Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists - a Study in Opioid naïve Individuals and Chronic Opioid Users Under Real-life Conditions
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Enrollment
- 58
- Locations
- 1
- Primary Endpoint
- Plasma concentration sufentanil/fentanyl
Study Overview
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:
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Healthy volunteers
- •Signed the informed consent form (ICF) and able to comply with the study requirements and restrictions listed therein;
- •Male and female subjects, age 18 to 70 years, inclusive;
- •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;
- •Body Mass Index (BMI) 18 to 30 kg/m2, inclusive;
- •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;
- •No history of substance use disorder;
- •Chronic opioid users
- •Signed the consent form and able to comply with the requirements and restrictions listed therein;
- •Males or females age 18 to 70 years, inclusive;
- •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.
- •BMI 18 to 32 kg/m2, inclusive;
- •Opioid tolerant patients administered prescription opioids at daily doses ≥ 60 mg oral morphine equivalents (See Table 3);
- •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
- •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;
- •Any other active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;
- •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);
- •Previous or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration;
- •Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
- •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;
- •Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
- •History or presence of allergic response to fentanyl, sufentanil or naloxone;
- •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;
- •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;
- •Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study;
- •Chronic opioid users
- •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;
- •Any active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;
- •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);
- •Currently receiving medication-assisted treatment for the treatment of opioid-use disorder;
- •Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
- •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;
- •Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
- •History or presence of allergic response to study medication;
- •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.
- •Estimated glomerular filtration rate <60 mL/min as estimated by the CKD-EPI equation;
- •Anemia at screening or donation of > 250 mL of blood or plasma within the last 3 months;
- •Positive serology tests for HIV, acute hepatitis B, or acute hepatitis C (OT patients with asymptomatic hepatitis B or C infection may be enrolled);
- •AST or ALT levels >3.0 times the upper limit of normal at screening;
- •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;
- •Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.
Arms & Interventions
Intravenous fentanyl year 1
continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.
Intervention: Narcan 40 MG/ML Nasal Spray (Drug)
Intravenous fentanyl year 2
continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.
Intervention: Nalmefene HCl injection (Drug)
IV fentanyl year 2
continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.
Intervention: Naloxone Hydrochloride (Drug)
Intravenous sufentanil year 1
continuous intravenous infusion of sufentanil to induce 40-60% respiratory depression.
Intervention: Narcan 40 MG/ML Nasal Spray (Drug)
IV fentanyl year 2
continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.
Intervention: Nalmefene HCl injection (Drug)
Intravenous fentanyl year 2
continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.
Intervention: Naloxone Hydrochloride (Drug)
Outcomes
Primary Outcomes
Plasma concentration sufentanil/fentanyl
Time Frame: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene
50 samples of 2ml arterial blood
Minute ventilation
Time Frame: Minute ventilation will be measured for up to 180 minutes following the start of opioid infusion
Minute ventilation (liters/minute)
Plasma concentration naloxone
Time Frame: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene
50 samples of 2ml arterial blood
Secondary Outcomes
- Pupil diameter(at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intramuscular/intravenous naloxone. After discontinuation of infusion every 20 min. up to 6 hrs. following the start of opioid infusion)
Investigators
Albert Dahan
Professor
Leiden University Medical Center