Clinical Study to Investigate the Effect of the Combination of Psychotropic Drugs and an Opioid on Ventilation

NCT04310579 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SCR-009
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

Opioids can decrease breathing and co-administration of benzodiazepines with opioids can further decrease breathing. It is unknown whether certain other drugs also decrease breathing when co-administered with opioids. The objective of this study is to determine whether certain drugs combined with an opioid decrease breathing compared to breathing with an opioid alone. In order to assess this, this study will utilize the Read Rebreathing method, where study participants breathe increased levels of oxygen and carbon dioxide. The increased levels of carbon dioxide cause the study participants to increase breathing. This increased breathing response can be decreased by opioids and benzodiazepines, and potentially other drugs. Using this procedure, low doses of opioids or benzodiazepines can be administered that have minimal-to-no effects on breathing when study participants are going about normal activities breathing room air, however breathing increases less than expected as carbon dioxide levels are increased. This study will also obtain quantitative pupillometry measurements before and after each rebreathing assessment to allow for comparisons of pupillary changes to ventilatory changes when subjects receive different drugs and drug combinations. This study includes three parts: A Lead-In Reproducibility Phase and two main parts (Part 1 and Part 2). The Lead-In Reproducibility Phase will measure the variability between study participants and between repeated uses of the method in the same study participant within a day and between days. Part 1 will study an opioid alone, benzodiazepine alone, and their combination to show the methodology will detect changes in breathing at low doses of the drugs that are known to affect breathing. Part 2 will assess whether two drugs, selected due to their effects on breathing in a nonclinical model, decrease the breathing response when combined with an opioid compared to when an opioid is administered alone.

Conditions

Hypercapnia; Ventilatory Depression

Keywords

Opioids; Sedative psychotropic drugs

Outcome Measures

Primary Outcomes (3)

• Part 1 - Minute Ventilation at the 55 mm Hg End Tidal Carbon Dioxide (CO2) Point (VE55) on Day 1 for Oxycodone Combined With Midazolam and Oxycodone Alone.

  VE55 was estimated by analyzing rebreathing data using linear regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2). Rebreathing data were reviewed by 2 independent assessors blinded to study treatment and time of assessments to evaluate completeness of data for study outcomes. Resulting VE55 data of midazolam combined with oxycodone vs. oxycodone alone was compared using a linear mixed effects model with baseline VE55 as a continuous variable; treatment, sequence, and period as categorical variables; and participant as a random effect. R software was used for all analyses.

  Part 1: 2 hour timepoint on treatment period Day 1

• Part 2 - Minute Ventilation at the 55 mm Hg End Tidal Carbon Dioxide (CO2) Point (VE55) on Day 1 for Paroxetine or Quetiapine Combined With Oxycodone and Oxycodone Alone.

  VE55 was estimated by analyzing rebreathing data using linear regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2). Rebreathing data were reviewed by 2 independent assessors blinded to study treatment and time of assessments to evaluate completeness of data for study outcomes. Resulting VE55 data of paroxetine or quetiapine combined with oxycodone vs. oxycodone alone on Day 1 was compared using a linear mixed effects model with baseline VE55 as a continuous variable; treatment, sequence, and period as categorical variables; and participant as a random effect. R software was used for all analyses.

  Part 2: 5 hour timepoint on Day 1

• Part 2 - Minute Ventilation at the 55 mm Hg End Tidal Carbon Dioxide (CO2) Point (VE55) on Day 5 for Paroxetine or Quetiapine Combined With Oxycodone and Oxycodone Alone.

  VE55 was estimated by analyzing rebreathing data using linear regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2). Rebreathing data were reviewed by 2 independent assessors blinded to study treatment and time of assessments to evaluate completeness of data for study outcomes. Resulting VE55 data of paroxetine or quetiapine combined with oxycodone vs. oxycodone alone on Day 5 was compared using a linear mixed effects model with baseline VE55 as a continuous variable; treatment, sequence, and period as categorical variables; and participant as a random effect. R software was used for all analyses.

  Part 2: 5 hour timepoint on Day 5

Secondary Outcomes (8)

• Part 1 - Minute Ventilation at the 55 mm Hg End Tidal Carbon Dioxide (CO2) Point (VE55) for Oxycodone, Midazolam, and Placebo.

  Part 1: 2 hour timepoint on Day 1

• Part 2 - Minute Ventilation at the 55 mm Hg End Tidal Carbon Dioxide (CO2) Point (VE55) on Day 4 for Paroxetine, Quetiapine, and Placebo

  Part 2: 5 hour timepoint on Day 4

• Part 1 - Maximum Observed Plasma Concentration (Cmax) of Oxycodone Alone vs. in Combination With Midazolam

  Part 1: Day 1 at 0, 1, 2, 3, 4, 6, 8, 12, 24 hour

• Part 2 - Cmax of Oxycodone Alone vs. in Combination With Paroxetine or Quetiapine on Day 1

  Part 2: Day 1 at 3, 4, 5, 6, 9, 12, 24 hour

• Part 2 - Cmax of Oxycodone Alone vs. in Combination With Paroxetine or Quetiapine on Day 5

  Part 2: Day 5 at 3, 4, 5, 6, 9, 12, 24 hour

Study Arms (3)

Lead-In

NO INTERVENTION

Read Rebreathing Reproducibility Assessment

Part 1 Oxycodone and Midazolam

ACTIVE COMPARATOR

In one period subjects receive oxycodone 10-15 mg immediate release (IR) tablets and intravenous (IV) placebo 1x per day. In a second period (randomized cross-over), subjects receive midazolam 0.0375-0.075 mg/kg IV and oral placebo tablet 1x per day. In a third period (randomized cross-over), subjects receive oxycodone 10-15 mg IR tablet and 0.0375-0.075 mg/kg midazolam IV 1x per day. In a fourth period (randomized cross-over), subjects receive oral placebo tablet and placebo IV 1x per day. Note: Initial doses of oxycodone will be 10 mg, but may be increased to 15 mg if necessary based on criteria specified in protocol. Initial doses of midazolam will be 0.0375 mg/kg but may be increased to 0.075 mg/kg based on criteria specified in protocol.

Drug: Oxycodone and Midazolam

Part 2 Oxycodone, Paroxetine, and Quetiapine

ACTIVE COMPARATOR

In one period, subjects receive: oxycodone 10-15 mg IR tablet 1x per day and oral placebo 3x per day on Days 1 and 5; and oral placebo 3x per day on Days 2-4. In a second period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, paroxetine 40 mg tablet 1x per day, and oral placebo 1x per day on Days 1 and 5; and paroxetine 40 mg tablet 1x per day and oral placebo 2x per day on Days 2-4. In a third period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, quetiapine 50 mg tablet 2x per day, and oral placebo 1x per day on Day 1; quetiapine 100 mg (2x50 mg tablets) 2x per day and oral placebo 1x per day on Day 2; quetiapine 150 mg (3x50 mg tablets) 2x per day and oral placebo 1x per day on Day 3; quetiapine 200 mg (4x50 mg tablets) 2x per day and oral placebo 1x per day on Day 4; and quetiapine 200 mg (4x50 mg tablets) 1x per day and oral placebo 1x per day on Day 5.

Drug: Oxycodone, Paroxetine, and Quetiapine

Interventions

Oxycodone and Midazolam DRUG

In one period subjects receive oxycodone 10-15 mg immediate release (IR) and placebo IV 1x per day. In a second period (randomized cross-over), subjects receive midazolam 0.0375-0.075 mg/kg IV and oral placebo tablet 1x per day. In a third period (randomized cross-over), subjects receive oxycodone 10-15 mg IR tablet and 0.0375-0.075 mg/kg midazolam IV 1x per day. In a fourth period (randomized cross-over), subjects receive oral placebo tablet and placebo IV 1x per day.

Part 1 Oxycodone and Midazolam

Oxycodone, Paroxetine, and Quetiapine DRUG

In one period, subjects receive: oxycodone 10-15 mg IR tablet 1x per day and oral placebo 3x per day on Days 1 and 5; and oral placebo 3x per day on Days 2-4. In a second period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, paroxetine 40 mg tablet 1x per day, and oral placebo 1x per day on Days 1 and 5; and paroxetine 40 mg tablet 1x per day and oral placebo 2x per day on Days 2-4. In a third period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, quetiapine 50 mg tablet 2x per day, and oral placebo 1x per day on Day 1; quetiapine 100 mg (2x50 mg tablets) 2x per day and oral placebo 1x per day on Day 2; quetiapine 150 mg (3x50 mg tablets) 2x per day and oral placebo 1x per day on Day 3; quetiapine 200 mg (4x50 mg tablets) 2x per day and oral placebo 1x per day on Day 4; and quetiapine 200 mg (4x50 mg tablets) 1x per day and oral placebo 1x per day on Day 5.

Part 2 Oxycodone, Paroxetine, and Quetiapine

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 man or woman, 18 to 50 years of age, inclusive, who has a body mass index of 18.5 to 29.9 kg/m2, inclusive, at Screening.
• Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead electrocardiogram (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 (Day -1).
• Subject has no known or suspected allergies or sensitivities to any of the study drugs.
• Female subjects must be of non-childbearing potential 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 1 month 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 last application of study drug.
• Male subjects must agree to practice 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 last application 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 history of opioid or psychotropic drug use within 60 days of the start of the study.
• 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 intubation score of \>2 (for Part 1 and 2 only).
• Subject Read Rebreathing data is of poor quality or subject does not agree to remain clean-shaven for all days when the Read Rebreathing procedure is being performed.
• Subject has used any prescription or nonprescription drugs (including aspirin or \[non-steroidal anti-inflammatory drugs\] 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.
• Subjects are currently participating in another clinical study of an investigational drug or are have 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) within 6 weeks of Screening.
• Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 48 h of dosing. Subjects must refrain from ingesting these throughout the study.
• Subject has a history of sleep disorders, Panic Disorder, Panic Attacks, Generalized Anxiety Disorder, or any associated Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis or condition.
• Subject has any underlying disease or surgical or medical condition (e.g., cancer, human immunodeficiency virus \[HIV\], severe hepatic or renal impairment) that could put the subject at risk or would normally prevent participation in a clinical study. This includes subjects with any underlying medical conditions that the Investigator believes would put subjects at increased risk of severe illness from COVID-19 based on the Centers for Disease Control and Prevention (CDC) guidelines. The CDC lists cancer, chronic kidney disease, chronic obstructive pulmonary disease, immunocompromised state from solid organ transplant, severe obesity, serious heart conditions, sickle cell disease, pregnancy, smoking and type 2 diabetes mellitus as conditions that put subjects at increased risk. Additionally, the CDC lists asthma (moderate-to-severe), cerebrovascular disease, cystic fibrosis, hypertension, immunocompromised state or immune deficiencies, neurologic conditions such as dementia, liver disease, pulmonary fibrosis, thalassemia, overweight, type 1 diabetes mellitus as conditions that might put subjects at increased risk.
• Subject has any signs or symptoms that are consistent with COVID-19 per CDC recommendations. These include subjects with fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhea may have COVID-19. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator.
• Subject tests positive for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a molecular diagnostic test performed prior to admission.
• Female subject is pregnant or lactating before enrollment in the study.
• Subject has known or suspected allergies or sensitivities to any study drug.
• Subject has clinical laboratory test results (hematology, serum chemistry) at Screening that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator.

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 (19)

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• 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.

  PMID: 28170358 BACKGROUND

• Xu L, Chockalingam A, Stewart S, Shea K, Matta MK, Narayanasamy S, Pilli NR, Volpe DA, Weaver J, Zhu H, Davis MC, Rouse R. Developing an animal model to detect drug-drug interactions impacting drug-induced respiratory depression. Toxicol Rep. 2020 Jan 25;7:188-197. doi: 10.1016/j.toxrep.2020.01.008. eCollection 2020.

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• Skulberg AK, Tylleskar I, Nilsen T, Skarra S, Salvesen O, Sand T, Loftsson T, Dale O. Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers. Eur J Clin Pharmacol. 2018 Jul;74(7):873-883. doi: 10.1007/s00228-018-2443-3. Epub 2018 Mar 22.

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• Gershuny V, Florian J, van der Schrier R, Davis MC, Salcedo P, Wang C, Burkhart K, Prentice K, Shah A, Racz R, Patel V, Matta M, Ismaiel O, Boughner R, Ford KA, Rouse R, Stone M, Sanabria C, Dahan A, Strauss DG. Effect of midazolam co-administered with oxycodone on ventilation: a randomised clinical trial in healthy volunteers. Br J Anaesth. 2025 Apr;134(4):1170-1180. doi: 10.1016/j.bja.2024.11.047. Epub 2025 Feb 21.

  PMID: 39986981 DERIVED

• Florian J, van der Schrier R, Gershuny V, Davis MC, Wang C, Han X, Burkhart K, Prentice K, Shah A, Racz R, Patel V, Matta M, Ismaiel OA, Weaver J, Boughner R, Ford K, Rouse R, Stone M, Sanabria C, Dahan A, Strauss DG. Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial. JAMA. 2022 Oct 11;328(14):1405-1414. doi: 10.1001/jama.2022.17735.

  PMID: 36219407 DERIVED

MeSH Terms

Conditions

Hypercapnia; Respiratory Insufficiency

Interventions

Oxycodone; Midazolam; Paroxetine; Quetiapine Fumarate

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; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Piperidines; Heterocyclic Compounds, 1-Ring; Dibenzothiazepines; Thiazepines; Thiepins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: David Strauss, MD, PhD
• Organization: U.S. Food and Drug Administration

David.Strauss@fda.hhs.gov

301-796-6323

Study Officials

• Carlos Sanabria, MD

  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 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. Subjects and staff will be blinded to treatment assignment. The blind will be maintained through a randomization schedule held by the dispensing pharmacist. Drugs will be over-encapsulated to maintain blinding during oral study drug administration.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: This clinical study consists of 3 parts: 1. Up to 10 subjects in the Lead-In reproducibility assessment will have no drug treatment, only Read Rebreathing assessments. 2. Approximately 20 subjects in Part 1 will be randomized to complete four treatments over four 1-day periods. Each period will be followed by 2 days of washout. Thus, Part 1 will have a cross-over component. 3. Approximately 20 subjects in Part 2 will be randomized to complete three treatments over three 5-day periods. Each period will be followed by 7 days of washout. Thus, Part 2 will have a cross-over component. A maximum of 10 additional replacement subjects may be enrolled.

Study Record Dates

• First Submitted: March 9, 2020
• First Posted: March 17, 2020
• Study Start: June 15, 2020
• Primary Completion: May 25, 2021
• Study Completion: May 25, 2021
• Last Updated: May 21, 2024
• Results First Posted: May 21, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

US (1)