Reversing opioid-induced breathing problems with naloxone

Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists - a Study in Opioid naïve Individuals and Chronic Opioid Users Under Real-life Conditions

This study tests if different ways of giving naloxone can help people with breathing problems caused by opioid overdoses, including both healthy volunteers and those who use opioids regularly.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: Leiden University Medical Center (Academic / other)
• Locations: 1 site (Leiden, South Holland)
• Trial ID: NCT05338632 on ClinicalTrials.gov

What this trial studies

This study investigates the effectiveness of intranasal and intravenous naloxone and nalmefene in reversing respiratory depression caused by opioids like fentanyl and sufentanil. It involves healthy volunteers and chronic opioid users, assessing how these medications can restore normal breathing and pupil response during opioid overdose situations. The study aims to develop optimized dosing recommendations for naloxone in clinical and out-of-hospital settings. It employs an open-label, randomized, crossover design to gather comprehensive pharmacokinetic and pharmacodynamic data.

Who should consider this trial

Good fit: Ideal candidates include healthy individuals aged 18-55 and chronic opioid users aged 18-55 who meet specific health criteria.

Not a fit: Patients with severe comorbid conditions or those outside the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved treatment protocols for opioid overdose, potentially saving lives by enhancing the effectiveness of naloxone.

How similar studies have performed: Other studies have shown promising results with naloxone in reversing opioid effects, but this specific approach is novel in its detailed pharmacokinetic modeling.

Eligibility 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 70 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, 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;

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 70 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;

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 or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration;
5. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
6. 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;
7. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
8. History or presence of allergic response to fentanyl, sufentanil or naloxone;
9. 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;
10. 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;
11. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study;

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. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
6. 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;
7. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
8. History or presence of allergic response to study medication;
9. 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.
10. Estimated glomerular filtration rate \<60 mL/min as estimated by the CKD-EPI equation;
11. Anemia at screening or donation of \> 250 mL of blood or plasma within the last 3 months;
12. Positive serology tests for HIV, acute hepatitis B, or acute hepatitis C (OT patients with asymptomatic hepatitis B or C infection may be enrolled);
13. AST or ALT levels \>3.0 times the upper limit of normal at screening;
14. 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;
15. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.

Where this trial is running

Leiden, South Holland

• Leiden University Medical Center — Leiden, South Holland, Netherlands (Recruiting)

Study contacts

• Principal investigator: Rutger van der Schrier, MD — Lumc
• Study coordinator: Rutger van der Schrier, MD

Conditions Opioid Induced Respiratory Depression; Chronic Opioid Use; Reversal of opioid induced respiratory depression; Intranasal naloxone