Healthy SubjectsPhase 1NCT04764630
Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone
A Phase 1 study testing Four naloxone nasal spray doses (1 every 2.5 min), Four naloxone nasal spray doses (2 every 2.5 min) and Two naloxone nasal spray doses (1 every 2.5 min) in people with Healthy Subjects and Opioid Antagonist, run by Food and Drug Administration (FDA) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Subjects, Opioid Antagonist, Pharmacokinetics
- What is being tested?
- Four naloxone nasal spray doses (1 every 2.5 min), Four naloxone nasal spray doses (2 every 2.5 min) and Two naloxone nasal spray doses (1 every 2.5 min)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Mar 2021to 20 Mar 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 13Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Spaulding Clinical Research
West Bend, Wisconsin, 53095
About this study
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.
Read more
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:
- 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)
Read the 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:
- 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.
- Conditions
- Healthy Subjects, Opioid Antagonist, Pharmacokinetics
- Being tested
- Four naloxone nasal spray doses (1 every 2.5 min), Four naloxone nasal spray doses (2 every 2.5 min), Two naloxone nasal spray doses (1 every 2.5 min)
- Keywords
- Opioid antagonist, Intranasal naloxone, Pharmacokinetics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Four naloxone nasal spray doses (1 every 2.5 min)Drug
Also called Narcan nasal spray
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 naloxone nasal spray doses (2 every 2.5 min)Drug
Also called Narcan nasal spray
Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min)
Two naloxone nasal spray doses (1 every 2.5 min)Drug
Also called Narcan nasal spray
Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
| Study group | Role | What they receive |
|---|---|---|
| A. Four naloxone nasal spray doses (1 every 2.5 min) | Experimental | 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) Receives: Drug: Four naloxone nasal spray doses (1 every 2.5 min) |
| B. Four naloxone nasal spray doses (2 every 2.5 min) | Experimental | Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min) Receives: Drug: Four naloxone nasal spray doses (2 every 2.5 min) |
| C. Two naloxone nasal spray doses (1 every 2.5 min) | Active comparator | Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min) Receives: Drug: Two naloxone nasal spray doses (1 every 2.5 min) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
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).
Measured: 10, 12.5, and 15 minutes, 10 minutes reported
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)
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).
Measured: 4.5, 7, and 10 minutes
Secondary outcomes (8)
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)
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)
Measured: 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).
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.
Measured: 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)
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.
Measured: 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)
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.
Measured: 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
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.
Measured: 720 minutes
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Fentanyl for a High Overdose Scenario
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.
Measured: 720 minutes
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Carfentanil for a Medium Overdose Scenario
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.
Measured: 720 min
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Carfentanil for a High Overdose Scenario
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.
Measured: 720 min
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Feb 2021
- Study start1 Mar 2021
- Primary completion20 Mar 2021
- Study completion20 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Healthy SubjectsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- This is a three-way crossover study where subjects will be randomized to one of six possible treatment sequences.
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Food and Drug Administration (FDA)
- Sponsor type
- US federal agency
- Collaborators
- Spaulding Clinical Research LLC
- Responsible party
- Sponsor
- Investigators
- Jennifer Deering, MSN, APNP, Principal investigator, Spaulding Clinical Research LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04764630
- Sponsor's protocol ID
- SCR-011
- Status last verified
- Nov 2023
- First submitted
- 16 Feb 2021
- Last updated
- 19 Apr 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual patient data will be shared at the time of the primary publication.
Publications
Strauss DG, Li Z, Chaturbedi A, Chakravartula S, Samieegohar M, Mann J, Nallani SC, Prentice K, Shah A, Burkhart K, Boston J, Fu YA, Dahan A, Zineh I, Florian JA. Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial. JAMA Netw Open. 2024 Jan 2;7(1):e2351839. doi: 10.1001/jamanetworkopen.2023.51839.
PubMed 38261323
Study at a glance
From the registry record, last updated by the sponsor on 19 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone
- ClinicalTrials.gov ID
- NCT04764630
- Acronym / sponsor ID
- SCR-011
- Conditions
- Healthy Subjects, Opioid Antagonist, Pharmacokinetics
- Keywords
- Opioid antagonist, Intranasal naloxone, Pharmacokinetics
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Food and Drug Administration (FDA)US federal agency
- Collaborators
- Spaulding Clinical Research LLC
- Study start
- 1 Mar 2021 (actual)
- Primary completion
- 20 Mar 2021 (actual)
- Study completion
- 20 Mar 2021 (actual)
- First posted
- 21 Feb 2021 (actual)
- Results
- Posted 15 Jul 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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)
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:
- 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 design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- This is a three-way crossover study where subjects will be randomized to one of six possible treatment sequences.
| Arm | Type | Receives |
|---|---|---|
| A. Four naloxone nasal spray doses (1 every 2.5 min) | Experimental | Drug: 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) |
| B. Four naloxone nasal spray doses (2 every 2.5 min) | Experimental | Drug: 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) |
| C. Two naloxone nasal spray doses (1 every 2.5 min) | Active comparator | Drug: 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) |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Four naloxone nasal spray doses (1 every 2.5 min)Also: Narcan nasal sprayFour 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 | Drug | A. Four naloxone nasal spray doses (1 every 2.5 min) |
| Four naloxone nasal spray doses (2 every 2.5 min)Also: Narcan nasal sprayFour 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min) | Drug | B. Four naloxone nasal spray doses (2 every 2.5 min) |
| Two naloxone nasal spray doses (1 every 2.5 min)Also: Narcan nasal sprayTwo 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min) | Drug | C. Two naloxone nasal spray doses (1 every 2.5 min) |
Primary outcome
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).
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).
8 secondary outcomes
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
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 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 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
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Fentanyl for a Medium Overdose Scenario
Time frame: 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
Predicted Time to Rescue a Patient From Simulated Opioid-induced Respiratory Depression From Carfentanil for a Medium Overdose Scenario
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Apr 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38261323Strauss DG, Li Z, Chaturbedi A, Chakravartula S, Samieegohar M, Mann J, Nallani SC, Prentice K, Shah A, Burkhart K, Boston J, Fu YA, Dahan A, Zineh I, Florian JA. Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial. JAMA Netw Open. 2024 Jan 2;7(1):e2351839. doi: 10.1001/jamanetworkopen.2023.51839.
- Individual participant dataSharing planned: Yes. Individual patient data will be shared at the time of the primary publication.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jennifer Deering, MSN, APNP principal investigator
Spaulding Clinical Research LLC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Four naloxone nasal spray doses (1 every 2.5 min), Four naloxone nasal spray doses (2 every 2.5 min) and Two naloxone nasal spray doses (1 every 2.5 min) in people with Healthy Subjects and Opioid Antagonist, run by Food and Drug Administration (FDA) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Jul 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04764630, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Apr 2024.