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

NCT05470465 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SCR-012
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypercapnia; Ventilatory Depression

Outcome Measures

Primary Outcomes (2)

• Minute Ventilation at 55mm Hg End Tidal CO2 (VE55) Under Hyperoxic Conditions on Day 21

  Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 21.

  5 hours on day 21

• VE55 Under Hyperoxic Conditions on Day 20

  Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 20.

  5 hours on day 20

Secondary Outcomes (4)

• VE55 Under Hyperoxic Conditions on Day 6

  5 hours on day 6

• VE55 Under Hyperoxic Conditions on Day 12

  5 hours on day 12

• VE55 Under Hyperoxic Conditions on Day 5

  5 hours on day 5

• VE55 Under Hyperoxic Conditions on Day 11

  5 hours on day 11

Study Arms (3)

Treatment A: Placebo

PLACEBO COMPARATOR

Participants will receive placebo on days 1-21 for this treatment period. Oxycodone will be administered on days 6, 12, and 21 of this treatment period.

Drug: Placebo and Oxycodone

Treatment B: Paroxetine

EXPERIMENTAL

Participants will receive paroxetine on days 1-21 for this treatment period. Oxycodone will be administered on days 6, 12, and 21 of this treatment period.

Drug: Paroxetine and Oxycodone

Treatment C: Escitalopram

EXPERIMENTAL

Participants will receive escitalopram on days 1-21 for this treatment period. Oxycodone will be administered on days 6, 12, and 21 of this treatment period.

Drug: Escitalopram and Oxycodone

Interventions

Placebo and Oxycodone DRUG

Participants will receive placebo on days 1-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.

Treatment A: Placebo

Paroxetine and Oxycodone DRUG

Participants will receive 40 mg paroxetine (2 x 20 mg tablets) on days 1-6 and 60 mg paroxetine (3 x 20 mg tablets) on days 7-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.

Treatment B: Paroxetine

Escitalopram and Oxycodone DRUG

Participants will receive 20 mg escitalopram (2 x 10 mg tablets) on days 1-6 and 30 mg escitalopram (3 x 10 mg tablets) on days 7-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.

Treatment C: Escitalopram

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.
• 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).
• Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in days.
• 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.
• 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.
• 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.
• Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

You may not qualify if:

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Subject has known or suspected allergies or sensitivities to any study drugs.
• 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.
• Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
• Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.
• Female subject is currently pregnant or lactating or was within 3 months of before enrollment.
• Subject has a history of opioid or psychotropic drugs within 60 days of the start of the study.
• Subject has a history of asthma that has required medication within the last five years.
• Subject has non-reactive or misshapen pupil(s) or damaged orbit structure or surrounding soft tissue is edematous or has an open lesion.
• Subject has a Mallampati score of \>2.

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• Spaulding Clinical Research LLC: collaborator
• Leiden University: collaborator

Study Sites (1)

Spaulding Clinical Research

West Bend, Wisconsin, 53095, United States

Location

Related Publications (13)

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MeSH Terms

Conditions

Hypercapnia; Respiratory Insufficiency

Interventions

Oxycodone; Paroxetine; Escitalopram

Condition Hierarchy (Ancestors)

Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Codeine; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Piperidines; Heterocyclic Compounds, 1-Ring; Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring

Limitations and Caveats

A limitation of this study was that the breathing assessments were conducted in a controlled experimental setting with healthy volunteers which may not be representative of actual at-risk individuals having an overdose. However, the methods used provide a safe way to assess ventilatory effects of drugs as carbon dioxide levels increase, which reflects the physiology of severe respiratory depression.

Results Point of Contact

• Title: Jeffry Florian
• Organization: U.S. Food and Drug Administration

Jeffry.Florian@fda.hhs.gov

301-796-4847

Study Officials

• Jan Matousek, D.O.

  Spaulding Clinical Research LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be double-blind, and the blind will be maintained through a randomization schedule held by the dispensing pharmacist. Treatments (escitalopram, paroxetine, or placebo) will be over-encapsulated. The pharmacist (and designated staff member responsible for confirmation of study drug dose) will be unblinded to subject treatment assignment; however, the pharmacist will not perform any study procedures other than study drug preparation and dispensing.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: July 14, 2022
• First Posted: July 22, 2022
• Study Start: September 1, 2022
• Primary Completion: September 17, 2023
• Study Completion: September 17, 2023
• Last Updated: May 22, 2025
• Results First Posted: May 22, 2025

Record last verified: 2025-05

Locations

US (1)