Reversal of opioid-induced respiratory depression with opioid antagonists - a pharmacokinetic pharmacodynamic modeling study in opioid naïve individuals and chronic opioid users under real-life conditions

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Leids Universitair Medisch Centrum (LUMC)

Participant type

Healthy volunteers, Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Physiological processes [G07], Phenomena and Processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

Trial duration

15 Jun 2022 → 23 Mar 2026

Decision date (initial)

2024-11-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518041-16-00

EudraCT number

2021-005373-51

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Efficacy, Safety

To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on ventilation and the ability of intranasal and intravenous naloxone and intravenous nalmefene in its ability to reverse respiratory depression (important model parameters include C50, a measure of potency and t½ke0).

Conditions and MedDRA coding

healthy volunteers

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Healthy 1. Signed the informed consent form (ICF) and able to comply with the study requirements and restrictions listed therein
2. Healthy 2. Male and female subjects, age 18 to 70 years, inclusive
3. Healthy 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. Healthy 4. Body Mass Index (BMI) 18 to 30 kg/m2, inclusive;
5. Healthy 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. Healthy 6. No history of substance use disorder
7. Chronic opioid users 1. Signed the consent form and able to comply with the requirements and restrictions listed therein;
8. Chronic opioid users 2. Males or females age 18 to 70 years, inclusive
9. Chronic opioid users 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.
10. Chronic opioid users 4. BMI 18 to 32 kg/m2, inclusive;
11. Chronic opioid users 5. Opioid tolerant patients administered prescription opioids at daily doses ≥ 60 mg oral morphine equivalents;
12. Chronic opioid users 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;
13. Chronic opioid users 7. positive opioid urine drug screening;
14. Chronic opioid users 8. positive naloxone challenge.

Exclusion criteria 26

1. Healthy 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. Healthy 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. Healthy 3. Consume, on average, >27 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. Healthy 4. Previous or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration
5. Healthy 5. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent
6. Healthy 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. Healthy 7. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening
8. Healthy 8. History or presence of allergic response to fentanyl, sufentanil or naloxone or nalmefene
9. Healthy 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. Healthy 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. Healthy 11. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study;
12. 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
13. Chronic opioid users 2. Any active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints
14. Chronic opioid users 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);
15. Chronic opioid users 4. Currently receiving medication-assisted treatment for the treatment of opioid-use disorder
16. Chronic opioid users 5. Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
17. Chronic opioid users 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;
18. Chronic opioid users 7. Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
19. Chronic opioid users 8. History or presence of allergic response to fentanyl, sufentanil, nalmefene or naloxone
20. Chronic opioid users 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.
21. Chronic opioid users 10. Estimated glomerular filtration rate <60 mL/min as estimated by the CKD-EPI equation;
22. Chronic opioid users 11. Anemia at screening or donation of > 250 mL of blood or plasma within the last 3 months;
23. Chronic opioid users 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);
24. Chronic opioid users 13. AST or ALT levels >3.0 times the upper limit of normal at screening;
25. Chronic opioid users 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
26. Chronic opioid users 15. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Our main study measurement is minute ventilation. Together with the plasma concentration of the opioid and naloxone/nalmefene), ventilation is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Leids Universitair Medisch Centrum (LUMC)

Sponsor organisation

Leids Universitair Medisch Centrum (LUMC)

Address

Albinusdreef 2

City

Leiden

Postcode

2333 ZA

Country

Netherlands

Scientific contact point

Organisation

Leids Universitair Medisch Centrum (LUMC)

Contact name

Monique van Velzen

Public contact point

Organisation

Leids Universitair Medisch Centrum (LUMC)

Contact name

Monique van Velzen

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications