Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone

• ClinicalTrials.gov Identifier: NCT04764630
• Recruitment Status: Completed
• First Posted: February 21, 2021
• Last Update Posted: August 23, 2021
• Sponsor: Food and Drug Administration (FDA)
• Collaborator: Spaulding Clinical Research LLC
• Information provided by (Responsible Party): Food and Drug Administration (FDA)

Study Description

Brief 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. 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)

Condition or disease	Intervention/treatment	Phase
Healthy Subjects; Opioid Antagonist; Pharmacokinetics	Drug: Four naloxone nasal spray doses (1 every 2.5 min); Drug: Four naloxone nasal spray doses (2 every 2.5 min); Drug: Two naloxone nasal spray doses (1 every 2.5 min)	Phase 1

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 PK assessments will occur at 16 different time points.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention 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)
• Masking Description: The study will be unblinded as the product is administered intranasally and different arms will have a different number of administrations at different times.
• Primary Purpose: Other
• Official Title: Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone
• Actual Study Start Date: March 1, 2021
• Actual Primary Completion Date: March 20, 2021
• Actual Study Completion Date: March 20, 2021

Arms and Interventions

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)	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; Other Name: Narcan nasal spray
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)	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); Other Name: Narcan nasal spray
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)	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); Other Name: Narcan nasal spray

Outcome Measures

Primary Outcome Measures :

1. First timepoint when there is a higher naloxone plasma concentration in the 4 naloxone dose arms compared to the 2 naloxone dose arm [ Time Frame: 720 minutes ]
   Naloxone plasma concentrations will be determined at specified timepoints. Both of the four naloxone nasal spray dose arms will be compared separately to the two naloxone nasal spray dose arm.

Secondary Outcome Measures :

1. 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: 720 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)
2. Dose-proportionality of the 4 naloxone dose arms in reference to the 2 naloxone dose arm based on maximum concentration (Cmax). [ Time Frame: 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.
3. 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: 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.
4. 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: 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.
5. Predicted time to rescue a patient from simulated opioid-induced respiratory depression from fentanyl 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
6. Predicted time to rescue a patient from simulated opioid-induced respiratory depression from fentanyl for a high overdose scenario [ Time Frame: 720 min ]
   Data from this study will be combined with an existing PK/PD model for opioid-induced respiratory depression to determine mean time to rescue
7. 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 PK/PD model for opioid-induced respiratory depression to determine mean time to rescue
8. 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 PK/PD model for opioid-induced respiratory depression to determine mean time to rescue

Other Outcome Measures:

1. Naloxone Cmax [ Time Frame: 720 min ]
   PK parameter for Cmax will be calculated
2. Naloxone AUC0-inf [ Time Frame: 720 min ]
   PK parameter AUC0-inf for naloxone will be calculated
3. Naloxone AUC0-t [ Time Frame: 720 min ]
   PK parameter AUC0-t for naloxone will be calculated
4. Naloxone time of maximum concentration (tmax) [ Time Frame: 720 min ]
   PK parameter tmax for naloxone will be calculated
5. Naloxone partial area under the curve [pAUC] from first dose to 30 minutes [ Time Frame: 30 min ]
   PK parameter pAUC from time 0 to 30 minutes for naloxone will be calculated

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Subject signs an 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.
2. 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.
3. 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).
4. Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in (Day -1).
5. 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.
6. 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.
7. 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.
8. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

Exclusion Criteria:

1. 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.
2. Subject has had an episode of epistaxis or an upper respiratory infection in the previous month.
3. 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.
4. 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.
5. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening.
6. 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.
7. 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.
8. 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.
9. Subject has known or suspected allergies or sensitivities to the study drug.
10. 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.
11. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
12. 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.
13. Female subject is pregnant or lactating before enrollment in the study.

Contacts and Locations

Locations

United States, Wisconsin

Spaulding Clinical Research

West Bend, Wisconsin, United States, 53095

Sponsors and Collaborators

Food and Drug Administration (FDA)

Spaulding Clinical Research LLC

Investigators

• Principal Investigator: Jennifer Deering, MSN, APNP; Spaulding Clinical Research LLC

  Study Documents (Full-Text)

Documents provided by Food and Drug Administration (FDA):

Informed Consent Form  [PDF] February 23, 2021

More Information

• Responsible Party: Food and Drug Administration (FDA)
• ClinicalTrials.gov Identifier: NCT04764630
• Other Study ID Numbers: SCR-011
• First Posted: February 21, 2021
• Last Update Posted: August 23, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual patient data will be shared at the time of the primary publication.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Individual patient data will be shared at the time of the primary publication, which is anticipated to be within 1 year of study completion.
• Access Criteria: No restrictions.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Food and Drug Administration (FDA):

Opioid antagonist; Intranasal naloxone; Pharmacokinetics

Additional relevant MeSH terms:

Naloxone; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents