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

Hypercapnia Clinical Trial

Official title:

Clinical Study to Investigate the Effect of Administration of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05470465
• Other study ID #: SCR-012
• Status: Completed
• Phase: Phase 1
• Start date: September 1, 2022
• Est. completion date: September 17, 2023

Study information

• Verified date: November 2023
• Source: Food and Drug Administration (FDA)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: September 17, 2023
• Est. primary completion date: September 17, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hypercapnia
• Respiratory Insufficiency
• Ventilatory Depression

Intervention

Drug:
• Placebo and Oxycodone
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.
• Paroxetine and Oxycodone
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.
• Escitalopram and Oxycodone
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.

Locations

Country	Name	City	State
United States	Spaulding Clinical Research	West Bend	Wisconsin

Sponsors (3)

Lead Sponsor	Collaborator
Food and Drug Administration (FDA)	Leiden University, Spaulding Clinical Research LLC

Country where clinical trial is conducted

United States, 

References & Publications (13)

Bertani A, Perna G, Arancio C, Caldirola D, Bellodi L. Pharmacologic effect of imipramine, paroxetine, and sertraline on 35% carbon dioxide hypersensitivity in panic patients: a double-blind, random, placebo-controlled study. J Clin Psychopharmacol. 1997 Apr;17(2):97-101. doi: 10.1097/00004714-199704000-00006. — View Citation

Casey K, Duffin J, McAvoy GV. The effect of exercise on the central-chemoreceptor threshold in man. J Physiol. 1987 Feb;383:9-18. doi: 10.1113/jphysiol.1987.sp016392. — View Citation

Czachura JF, Rasmussen K. Effects of acute and chronic administration of fluoxetine on the activity of serotonergic neurons in the dorsal raphe nucleus of the rat. Naunyn Schmiedebergs Arch Pharmacol. 2000 Sep;362(3):266-75. doi: 10.1007/s002100000290. — View Citation

Dong TW, MacLeod DB, Santoro A, Augustine Z, Barth S, Cooter M, Moon RE. A methodology to explore ventilatory chemosensitivity and opioid-induced respiratory depression risk. J Appl Physiol (1985). 2020 Sep 1;129(3):500-507. doi: 10.1152/japplphysiol.00460.2020. Epub 2020 Jul 16. — View Citation

Duffin J, McAvoy GV. The peripheral-chemoreceptor threshold to carbon dioxide in man. J Physiol. 1988 Dec;406:15-26. doi: 10.1113/jphysiol.1988.sp017365. — View Citation

Gorman JM, Browne ST, Papp LA, Martinez J, Welkowitz L, Coplan JD, Goetz RR, Kent J, Klein DF. Effect of antipanic treatment on response to carbon dioxide. Biol Psychiatry. 1997 Dec 1;42(11):982-91. doi: 10.1016/s0006-3223(97)00160-1. — View Citation

Nutt DJ, Forshall S, Bell C, Rich A, Sandford J, Nash J, Argyropoulos S. Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Eur Neuropsychopharmacol. 1999 Jul;9 Suppl 3:S81-6. doi: 10.1016/s0924-977x(99)00030-9. — View Citation

Read DJ. A clinical method for assessing the ventilatory response to carbon dioxide. Australas Ann Med. 1967 Feb;16(1):20-32. doi: 10.1111/imj.1967.16.1.20. No abstract available. — View Citation

Rebuck AS. Measurement of ventilatory response to CO2 by rebreathing. Chest. 1976 Jul;70(1 Suppl):118-21. doi: 10.1378/chest.70.1_supplement.118. No abstract available. — View Citation

Robillard R, Saad M, Ray LB, BuJaki B, Douglass A, Lee EK, Soucy L, Spitale N, De Koninck J, Kendzerska T. Selective serotonin reuptake inhibitor use is associated with worse sleep-related breathing disturbances in individuals with depressive disorders and sleep complaints: a retrospective study. J Clin Sleep Med. 2021 Mar 1;17(3):505-513. doi: 10.5664/jcsm.8942. — View Citation

van der Schrier R, Jonkman K, van Velzen M, Olofsen E, Drewes AM, Dahan A, Niesters M. An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers. Br J Anaesth. 2017 Dec 1;119(6):1169-1177. doi: 10.1093/bja/aex295. — View Citation

van der Schrier R, Roozekrans M, Olofsen E, Aarts L, van Velzen M, de Jong M, Dahan A, Niesters M. Influence of Ethanol on Oxycodone-induced Respiratory Depression: A Dose-escalating Study in Young and Elderly Individuals. Anesthesiology. 2017 Mar;126(3):534-542. doi: 10.1097/ALN.0000000000001505. — View Citation

Xu L, Krishna A, Stewart S, Shea K, Racz R, Weaver JL, Volpe DA, Pilli NR, Narayanasamy S, Florian J, Patel V, Matta MK, Stone MB, Zhu H, Davis MC, Strauss DG, Rouse R. Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat. Clin Transl Sci. 2021 Nov;14(6):2208-2219. doi: 10.1111/cts.13080. Epub 2021 Jun 16. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	VE55 under hyperoxic conditions on day 6	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 6.	5 hours on day 6
Secondary	VE55 under hyperoxic conditions on day 12	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 12.	5 hours on day 12
Secondary	VE55 under hyperoxic conditions on day 5	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 5.	5 hours on day 5
Secondary	VE55 under hyperoxic conditions on day 11	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 11.	5 hours on day 11