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

• Status: Completed
• Trial end date: 2021-05-25
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Food and Drug Administration (FDA)
• Collaborators: Leiden University; Leiden University Medical Center; Spaulding Clinical Research LLC
• Treatments: Analgesics, Opioid; Midazolam; Oxycodone; Paroxetine; Psychotropic Drugs; Quetiapine Fumarate

Criteria

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 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.

3. 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).

4. Subject must have a negative test result for alcohol and drugs of abuse at Screening and Check-in (Day -1).

5. Subject has no known or suspected allergies or sensitivities to any of the study drugs.

6. 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.

7. 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.

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 history of opioid or psychotropic drug use within 60 days of the start of the study.

2. Subject has non-reactive or misshapen pupil(s) or damaged orbit structure or surrounding soft tissue is edematous or has an open lesion.

3. Subject has a Mallampati intubation score of >2 (for Part 1 and 2 only).

4. 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.

5. 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.

6. 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.

7. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening.

8. 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.

9. 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.

10. 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.

11. 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.

12. Subject tests positive for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a molecular diagnostic test performed prior to admission.

13. Female subject is pregnant or lactating before enrollment in the study.

14. Subject has known or suspected allergies or sensitivities to any study drug.

15. 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.

16. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.

17. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.

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