Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone
Condition: Healthy Subjects; Opioid Antagonist; Pharmacokinetics
Intervention: 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)
Intervention description: 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 and right nostrils at 0 min, left and right nostrils at 2.5 min); Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Intervention MeSH terms: Naloxone
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
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.
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Opioid antagonist; Intranasal naloxone; Pharmacokinetics

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)
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          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.