Effect of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation

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.