rise in the body that stimulates breathing, which in turn increases minute ventilation (L/min). The rate of this increase in minute ventilation with each mm Hg rise in CO2 is the HCVR slope, which is calculated for baseline testing and 4 weeks after receiving an intervention. HCVR slope at 4 weeks after receiving an intervention compared to the baseline HCVR slope in each group.
| Liters/minute/mm Hg (L/min/mm Hg) | Fluoxetine | Placebo |
|---|---|---|
| Change in Slope of HCVR | -0.049 (-0.511 to 0.412) | 0.072 (-0.686 to 0.830) |
Collected over Adverse events were monitored and collected after randomization up to 7 weeks from study drug initiation or study dropout which ever was closer.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Fluoxetine | 0/11 (0%) | 0/11 (0%) | 1/11 (9.1%) |
| Placebo | 0/11 (0%) | 0/11 (0%) | 0/11 (0%) |
| Event | Fluoxetine | Placebo |
|---|---|---|
| Moderate, probably relatedNervous system disorders | 1/11 | 0/11 |
| Age, Categorical(Participants) | Treatment | Control | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 11 | 11 | 22 |
| >=65 years | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | Treatment | Control | Total |
|---|---|---|---|
| Female | 1 | 4 | 5 |
| Male | 10 | 7 | 17 |
| Race (NIH/OMB)(Participants) | Treatment | Control | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 11 | 11 | 22 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Treatment | Control | Total |
|---|---|---|---|
| United States | 11 | 11 | 22 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: No
This study is completed, as verified in Apr 2020. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.