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

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

Interventions

DRUG

Oxycodone and Midazolam

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.

DRUG

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.

Sponsors & Collaborators

• Spaulding Clinical Research LLC

  collaborator OTHER

• Leiden University

  collaborator OTHER

• Food and Drug Administration (FDA)

  lead FED

Principal Investigators

• Carlos Sanabria, MD · Spaulding Clinical Research LLC

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

QUADRUPLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

50 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2020-06-15

Primary Completion

2021-05-25

Completion

2021-05-25

FDA Drug

Yes

Countries

• United States

Study Locations