Ignite Creation Date:
2025-12-24 @ 9:44 PM
Ignite Modification Date:
2025-12-25 @ 7:25 PM
Study NCT ID:
NCT05338632
Status:
RECRUITING
Last Update Posted:
2025-01-31
First Post:
2022-04-14
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists
Sponsor:
Leiden University Medical Center
Organization:
Study Overview
Official Title:
Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists - a Study in Opioid naïve Individuals and Chronic Opioid Users Under Real-life Conditions
Status:
RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ROAR
Brief Summary:
n this pharmacokinetic/pharmacodynamic modelling study we will determine the ability of intranasal and intravenous naloxone and intravenous nalmefene 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.
Detailed Description:
Primary objective:
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on ventilation 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). 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 potent opioids, with respiratory depression ranging from moderate to severe.
Secondary objectives:
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on pupil diameter and intranasal and intravenous naloxone and intravenous nalmefene in its ability to reverse miosis (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to compare the ventilatory and pupil effects of the opioids and of naloxone.
Study design:
This is an open-label, randomized, crossover study in a mixed population
Study population:
We will study 12 healthy individuals of either sex aged 18-55 years and 12 individuals that are chronic opioids users (\> 60 daily oral morphine equivalents; 18-55 years).
Intervention:
Study 1: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation \> 85%), intranasal naloxone (IN, 4 mg) will be administered twice with a maximum of 180 minutes in between. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intranasal bioavailability.
Study 2: Infusion of low-dose fentanyl whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation \> 85%), intravenous naloxone (IV, 0.4mg/mL) or intravenous nalmefene (IV, 1 mg/mL) will be administered at 5 min intervals with each bolus is 0.08 mg.
At regular intervals blood will be drawn for measurement of drug concentration; at regular intervals pupil diameter will be measured.
Main study parameters:
The main study measurement is minute ventilation. Together with the plasma concentration of the opioid and naloxone and 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.
The secondary study measurement is pupil diameter. Together with the plasma concentration of the opioid and naloxone and nalmefene), the pupil diameter 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. See Data analysis below. Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
In this pharmacokinetic-pharmacodynamic modeling study, the effect of intravenous and intranasal naloxone and intravenous nalmefene is studied during infusion of two opioids, fentanyl and sufentanil, in mixed population of healthy volunteers and chronic opioid users. The PK/PD analysis will yield important information regarding dosing regimens of IM and IN naloxone at fentanyl and sufentanil doses much higher than we will administer here, but that may represent doses in case of an overdose both in clinical patients and opioid abusers. Side effects related to the medication will be mild to moderate with most common side effects: nausea, vomiting, dizziness, somnolence, dry mouth and respiratory depression (from the opioids), and possibly mild withdrawal symptoms from naloxone. Side effects will dissipate over time while severe occurrences of nausea and vomiting will be treated with an antiemetic; severe occurrence of withdrawal symptoms will be treated with clonidine.
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on ventilation 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). 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 potent opioids, with respiratory depression ranging from moderate to severe.
Secondary objectives:
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on pupil diameter and intranasal and intravenous naloxone and intravenous nalmefene in its ability to reverse miosis (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to compare the ventilatory and pupil effects of the opioids and of naloxone.
Study design:
This is an open-label, randomized, crossover study in a mixed population
Study population:
We will study 12 healthy individuals of either sex aged 18-55 years and 12 individuals that are chronic opioids users (\> 60 daily oral morphine equivalents; 18-55 years).
Intervention:
Study 1: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation \> 85%), intranasal naloxone (IN, 4 mg) will be administered twice with a maximum of 180 minutes in between. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intranasal bioavailability.
Study 2: Infusion of low-dose fentanyl whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation \> 85%), intravenous naloxone (IV, 0.4mg/mL) or intravenous nalmefene (IV, 1 mg/mL) will be administered at 5 min intervals with each bolus is 0.08 mg.
At regular intervals blood will be drawn for measurement of drug concentration; at regular intervals pupil diameter will be measured.
Main study parameters:
The main study measurement is minute ventilation. Together with the plasma concentration of the opioid and naloxone and 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.
The secondary study measurement is pupil diameter. Together with the plasma concentration of the opioid and naloxone and nalmefene), the pupil diameter 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. See Data analysis below. Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
In this pharmacokinetic-pharmacodynamic modeling study, the effect of intravenous and intranasal naloxone and intravenous nalmefene is studied during infusion of two opioids, fentanyl and sufentanil, in mixed population of healthy volunteers and chronic opioid users. The PK/PD analysis will yield important information regarding dosing regimens of IM and IN naloxone at fentanyl and sufentanil doses much higher than we will administer here, but that may represent doses in case of an overdose both in clinical patients and opioid abusers. Side effects related to the medication will be mild to moderate with most common side effects: nausea, vomiting, dizziness, somnolence, dry mouth and respiratory depression (from the opioids), and possibly mild withdrawal symptoms from naloxone. Side effects will dissipate over time while severe occurrences of nausea and vomiting will be treated with an antiemetic; severe occurrence of withdrawal symptoms will be treated with clonidine.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?: