Abnormal Ventilatory Response to Carbon Dioxide: a Potential Biomarker for Seizure Induced Respiratory Depression & Modification by SSRI

NCT02929667 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 201607761
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

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.

Conditions

Epilepsy; SUDEP

Keywords

Fluoxetine

Outcome Measures

Primary Outcomes (2)

• Study Recruitment Rate

  Number of participants enrolled every 3 months.

  From the date of enrollment every 3 months up to 2 years

• Study Retention Rate

  Number of participants completing the study every 3 months.

  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

  At the end of HCVR testing- at baseline and 4 weeks after receiving an intervention

• Change in PHQ-9 Score.

  At baseline and 4 weeks after randomization to an intervention

• Change in Slope of HCVR

  At baseline and 4 weeks after receiving an intervention

Study Arms (2)

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.

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.

Drug: Placebo

Interventions

Fluoxetine DRUG

Standard 6 weeks titration, starting 10 mg per day.

Also known as: Prozac

Treatment

Placebo DRUG

Standard 6 weeks titration.

Control

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Rup Kamal Sainju: lead

Study Sites (2)

The Univeristy of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Univeristy of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

MeSH Terms

Conditions

Epilepsy; Sudden Unexpected Death in Epilepsy

Interventions

Fluoxetine

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Death, Sudden; Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals

Results Point of Contact

• Title: Dr. Rup Sainju
• Organization: University of Iowa

rup-sainju@uiowa.edu

319-356-4337

Study Officials

• Rup Sainju

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Assistant Professor of Neurology

Study Record Dates

• First Submitted: July 26, 2016
• First Posted: October 11, 2016
• Study Start: February 16, 2017
• Primary Completion: March 6, 2019
• Study Completion: March 6, 2019
• Last Updated: May 4, 2020
• Results First Posted: May 4, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)