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

NCT04764630 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SCR-011
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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)

Conditions

Healthy Subjects; Opioid Antagonist; Pharmacokinetics

Keywords

Opioid antagonist; Intranasal naloxone; Pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• 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).

  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).

  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)

  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).

  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)

  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)

  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

  720 minutes

Other Outcomes (5)

• Naloxone Cmax

  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

  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

  0 [pre-dose], 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes

Study Arms (3)

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)

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)

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)

Drug: Two naloxone nasal spray doses (1 every 2.5 min)

Interventions

Four naloxone nasal spray doses (1 every 2.5 min) DRUG

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

Also known as: Narcan nasal spray

A. Four naloxone nasal spray doses (1 every 2.5 min)

Four naloxone nasal spray doses (2 every 2.5 min) DRUG

Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min)

Also known as: Narcan nasal spray

B. Four naloxone nasal spray doses (2 every 2.5 min)

Two naloxone nasal spray doses (1 every 2.5 min) DRUG

Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)

Also known as: Narcan nasal spray

C. Two naloxone nasal spray doses (1 every 2.5 min)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• Spaulding Clinical Research LLC: collaborator

Study Sites (1)

Spaulding Clinical Research

West Bend, Wisconsin, 53095, United States

Location

Related Publications (1)

• 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.

  PMID: 38261323 DERIVED

Results Point of Contact

• Title: David Strauss, MD, PhD
• Organization: U.S. Food and Drug Administration

David.Strauss@fda.hhs.gov

301-796-6323

Study Officials

• Jennifer Deering, MSN, APNP

  Spaulding Clinical Research LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: The study will be unblinded as the product is administered intranasally and different arms will have a different number of administrations at different times.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: This is a three-way crossover study where subjects will be randomized to one of six possible treatment sequences.

Study Record Dates

• First Submitted: February 16, 2021
• First Posted: February 21, 2021
• Study Start: March 1, 2021
• Primary Completion: March 20, 2021
• Study Completion: March 20, 2021
• Last Updated: April 19, 2024
• Results First Posted: July 15, 2022

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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.

Locations

US (1)