Clinical trial NCT05470465: Effect of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation
Official title: Clinical Study to Investigate the Effect of Administration of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypercapnia
Ventilatory Depression
Lead sponsor: Food and Drug Administration (FDA)
Sponsor class: FED
Collaborators: name: Spaulding Clinical Research LLC
name: Leiden University
First posted: 2022-07-22
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a 3-period, double-blind, randomized crossover study. The duration of each treatment period will be 21 days in addition to a three-week washout between periods. The duration of study participation will be 106 days (excluding the screening period).
Primary purpose: OTHER

Brief summary: This study is designed to evaluate the effects of the coadministration of paroxetine or escitalopram with an opioid on ventilation. Ventilation will be assessed using a rebreathing methodology. This study will evaluate chronic and acute dosing of paroxetine and escitalopram combined with an opioid as well as chronic and acute dosing of the two drugs without coadministration of an opioid.

This study is a 3-period, randomized, placebo-controlled crossover study conducted with 25 healthy participants. Each participant will receive each of the 3 treatments (placebo/oxycodone, paroxetine/oxycodone, escitalopram/oxycodone) in a randomized order.

Detailed description: This study is designed to evaluate the effects of the coadministration of paroxetine or escitalopram, two selective serotonin reuptake inhibitors (SSRI), with an opioid on hypercapnic ventilation. Hypercapnic ventilation will be assessed under both hyperoxic and hypoxic conditions using the Duffin rebreathing method. This method allows for critical physiological measurements and thresholds to be captured that can then be used to model the effects of drugs when there are dynamic changes in oxygen partial pressure (PO2) and carbon dioxide partial pressure (PCO2), such as during a real-world opioid overdose.

SSRIs take approximately 3 weeks to reach maximal therapeutic effect, which correlates with the time required for pre-synaptic inhibitory serotonergic receptors to desensitize. Therefore, drug-effects on ventilation should be evaluated under steady state conditions.

This study is randomized, placebo-controlled crossover study which includes three 21-day periods conducted with 25 healthy participants. Participants will receive each of the 3 treatments (placebo/oxycodone, paroxetine/oxycodone, or escitalopram/oxycodone) in a randomized order. Paroxetine dosing will range from 40-60 mg once daily (QD) and escitalopram dosing will range from 20-30 mg QD. Subjects will receive 10 mg oxycodone on three different days each period. Subjects will undergo 6 days of rebreathing and time-matched pupillary assessments along with 3 separate days of ECG assessments each period. Additionally, blood samples will be collected for determination of plasma concentrations for each study drug on days with rebreathing and ECG assessments.

Eligibility criteria: Inclusion Criteria:

1. Subject signs an Institutional Review Board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed.
2. Subject is a healthy, non-smoking man or woman, 18 to 50 years of age, inclusive, who has a body mass index of 18.5 to 33.0 kg/m2, inclusive, at Screening.
3. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, pulse oximetry, 12-lead ECG results, and physical examination findings at screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
4. Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in days.
5. Subject must test negative for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a rapid antigen test at check-in for all study periods. If a subject's test comes back as invalid, the test can be repeated.
6. Female subjects must be of non-childbearing potential (confirmed with follicle-stimulating hormone levels \> 40 milli-international unit \[mIU\]/mL) or, if they are of childbearing potential, they must: 1) have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 2) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before check-in (Day -1) until at least 1 month after the end of the study.
7. Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee) from at least 1 month before check-in (Day -1) until at least 1 month after the last dose of study drug.
8. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

Exclusion Criteria:

1. Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug. This includes prescription or nonprescription ophthalmic drugs.
2. Subject is currently participating in another clinical study of an investigational drug or has been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of the compound.
3. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, electronic cigarettes) within 6 weeks of Screening. Subjects must refrain from using these throughout the study.
4. Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, cola), caffeine, grapefruit, or grapefruit juice within 24 h of check-in. Subjects must refrain from ingesting these throughout the study.
5. Subject has a history or evidence of a clinically significant disorder, condition, or disease (e.g., cancer, human immunodeficiency virus \[HIV\], hepatic or renal impairment) that, in the opinion of the investigator would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. This includes subjects with any underlying medical conditions that put subjects at increased risk of severe illness from coronavirus disease 2019 (COVID-19) based on the Centers for Disease Control and Prevention (CDC) guidelines.
6. Subject has any signs or symptoms at screening or check-in of any study periods that are consistent with COVID-19. Per current CDC recommendations this includes subjects with the symptoms cough or shortness of breath or difficulty breathing, or at least two of the following symptoms: fever, chills, repeated shaking with chills, muscle pain, headache, sore throat or new loss of taste/smell. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator.
7. Subject has known or suspected allergies or sensitivities to any study drugs.
8. Subject has clinical laboratory test results (hematology, serum chemistry and urinalysis) at Screening or period check-in that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator. Clinical laboratory results may be repeated once, as needed, for confirming results at Screening and period check-in.
9. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
10. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.
11. Female subject is currently pregnant or lactating or was within 3 months of before enrollment.
12. Subject has a history of opioid or psychotropic drugs within 60 days of the start of the study.
13. Subject has a history of asthma that has required medication within the last five years.
14. Subject has non-reactive or misshapen pupil(s) or damaged orbit structure or surrounding soft tissue is edematous or has an open lesion.
15. Subject has a Mallampati score of \>2.
16. Subject's Duffin rebreathing data is of poor quality or subject does not agree to remain clean-shaven for all days when the Duffin rebreathing procedure is performed.
17. Subject has a history of sleep disorders, Panic disorders, Panic Attacks, Generalized Anxiety Disorder, or any associated Diagnostic and Statistical Manual of Mental Disorders diagnosis or condition.
18. Subject has a history of or currently has hypoventilation syndrome or sleep apnea and is on non-invasive ventilation.
19. Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, Torsades de Pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will be also excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative to cardiac causes at a young age) or Brugada syndrome.
20. Subject has a history of suicidal ideation or previous suicide attempts.
21. Subject has a safety 12-lead ECG result at Screening or check-in at any study period with evidence of any of the following abnormalities:

    * QTc using Fridericia correction (QTcF)\>430 msec
    * PR interval\>220 msec or \<120msec
    * QRS duration\>110 msec
    * Second- or third-degree atrioventricular block
    * Complete left or right bundle branch block or incomplete right bundle branch block
    * Heart rate \<50 or \>90 beats per minute
    * Pathological Q-waves (defined as Q-wave\>40 msec)
    * Ventricular pre-excitation
22. Subject has a skin condition likely to compromise ECG electrode placement.
23. Any individual with breast implants.

Primary outcomes:
measure: Minute Ventilation at 55mm Hg End Tidal CO2 (VE55) Under Hyperoxic Conditions on Day 21
timeFrame: 5 hours on day 21
measure: VE55 Under Hyperoxic Conditions on Day 20
timeFrame: 5 hours on day 20
Secondary outcomes:
measure: VE55 Under Hyperoxic Conditions on Day 6
timeFrame: 5 hours on day 6
measure: VE55 Under Hyperoxic Conditions on Day 12
timeFrame: 5 hours on day 12
measure: VE55 Under Hyperoxic Conditions on Day 5
timeFrame: 5 hours on day 5
measure: VE55 Under Hyperoxic Conditions on Day 11
timeFrame: 5 hours on day 11
Other outcomes:
Locations:
city: West Bend
country: United States
facility: Spaulding Clinical Research
state: Wisconsin
Study officials:
affiliation: Spaulding Clinical Research LLC
name: Jan Matousek, D.O.
role: PRINCIPAL_INVESTIGATOR
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