Pharmacokinetics (PK) and Safety of Multiple Doses of Intranasal Naloxone in Healthy Adults

A Phase 1, Open Label, Randomized Study to Investigate the Pharmacokinetics and Safety of Multiple Doses of Intranasal Naloxone in Healthy Adult Participants

This study will be a Phase 1, single-center, open-label, randomized cross-over study to evaluate the PK of a new AP003 device which delivers two sprays of 4 mg naloxone hydrochloride intranasally.

Based on the intended AP003 product presentation there will be two devices in each carton allowing for administration of a total of 16 mg. This study is designed for subjects to receive naloxone therapy either through the AP003 device or through the currently approved NARCAN® nasal spray (4 mg) device (per label), reference therapy. After administration of the therapy patients will be followed by a 48-hour washout period before treatment crossover. Key study parameters include safety and PK. Safety evaluations will include but not limited to complete and system directed physical examinations (including signs of nasal irritation such as erythema, edema, and erosion), administration of a Brief Smell Identification Test (B-SIT), assessments of vital signs, 12 lead electrocardiogram (ECG), continuous cardiac telemetry monitoring (CCT) , clinical laboratory tests (e.g., hematology, chemistry, urinalysis, pregnancy test), and evaluation of adverse events.

Inclusion Criteria:

• Are able to consent and freely provide informed consent.

• Females and males 18-55 years of age, inclusive.

• Have a body mass index (BMI) less than or equal to 34.0 kg/m2.

• Generally healthy, in the opinion of the Investigator, based on medical history, physical examination, vital signs, screening laboratory assessments and 12-lead ECG evaluation.

• If female:

  1. Have a negative pregnancy test at Screening (serum pregnancy test) and before dosing at Day -1 (urine pregnancy test)

  2. Female subjects of non-childbearing potential must be:

     • Post-menopausal (spontaneous amenorrhea for at least 12 months prior to dosing) with confirmation by documented FSH levels ≥40 mIU/mL; or
     • Surgically sterile (bilateral oophorectomy, bilateral salpingectomy, hysterectomy, or tubal ligation) at least 3 months prior to dosing.

  3. Women of childbearing potential who are not planning to be pregnant during the study period and who are using one of the following effective methods of contraception during the study period and for at least 30 days after last study visit:

     • Simultaneous use of hormonal contraceptive (e.g. oral, patch, depot injection, implant, vaginal ring, intrauterine device) or non- hormonal intrauterine device for at least 4 weeks prior to dosing (must agree to use the same contraceptive throughout the study) and condom for the male partner.
     • Simultaneous use of diaphragm or cervical cap with spermicide and condom for the male partner, started at least 21 days prior to dosing.

Exclusion Criteria:

• Participants planning to become pregnant during the study or currently breastfeeding.

• Any acute condition, in the opinion of the Investigator, that is not fully resolved at least 4 weeks prior to baseline.

• Participant has a deviated septum, previous rhinoplasty, abnormal nasal anatomy, other nasal symptoms (i.e., blocked and/or runny nose), or other nasal surgeries (i.e., polyp removal) within 1 year, or needs to use another nasal spray product during study.

• Participant with current upper respiratory infection (URI) or has had URI within 7 days prior to screening.

• Subject has had an episode of epistaxis within 30 days prior screening or has experienced recurrent episodes of epistaxis within 1 year prior to screening.

• Participant has used any prescription or nonprescription drugs/supplements with increased risk of bleeding within 28 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug with exception of oral contraceptives. All other prescription medications, over-the-counter, and natural health products within 14 days or 5 half-lives prior to the first dosing.

• Participant 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.

• Had a history of abuse or current misuse of illicit drugs, alcohol, or tobacco:

  1. alcohol abuse (regularly drinks more than 14 units of alcohol per week; 1 unit = 360 mL of beer, 150 mL of wine, or 45 mL of spirit [40% a/v]) or history of alcohol abuse within 6 months prior to Screening
  2. positive for recent alcohol use (by breathalyzer) at Screening or Baseline (Day -1)
  3. a history or evidence of abuse of licit or illicit drug substances or a positive urine drug screen (a urine sample was obtained for testing to determine the presence or absence of Schedule 1 or Schedule 2 typical drugs of abuse or their metabolites, including opioids, amphetamine derivatives, cocaine, and other analytes as needed) or drugs of abuse prior to Screening. History of cannabinoid use within 1 year prior to Screening or any current evidence of abuse.
  4. use of tobacco-containing products or had a history of tobacco use within 1 year prior to the screening visit
  5. use of e-cigarettes and/or nicotine replacement products or had used these products within 1 year prior to the screening visit.

• Participant who had consumed xanthine containing products (e.g., tea, coffee, cola), caffeine, within 24 hours of check-in. Participants had to refrain from ingesting these throughout the study

• History of severe allergic reaction or anaphylaxis to any component of the investigational product

• Participant had a positive test result at Screening for human immunodeficiency virus (HIV) 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen

• Participant was unable or unwilling to undergo venipuncture for blood sample collection because of poor tolerability or unlikely to complete the trial due to poor venous access

• Participant who had donated plasma or whole blood within 30 days and 60 days, respectively, prior to dosing

• On standard 12-lead ECG, a corrected QT interval using the Fredericia formula (QTcF) interval >450 msec for males and females. If a single ECG QTcF is >450, two more ECGs were obtained over a 5-10 min period and the average of the QTcF interval from the 3 ECGs readings were to be used to determine eligibility

• Planned medical or surgical procedure that could have adversely impact the participant's participation or the conduct of the study

• Any disease, including serious medical or psychiatric condition and/or clinically significant abnormality of laboratory parameters and/or any other reason, which in the opinion of the Investigator and/or medical monitor (MM) compromised the safety of the participant or integrity of the study, interfered with the participant participation in the trial, or compromised the trial objectives

• Participant had a B-SIT score outside of the normative range (10-12) at screening.