Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists

NCT05338632 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: P21.112
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Opioid Induced Respiratory Depression; Chronic Opioid Use

Keywords

Reversal of opioid induced respiratory depression; Intranasal naloxone

Outcome Measures

Primary Outcomes (3)

• Minute ventilation

  Minute ventilation (liters/minute)

  Minute ventilation will be measured for up to 180 minutes following the start of opioid infusion

• Plasma concentration sufentanil/fentanyl

  50 samples of 2ml arterial blood

  at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene

• Plasma concentration naloxone

  50 samples of 2ml arterial blood

  at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene

Secondary Outcomes (1)

• 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

Study Arms (4)

Intravenous fentanyl year 1

EXPERIMENTAL

continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.

Drug: Narcan 40 MG/ML Nasal Spray

Intravenous sufentanil year 1

EXPERIMENTAL

continuous intravenous infusion of sufentanil to induce 40-60% respiratory depression.

Drug: Narcan 40 MG/ML Nasal Spray

Intravenous fentanyl year 2

EXPERIMENTAL

continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.

Drug: Naloxone Hydrochloride; Drug: Nalmefene HCl injection

IV fentanyl year 2

EXPERIMENTAL

continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression.

Drug: Naloxone Hydrochloride; Drug: Nalmefene HCl injection

Interventions

Narcan 40 MG/ML Nasal Spray DRUG

naloxone 4mg/0.1 mL intranasal spray, up to 4 doses intranasally, followed by 1ml 0.4 mg/ml naloxone hydrochloride intravenously

Also known as: Intranasal naloxone

Intravenous fentanyl year 1; Intravenous sufentanil year 1

Naloxone Hydrochloride DRUG

Naloxone 0.4mg/mL

Also known as: IV naloxone

IV fentanyl year 2; Intravenous fentanyl year 2

Nalmefene HCl injection DRUG

Nalmefene 1 ng/mL

Also known as: Nalmefene IV

IV fentanyl year 2; Intravenous fentanyl year 2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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;

Sponsors & Collaborators

• Leiden University Medical Center: lead
• U.S. Food and Drug Administration (FDA): collaborator

Study Sites (1)

Leiden University Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

RECRUITING

Related Publications (8)

• Algera MH, Kamp J, van der Schrier R, van Velzen M, Niesters M, Aarts L, Dahan A, Olofsen E. Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal. Br J Anaesth. 2019 Jun;122(6):e168-e179. doi: 10.1016/j.bja.2018.12.023. Epub 2019 Feb 1.

  PMID: 30915997 BACKGROUND

• Algera MH, Olofsen E, Moss L, Dobbins RL, Niesters M, van Velzen M, Groeneveld GJ, Heuberger J, Laffont CM, Dahan A. Tolerance to Opioid-Induced Respiratory Depression in Chronic High-Dose Opioid Users: A Model-Based Comparison With Opioid-Naive Individuals. Clin Pharmacol Ther. 2021 Mar;109(3):637-645. doi: 10.1002/cpt.2027. Epub 2020 Oct 5.

  PMID: 32865832 BACKGROUND

• Dahan A, Aarts L, Smith TW. Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression. Anesthesiology. 2010 Jan;112(1):226-38. doi: 10.1097/ALN.0b013e3181c38c25.

  PMID: 20010421 BACKGROUND

• Olofsen E, van Dorp E, Teppema L, Aarts L, Smith TW, Dahan A, Sarton E. Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology. 2010 Jun;112(6):1417-27. doi: 10.1097/ALN.0b013e3181d5e29d.

  PMID: 20461002 BACKGROUND

• Olofsen E, Boom M, Nieuwenhuijs D, Sarton E, Teppema L, Aarts L, Dahan A. Modeling the non-steady state respiratory effects of remifentanil in awake and propofol-sedated healthy volunteers. Anesthesiology. 2010 Jun;112(6):1382-95. doi: 10.1097/ALN.0b013e3181d69087.

  PMID: 20461001 BACKGROUND

• van Dorp E, Yassen A, Dahan A. Naloxone treatment in opioid addiction: the risks and benefits. Expert Opin Drug Saf. 2007 Mar;6(2):125-32. doi: 10.1517/14740338.6.2.125.

  PMID: 17367258 BACKGROUND

• Yassen A, Olofsen E, van Dorp E, Sarton E, Teppema L, Danhof M, Dahan A. Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : a study in healthy volunteers. Clin Pharmacokinet. 2007;46(11):965-80. doi: 10.2165/00003088-200746110-00004.

  PMID: 17922561 BACKGROUND

• Gepts E, Shafer SL, Camu F, Stanski DR, Woestenborghs R, Van Peer A, Heykants JJ. Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology. 1995 Dec;83(6):1194-204. doi: 10.1097/00000542-199512000-00010.

  PMID: 8533912 BACKGROUND

MeSH Terms

Interventions

Naloxone; Nasal Sprays; nalmefene

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Aerosols; Colloids; Complex Mixtures; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Rutger van der Schrier, MD

  LUMC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rutger van der Schrier, MD

CONTACT

+31 (0)71 5299893; r.m.van_der_schrier@lumc.nl

Albert Dahan, MD PhD

CONTACT

+31 (0)71 5299780; a.dahan@lumc.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: This is an open-label, randomized (IM versus IN naloxone), crossover study in a mixed population.

Study Record Dates

• First Submitted: April 14, 2022
• First Posted: April 21, 2022
• Study Start: June 24, 2022
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: January 31, 2025

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Immediately following publication. No end date
• Access Criteria: Researchers who provide a methodologically sound proposal to achieve aims in the approved proposal. Proposals should be directed at. A.Dahan@lumc.nl

Locations

NL (1)