Treatment of respiratory depression from opioids in healthy volunteers and opioid users

Phase 1

• Conditions: Pain in chronic opioid users; Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

• Registration Number: EUCTR2021-005373-51-NL
• Lead Sponsor: eiden University Medical Center

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-10-21
• Last Update Posted: 17 January 2022

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 24

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 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 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;
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 3 months 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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 24
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 12

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, >20 units/week of alcohol in men and >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 infor

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To describe the pharmacokinetics and pharmacodynamics of intranasal and intramuscular naloxone in its ability to reverse respiratory depression and miosis (important model parameters include C50, a measure of potency and t½ke0). ;Secondary Objective: 1. To describe the pharmacokinetics of intravenously administered fentanyl and sufentanil;<br>2. To describe the pharmacodynamics of intravenously administered fentanyl and sufentanil for respiratory depression and miosis (reduction of pupil size).<br>3. Finally, the results of these studies will allow us to perform simulation studies aimed at optimizing dosing regimens for intranasal and intramuscular naloxone in individuals that overdosed on fentanyl and sufentanil, with respiratory depression ranging from moderate to severe.<br>;Primary end point(s): Minute ventilation;Timepoint(s) of evaluation of this end point: Continuous over 3-4 hours

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): PKPD related parameters on ventilation and pupil diameter;Timepoint(s) of evaluation of this end point: Continuous over 3-4 h