Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists

• Status: Not yet recruiting
• Trial end date: 2024-05-30
• Target enrollment: 0
• Participant gender: All

Summary

In this pharmacokinetic/pharmacodynamic modelling study we will determine the ability of intranasal and intramuscular naloxone to reverse opioid (fentanyl and sufentanil)- induced respiratory depression in healthy volunteers and chronic opioid users to develop dosing recommendations in case of opioid-induced respiratory depression from an opioid overdose in clinical practice and in the out-of-hospital overdose.

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

Details

• Lead Sponsor: Leiden University Medical Center
• Collaborator: U.S. Food and Drug Administration (FDA)
• Treatments: Naloxone

Criteria

Inclusion Criteria:

Healthy volunteers

1. Signed the informed consent form (ICF) and able to comply with the study requirements and restrictions listed therein;

2. Male and female subjects, age 18 to 55 45 years, inclusive;

3. Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 month after the last dose of study drug;

4. Body Mass Index (BMI) 18 to 32 30 kg/m2, inclusive;

5. Healthy as defined by the Investigator, based on a medical evaluation that includes the subject's medical and surgical history, physical examination, vital signs, lab chemistry: estimated glomerular filtration rate >60 mL/min as estimated by the CKD-EPI equation, and AST or ALT levels < 3.0 times the upper limit of normal at screening, and negative serology tests for HIV, acute hepatitis B, or acute hepatitis C;

6. No history of substance use disorder;

7. No current use of any central nervous system (CNS) depressants prescribed or otherwise.

Chronic opioid users

1. Signed the consent form and able to comply with the requirements and restrictions listed therein;

2. Males or females age 18 to 55 years, inclusive;

3. Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 3 month after the last dose of study drug.

4. BMI 18 to 32 kg/m2, inclusive;

5. Opioid tolerant patients administered prescription opioids at daily doses ≥ 60 mg oral morphine equivalents (See Table 3);

6. Stable as defined by the Investigator, based on a medical evaluation that includes the subject's medical and surgical history, physical examination, vital signs, 12-lead ECG, hematology, and blood chemistry;

7. No current use of any CNS depressants, besides opioids, prescribed or otherwise for 5 half-lives of the product before first study drug administration.

Exclusion Criteria:

Healthy volunteers

1. Currently meet the criteria for diagnosis of substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria on any substance;

2. Any other active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;

3. Consume, on average, >27 20 units/week of alcohol in men and > 20 13 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);

4. Previous treatment with any prescribed medications or over-the-counter (OTC) medications (including homeopathic preparations, vitamins, and minerals) within 14 days or 5 half-lives (whichever is longer) prior to first study treatment administration;

5. Previous or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration;

6. Require on-going prescription or OTC medications that are clinically relevant CYP P450 3A4 or CYP P450 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]);

7. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;

8. History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;

9. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;

10. History or presence of allergic response to fentanyl, sufentanil or naloxone;

11. Subjects who have demonstrated allergic reactions (e.g., food, drug, atopic reactions or asthmatic episodes) which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial;

12. Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;

13. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study;

14. Require on-going prescription or over-the-counter medications that are clinically relevant CYP P450 3A4 or CYP P450 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]).

Chronic opioid users

1. Currently meet the criteria for diagnosis of moderate or severe substance use disorder according to the DSM-5 criteria on any substances other than opioids, caffeine, or nicotine;

2. Any active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;

3. Consume, on average, >27 units/week of alcohol in men and >20 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);

4. Currently receiving medication-assisted treatment for the treatment of opioid-use disorder;

5. Require on-going prescription or over-the-counter medications that are clinically relevant CYP P450 3A4 or CYP P450 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]);

6. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;

7. History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;

8. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;

9. History or presence of allergic response to study medication;

10. Opioid tolerant patients who have demonstrated allergic reactions (e.g., food, drug, atopic reactions or asthmatic episodes) which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial.

11. Estimated glomerular filtration rate <60 mL/min as estimated by the CKD-EPI equation;

12. Anemia at screening or donation of > 250 mL of blood or plasma within the last 3 months;

13. Positive serology tests for HIV, acute hepatitis B, or acute hepatitis C (OT patients with asymptomatic hepatitis B or C infection may be enrolled);

14. AST or ALT levels >3.0 times the upper limit of normal at screening;

15. Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;

16. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.