- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04764630
Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone
Intranasal (IN) naloxone is available as 2 mg or 4 mg dose with the indication to re-administer additional doses every 2 to 3 minutes (using alternating nostrils) if needed until emergency medical assistance arrives. The 4 mg dose is distributed in packages of two nasal sprays (1 dose per nasal spray), but additional doses can be administered if needed and available.
While the pharmacokinetics of IN naloxone have been determined following administration of a 4 mg dose in each nostril concurrently, the pharmacokinetics have not been determined following multiple doses when there is a 2-3 minute delay between doses and when doses are re-administered to the same nostril.
Obtaining data with repeat dosing will inform if and how fast naloxone plasma concentrations can be reached to be able to reverse highly-potent opioid overdoses. This study will be a randomized, unblinded, three-way crossover study to determine naloxone plasma concentration after administration of multiple doses:
A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes) B. Four 4 mg IN naloxone doses (2 doses every 2.5 minutes) C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)
Study Overview
Status
Conditions
Detailed Description
Naloxone, a fast-acting mu-opioid antagonist, is a treatment commonly used in reversing opioid overdose. Naloxone is available in multiple formulations, including for injection intravenously, intramuscularly or subcutaneously, and more recently as a spray administered intranasally (IN). The IN naloxone formulation, which was approved in 2015, is of particular interest as there is a need for naloxone formulations for community use by caregivers and first responders/law enforcement who do not have medical training. It is critical to administer naloxone as quickly as possible to prevent irreversible brain damage and death.
The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Division of Applied Regulatory Science (DARS) has conducted modeling and simulation, evaluating how many doses of IN naloxone may be needed to reverse opioid-induced respiratory depression from fentanyl and fentanyl derivates under a range of overdose scenarios. These analyses have suggested that more than two doses of IN naloxone are sometimes required to reverse the effects of highly potent opioids (e.g., certain fentanyl derivatives). Experience with intranasal formulations for other products has shown that repeat administration of doses given in close proximity to the same nostril can influence drug exposure due to run-off from the application site, limited absorption, or other factors. While the pharmacokinetics of IN naloxone have been determined following administration of a 4 mg dose in each nostril concurrently, the pharmacokinetics have not been determined following multiple doses according to the FDA product label:
- Administer a single spray intranasally into one nostril.
- Administer additional doses using a new nasal spray with each dose, if the patient does not respond or responds and then relapses into respiratory depression, additional doses may be given every 2 to 3 minutes until emergency medical assistance arrives.
This involves a 2-3 minute delay between each dose and re-administering to a previously dosed nostril starting with the 3rd dose, which may result in a less than dose-proportional increase in naloxone plasma concentration and/or delayed increase in naloxone exposure compared to the first 2 doses. Obtaining data with repeat dosing will inform if and how fast naloxone plasma concentrations can be reached to be able to reverse highly-potent opioid overdoses.
This study will be a randomized, unblinded, three-way crossover study to determine naloxone plasma concentration after administration of multiple doses:
A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes) B. Four 4 mg IN naloxone doses (2 doses every 2.5 minutes) C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)
The above 3 treatments will be evaluated in a randomized order over 3 treatment periods. Healthy subjects will be randomized to one of six treatment sequences (i.e., ABC, ACB, BAC, BCA, CAB, CBA). Subjects will report to the study site for screening from Days -28 to -2 and then will return to the site on Day -1 for baseline assessments and check-in. After check-in (Day -1), subjects will receive dosing for the 3 respective treatment periods on Days 1, 4 and 7. There will be two days of washout between each treatment period. Participants will be confined in the study clinic from Day -1 until the morning of Day 8. On dosing days, dosing will occur as per the treatment description and pharmacokinetic (PK) assessments will occur at 16 different time points.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Wisconsin
-
West Bend, Wisconsin, United States, 53095
- Spaulding Clinical Research
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Subject signs an Institutional Review Board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization [HIPAA]) before any study related procedures are performed.
- Subject is a healthy, non-smoking man or woman, 18 to 55 years of age, inclusive, who has a body mass index of 18.5 to 32 kg/m2, inclusive, at Screening.
- Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead ECG results, and physical examination findings at screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
- Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in (Day -1).
- Subject must test negative for severe acute respiratory syndrome coronavirus (SARS-CoV-2) by a molecular diagnostic test at check-in (Day -1). If a subject's test comes back inconclusive, it can be repeated.
- Female subjects must be of non-childbearing potential or, if they are of childbearing potential, they must: 1) have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 2) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before check-in (Day -1) until at least 1 month after the end of the study.
- Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee) from at least 1 month before check-in (Day -1) until at least 1 month after the last application of study drug.
- Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.
Exclusion Criteria:
- Subject has a deviated septum or previous nasal surgeries or need to use another nasal spray product during study that would impact administration of the intranasal drug.
- Subject has had an episode of epistaxis or an upper respiratory infection in the previous month.
- Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug.
- Subject is currently participating in another clinical study of an investigational drug or has been dosed with any investigational drug within 30 days or 5 half-lives (whichever is longer) of the compound.
- Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening.
- Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, cola), caffeine, grapefruit, or grapefruit juice within 24 h of check-in. Subjects must refrain from ingesting these throughout the study.
- Subject has any underlying disease or surgical or medical condition (e.g., cancer, human immunodeficiency virus [HIV], severe hepatic or renal impairment) that could put the subject at risk or would normally prevent participation in a clinical study. This includes subjects with any underlying medical conditions that the Investigator believes would put subjects at increased risk of severe illness from COVID-19 based on the Centers for Disease Control and Prevention (CDC) guidelines. The CDC lists cancer, chronic kidney disease, chronic obstructive pulmonary disease, immunocompromised state from solid organ transplant, severe obesity, serious heart conditions, sickle cell disease, pregnancy, smoking and type 2 diabetes mellitus as conditions that put subjects at increased risk. Additionally, the CDC lists asthma (moderate-to-severe), cerebrovascular disease, cystic fibrosis, hypertension, immunocompromised state or immune deficiencies, neurologic conditions such as dementia, liver disease, pulmonary fibrosis, thalassemia, overweight, type 1 diabetes mellitus as conditions that might put subjects at increased risk.
- Subject has any signs or symptoms that are consistent with COVID-19 per CDC recommendations. These include subjects with fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhea may have COVID-19. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator.
- Subject has known or suspected allergies or sensitivities to the study drug.
- Subject has clinical laboratory test results (hematology, serum chemistry and urinalysis) at Screening or check-In that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator.
- Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
- Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or unlikely to complete the trial due to poor venous access.
- Female subject is pregnant or lactating before enrollment in the study.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: A. Four naloxone nasal spray doses (1 every 2.5 min)
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min)
|
Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min
Other Names:
|
Experimental: B. Four naloxone nasal spray doses (2 every 2.5 min)
Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min)
|
Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min)
Other Names:
|
Active Comparator: C. Two naloxone nasal spray doses (1 every 2.5 min)
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
|
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
First Timepoint When There is a Higher Naloxone Plasma Concentration in the 4 Naloxone Dose Arm (2 Doses Every 2.5 Min) Compared to the 2 Naloxone Dose Arm (1 Every 2.5 Min)
Time Frame: 4.5, 7, and 10 minutes
|
Naloxone plasma concentrations will be determined at specified timepoints.
The four naloxone nasal spray dose arm (2 doses every 2.5 min) will be compared separately to the two naloxone nasal spray dose arm (1 dose every 2.5 min).
|
4.5, 7, and 10 minutes
|
First Timepoint When There is a Higher Naloxone Plasma Concentration in the 4 Naloxone Dose Arm (1 Every 2.5 Min) Compared to the 2 Naloxone Dose Arm (1 Every 2.5 Min)
Time Frame: 10, 12.5, and 15 minutes, 10 minutes reported
|
Naloxone plasma concentrations will be determined at specified timepoints.
The four naloxone nasal spray dose arm (1 dose every 2.5 min) will be compared separately to the two naloxone nasal spray dose arm (1 dose every 2.5 min).
|
10, 12.5, and 15 minutes, 10 minutes reported
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
First Timepoint When There is a Higher Naloxone Plasma Concentration in the 4 Naloxone Dose Arm B (2 Doses Every 2.5 Min) Compared to the 4 Naloxone Dose Arm A (1 Dose Every 2.5 Minutes)
Time Frame: 4.5, 7, and 10 minutes
|
Naloxone plasma concentrations will be determined at specified timepoints.
The 4 naloxone dose arm B (2 doses every 2.5 min) will be compared to the 4 naloxone dose arm A (1 dose every 2.5 min)
|
4.5, 7, and 10 minutes
|
Dose-proportionality of the 4 Naloxone Dose Arms in Reference to the 2 Naloxone Dose Arm Based on Maximum Concentration (Cmax).
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Dose proportionality based on Cmax will be compared between each of the three IN naloxone treatments as a secondary endpoint.
For the comparisons, the 4 naloxone dose arms will be considered as the test and the reference will be the 2 naloxone dose arm.
An additional comparison will be performed between the 4 naloxone dose arm B (2 doses every 2.5 min) as test and the 4 naloxone dose arm A (1 dose every 2.5 min) as reference.
Values are reported as dose-normalized Cmax.
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Dose-proportionality of the 4 Naloxone Dose Arms in Reference to the 2 Naloxone Dose Arm Based on Area Under the Curve From Time 0 to Infinity (AUC0-inf)
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Dose proportionality based on AUC0-inf will be compared between each of the three IN naloxone treatments as a secondary endpoint.
For the comparisons, the 4 naloxone dose arms will be considered as the test and the reference will be the 2 naloxone dose arm.
An additional comparison will be performed between the 4 naloxone dose arm B (2 doses every 2.5 min) as test and the 4 naloxone dose arm A (1 dose every 2.5 min) as reference.
Values are reported as dose-normalized AUC0-inf.
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Dose-proportionality of the 4 Naloxone Dose Arms in Reference to the 2 Naloxone Dose Arm Based on Area Under the Curve From Time 0 to Last Sample (AUC0-t)
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Dose proportionality based on AUC0-t will be compared between each of the three IN naloxone treatments as a secondary endpoint.
For the comparisons, the 4 naloxone dose arms will be considered as the test and the reference will be the 2 naloxone dose arm.
An additional comparison will be performed between the 4 naloxone dose arm B (2 doses every 2.5 min) as test and the 4 naloxone dose arm A (1 dose every 2.5 min) as reference.
Values are reported as dose-normalized AUC0-t.
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Fentanyl for a Medium Overdose Scenario
Time Frame: 720 minutes
|
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue.
An intravenous fentanyl dose of 1.63 mg was selected as representative of a medium overdose scenario.
The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline.
Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min.
A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
|
720 minutes
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Fentanyl for a High Overdose Scenario
Time Frame: 720 minutes
|
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue.
An intravenous fentanyl dose of 2.97 mg was selected as representative of a medium overdose scenario.
The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline.
Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min.
A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
|
720 minutes
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Carfentanil for a Medium Overdose Scenario
Time Frame: 720 min
|
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue.
An intravenous carfentanil dose of 0.012 mg was selected as representative of a medium overdose scenario.
The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline.
Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min.
A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
|
720 min
|
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Carfentanil for a High Overdose Scenario
Time Frame: 720 min
|
Data from this study will be combined with an existing pharmacokinetic/pharmacodynamic (PK/PD) model for opioid-induced respiratory depression to determine mean time to rescue.
An intravenous carfentanil dose of 0.022 mg was selected as representative of a medium overdose scenario.
The first naloxone dose in the simulations was administered 1 minute after ventilation decreased to 40% of baseline.
Brain hypoxia (time to rescue a simulated patient) was defined as time brain oxygen partial pressure was less than 20 mm Hg and cardiac arrest was defined as the time cardiac output was less than 0.01 L/min.
A value of 120 minutes means that simulated patients for that measure/dispersion metric were not predicted to recovered for the opioid dose and intervention.
|
720 min
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Naloxone Cmax
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
PK parameter for Cmax will be calculated
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Naloxone AUC0-inf
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
PK parameter AUC0-inf for naloxone will be calculated
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Naloxone AUC0-t
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
PK parameter AUC0-t for naloxone will be calculated
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Naloxone Time of Maximum Concentration (Tmax)
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
PK parameter tmax for naloxone will be calculated
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes
|
Naloxone Partial Area Under the Curve (pAUC) From First Dose to 30 Minutes
Time Frame: 0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, and 30 minutes
|
PK parameter pAUC from time 0 to 30 minutes for naloxone will be calculated
|
0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, and 30 minutes
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Jennifer Deering, MSN, APNP, Spaulding Clinical Research LLC
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- SCR-011
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Healthy Subjects
-
BiogenCompletedHealthy Adult Subjects | Healthy Elderly SubjectsUnited States
-
PfizerCompletedHealthy Adult Subjects and Healthy Elderly SubjectsBelgium
-
PfizerRecruitingHealthy Subjects | Healthy ParticipantsUnited States
-
National Heart, Lung, and Blood Institute (NHLBI)CompletedHealthy | Healthy Subjects | ImmunosuppressionUnited States
-
Lund UniversityCompletedHealthy Subjects | Diet, HealthySweden
-
Maastricht University Medical CenterCompletedHealthy Volunteers | Healthy Subjects | Healthy AdultsNetherlands
-
NeuShen TherapeuticsNot yet recruiting
-
GEN İlaç ve Sağlık Ürünleri A.Ş.Sulfateq B.V.Recruiting
-
Bio-innova Co., LtdNot yet recruiting
-
Bio-innova Co., LtdNot yet recruiting
Clinical Trials on Four naloxone nasal spray doses (1 every 2.5 min)
-
Region SkaneActive, not recruiting
-
Zosano Pharma CorporationCompleted
-
Eyenovia Inc.CompletedMydriasisUnited States
-
St. Renatus, LLCRho, Inc.; Triligent International; Analytical Bio-Chemistry Laboratories, Inc.CompletedAnesthesiaUnited States
-
Memorial Sloan Kettering Cancer CenterTufts Medical Center; Lahey ClinicCompleted