EpilepsyPhase 2NCT02929667
Abnormal Ventilatory Response to Carbon Dioxide: a Potential Biomarker for Seizure Induced Respiratory Depression & Modification by SSRI
A Phase 2 study testing Fluoxetine in people with Epilepsy and SUDEP, run by Rup Kamal Sainju at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- What is being tested?
- Fluoxetine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 2 sitesUnited States
- Study dates
- 16 Feb 2017to 6 Mar 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult patients aged 18 or older
- Patients with epilepsy
- Native English speaker or adequate fluency in English to provide informed consent.
- Female patients of child-bearing potential must be using an acceptable method of contraception, and willing to refrain from sexual intercourse during the study.
Who cannot join
- Progressive neurological disease.
- Clinical diagnosis of bipolar disease, panic disorder, psychosis or severe depression, or PHQ-9 score > 20
- Patients with prior hospitalization related to depression or Electroconvulsive therapy.
- History of suicidal ideation or intent in past or present
- Clinical history or laboratory evidence of hepatic or renal insufficiency.
- Pregnant or lactating women.
Show all 16Show fewer
- Current heavy alcohol use (>14 drinks per week for men or >7 drinks per week for women) or) known medical disorder related to alcohol use or current illicit drug use, other than marijuana and its derivatives.
- Patients with recent use (<1 month) or already taking fluoxetine or other selective serotonin reuptake inhibitors (SSRIs).
- Concurrent use of monoamine oxidase inhibitors, antipsychotic agents, antidepressant agents other than SSRIs or frequent use of triptan agents (>2/week).
- History of a previous allergic reaction or adverse effects with fluoxetine, hypersensitive reaction-anaphylaxis; laryngeal edema; hives
- History of serotonin syndrome.
- History of uncontrolled pulmonary or cardiac illness.
- Patients with hypercapnic ventilatory response (HCVR) slope of > 2.0
- Patients with known prolong QT interval
- Patients with family history of prolong QT interval
- Patients with family history of sudden cardiac death under the age of 40 in a first degree relative.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
The Univeristy of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
Univeristy of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
About this study
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.
Read the 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.
- Being tested
- Fluoxetine, Placebo
- Keywords
- Fluoxetine
- Medical subject headings
- Epilepsy, Sudden Unexpected Death in Epilepsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FluoxetineDrug
Also called Prozac
Standard 6 weeks titration, starting 10 mg per day.
PlaceboDrug
Standard 6 weeks titration.
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Active comparator | 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. Receives: Drug: Fluoxetine |
| Control | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Study Recruitment Rate
Number of participants enrolled every 3 months.
Measured: From the date of enrollment every 3 months up to 2 years
Study Retention Rate
Number of participants completing the study every 3 months.
Measured: From date of enrollment until either completion of study or lost to follow up every 3 months up to 2 years and 3 months
Secondary outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: At baseline and 4 weeks after receiving an intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Oct 2016 (estimated)
- Study start16 Feb 2017
- Primary completion6 Mar 2019
- Study completion6 Mar 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for EpilepsyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rup Kamal Sainju
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Rup Kamal Sainju, University of Iowa
- Investigators
- Rup Sainju, Principal investigator, University of Iowa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02929667
- Sponsor's protocol ID
- 201607761
- Status last verified
- Apr 2020
- First submitted
- 26 Jul 2016
- Last updated
- 4 May 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Abnormal Ventilatory Response to Carbon Dioxide: a Potential Biomarker for Seizure Induced Respiratory Depression & Modification by SSRI
- ClinicalTrials.gov ID
- NCT02929667
- Acronym / sponsor ID
- 201607761
- Keywords
- Fluoxetine
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Rup Kamal SainjuUniversity, hospital or other
- Study start
- 16 Feb 2017 (actual)
- Primary completion
- 6 Mar 2019 (actual)
- Study completion
- 6 Mar 2019 (actual)
- First posted
- 11 Oct 2016 (estimated)
- Results
- Posted 4 May 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment | Active comparator | Drug: FluoxetineSubjects 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. |
| Control | Placebo comparator | Drug: PlaceboSubjects 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Adult patients aged 18 or older
- Patients with epilepsy
- Native English speaker or adequate fluency in English to provide informed consent.
- Female patients of child-bearing potential must be using an acceptable method of contraception, and willing to refrain from sexual intercourse during the study.
Key exclusion criteria (16 listed)
- Progressive neurological disease.
- Clinical diagnosis of bipolar disease, panic disorder, psychosis or severe depression, or PHQ-9 score > 20
- Patients with prior hospitalization related to depression or Electroconvulsive therapy.
- History of suicidal ideation or intent in past or present
- Clinical history or laboratory evidence of hepatic or renal insufficiency.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FluoxetineAlso: ProzacStandard 6 weeks titration, starting 10 mg per day. | Drug | Treatment |
| PlaceboStandard 6 weeks titration. | Drug | Control |
Primary outcome
Study Recruitment Rate
Time frame: From the date of enrollment every 3 months up to 2 years
Number of participants enrolled every 3 months.
Study Retention Rate
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
Number of participants completing the study every 3 months.
3 secondary outcomes
Change in Minute Ventilation During Hypercapnic Ventilatory Response (HCVR) Testing
Time frame: At the end of HCVR testing- at baseline and 4 weeks after receiving an intervention
Change in PHQ-9 Score.
Time frame: At baseline and 4 weeks after randomization to an intervention
Change in Slope of HCVR
Time frame: At baseline and 4 weeks after receiving an intervention
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 May 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rup Sainju principal investigator
University of Iowa
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Fluoxetine in people with Epilepsy and SUDEP, run by Rup Kamal Sainju at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 May 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 May 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Study Recruitment Rate (time frame: From the date of enrollment every 3 months up to 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2020; AzTrials last refreshed its copy on 2 Nov 2026.