Clinical Study to Investigate the Effect of the Combination of Psychotropic Drugs and an Opioid on Ventilation
Condition: Hypercapnia; Ventilatory Depression
MeSH terms: Respiratory Insufficiency; Hypercapnia
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Oxycodone and Midazolam; Oxycodone, Paroxetine, and Quetiapine
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Intervention MeSH terms: Midazolam; Oxycodone; Quetiapine Fumarate; Paroxetine
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This clinical study consists of 3 parts:
Up to 10 subjects in the Lead-In reproducibility assessment will have no drug treatment, only Read Rebreathing assessments.
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.
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Opioids; Sedative psychotropic drugs