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

Phase 1

Completed

Conditions: Hypercapnia
Ventilatory Depression

Interventions: Drug: Oxycodone, Paroxetine, and Quetiapine
Drug: Oxycodone and Midazolam

Registration Number: NCT04310579

Lead Sponsor: Food and Drug Administration (FDA)

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.

Detailed Description: Opioids can cause respiratory/ventilatory depression, and this can be exacerbated when opioids are co-administered with benzodiazepines. Research suggests this is caused by a reduced respiratory/ventilatory response to counteract increasing levels of systemic carbon dioxide (CO2). It is unknown whether certain other sedative psychotropic drugs can exacerbate opioid-induced respiratory/ventilatory depression. Studies were conducted to evaluate the effects of selected drugs in a non-clinical model. This clinical study will evaluate two drugs (quetiapine and paroxetine) that caused an effect when combined with oxycodone in the non-clinical model.

Study designs were evaluated that would allow a safe and controlled assessment of the effects of drug combinations on respiratory/ventilatory depression and a methodology was selected called the Read breathing procedure which introduces increased levels of CO2 to cause study participants to increase ventilation by having study participants rebreathe through a circuit with 93% oxygen (O2) and 7% CO2. Previous studies have shown this "hypercapnic ventilatory 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 respiration/ventilation when study participants are going about normal activities breathing room air, however ventilation is decreased relative to the expected increase in ventilation as CO2 levels are increased during rebreathing. Thus, there is minimal risk of true respiratory depression (i.e. inadequate gas exchange) and, if needed, the investigators can immediately halt the experiment and have the study participant breathe room air or 100% O2.

Using the Read rebreathing methodology, the current clinical study was designed to generate data characterizing changes in the ventilatory response to hypercapnia when administering quetiapine and paroxetine alone or in combination with oxycodone. Information obtained from this study will inform on the potential for the specific studied drugs to affect ventilation when combined with an opioid and may also demonstrate the utility of this study design and methodology as an approach for evaluating the effect of an investigational drug and drug combinations on ventilatory depression. Thus, this study includes a lead-in reproducibility phase to quantify the intra- and inter-subject variability within a day and between days. In addition, this study includes a positive control phase with relatively low doses of opioid (oxycodone) alone, benzodiazepine (midazolam) alone and their combination to help assess assay sensitivity. While opioids and benzodiazepines have been studied alone and in combination with the rebreathing method previously, many of these studies are older and it is important to define the reproducibility and effects of the drugs at relatively low doses. Together, these components of the study will further define the reproducibility and sensitivity of the methodology that could be applied to a broader range of investigational drugs in the future to assess their safety when combined with opioids.

In addition, pupillary measurements have been used to study the pharmacodynamic effects of opioids and opioid antagonists (Skulberg et al, 2018; Rollins et al, 2014) and there has been interest in expanding its use in clinical studies. However, there are limited data directly comparing pupillary changes to ventilatory changes and some drugs may influence the pupillary response to opioids (Kummer et al, 2011). As an exploratory endpoint, this study will 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 quantify the intra- and inter-subject variability of the Read Rebreathing methodology within a day and between days. Part 1 is a positive control phase with doses of an opioid (oxycodone) alone, benzodiazepine (midazolam) alone, their combination, and placebo to help assess ability of the procedure to detect changes in ventilation. Part 2 will assess whether two sedative psychotropic drugs (quetiapine and paroxetine), selected due to their effects in a nonclinical model, decrease the ventilatory response to hypercapnia compared to an opioid (oxycodone) alone. The doses of oxycodone and midazolam were selected to be less than those previously administered in healthy volunteers undergoing the Read Rebreathing or similar respiratory circuit procedures that increase the inspired level of CO2. The doses of quetiapine and paroxetine were selected to reach clinical steady-state levels.

The Lead-In Reproducibility Phase will have up to 10 healthy volunteer participants enrolled in two cohorts of approximately five. Participants will perform the Read Rebreathing procedure five times on day 1 and five times on day 2.

Part 1 will be a 4-period randomized crossover study with approximately 20 healthy volunteer participants. Participants will receive four different treatments (oxycodone, midazolam, oxycodone + midazolam, and placebo) in a random order across each of the 1-day study periods. There will be two days of washout between each period. During each period, participants will perform the Read Rebreathing procedure seven times, for a total of 28 rebreathing assessments in Part 1. For Part 1, blood samples will also be collected for determination of study drug concentration.

Part 2 will be a 3-period randomized crossover study with approximately 20 healthy volunteer participants. Participants will receive three different treatments (oxycodone, oxycodone + quetiapine, and oxycodone + paroxetine) in a random order across each of the 5-day periods. Oxycodone will only be administered on day 1 and day 5 of each treatment period. The other drugs will be administered every day of the treatment period such that there will be lower concentrations on day 1 and higher concentrations on day 5, which are the days when oxycodone is co-administered. Read Rebreathing assessments will be performed on day 1 and day 5 to investigate the effect of paroxetine and quetiapine when combined with oxycodone compared to oxycodone alone. In addition, Read Rebreathing assessments will be performed on day 4 to determine the effect of paroxetine alone and quetiapine alone compared to placebo. There will be seven days of washout between each period. During each period, participants will perform the Read Rebreathing procedure 17 times, for a total of 51 rebreathing assessments in Part 2. For Part 2, blood samples will also be collected for determination of study drug concentration.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

Inclusion Criteria

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

Exclusion Criteria

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.
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.
Subject has a history of or currently has hypoventilation syndrome or sleep apnea and is on non-invasive ventilation.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Part 2 Oxycodone, Paroxetine, and Quetiapine	Oxycodone, Paroxetine, and Quetiapine	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 1 Oxycodone and Midazolam	Oxycodone and Midazolam	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.

Primary Outcome Measures

Name	Time	Method
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.	Part 1: 2 hour timepoint on treatment period Day 1	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 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.	Part 2: 5 hour timepoint on Day 1	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 - 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.	Part 2: 5 hour timepoint on Day 5	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.

Secondary Outcome Measures

Name	Time	Method
Part 2 - AUC of Oxycodone Alone vs. in Combination With Paroxetine or Quetiapine on Day 1	Part 2: Day 1 at 0 (pre-dose), 3, 4, 5, 6, 8, 9, 12, 24 hours	AUC will be calculated using noncompartmental methods for each treatment. Observations will be summarized using descriptive statistics.
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	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 oxycodone or midazolam alone compared to placebo 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 - 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	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, quetiapine, and placebo on Day 4 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 - 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	Cmax will be the maximum observed concentration for each treatment. Observations will be summarized using descriptive statistics.
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	Cmax will be the maximum observed concentration for each treatment. Observations will be summarized using descriptive statistics.
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	Cmax will be the maximum observed concentration for each treatment. Observations will be summarized using descriptive statistics.
Part 1 - Area Under the Plasma Concentration-time Curve (AUC) of Oxycodone Alone vs. in Combination With Midazolam	Part 1: Day 1 at 0 (pre-dose), 1, 2, 3, 4, 6, 8, 12, 24 hour	AUC will be calculated using noncompartmental methods for each treatment. Observations will be summarized using descriptive statistics.
Part 2 - AUC of Oxycodone Alone vs. in Combination With Paroxetine or Quetiapine on Day 5	Part 2: Day 5 on 0 (pre-dose), 3, 4, 5, 6, 8, 9, 12, 24 hours	AUC will be calculated using noncompartmental methods for each treatment. Observations will be summarized using descriptive statistics.