A Study to Compare Bioavailability of Naloxone Nasal Spray and Naloxone Hydrochloride (HCl) Intramuscular Injection (IM) in Healthy Volunteers

Study Overview
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Brief Summary
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The main objective of this study is to compare early exposures of two test formulations of Naloxone Nasal Spray with the reference formulation of Naloxone HCl IM Injection under fasted conditions.

Official Title
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A Phase 1, Open-Label, Randomized, Crossover, Comparative Bioavailability Study of Naloxone Nasal Spray and Naloxone Hydrochloride Intramuscular Injection in Healthy Volunteers

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Drug: Treatment A: Naloxone Nasal Spray
* Drug: Treatment B: Naloxone Nasal Spray
* Drug: Treatment C: Naloxone HCL Intramuscular (IM) Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A minimum body weight of 50 kg and a body mass index (BMI) between 18.0 and 32.0 kilogram per square meter (kg/m2) A seated blood pressure between 90 and 140 millimeters of mercury (mmHg) systolic/50 and 90 mmHg diastolic (inclusive) Female subjects had a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening Exclusion Criteria: A known allergy or history of significant adverse reaction to naloxone, other opioids or related compounds, or to any of the excipients. Any documented clinically significant infection, injury, or illness within 1 month prior to screening. An active malignancy of any type, or had been diagnosed with cancer within 5 years prior to screening. A documented history of alcohol or drug abuse/dependence/misuse or narcotic analgesic abuse/dependence/misuse within 2 years prior to screening. Alcohol abuse was defined as greater than 14 drinks per week. Positive serology test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening. A positive urine test result for alcohol, drugs, or cotinine at screening or check-in. A condition that the Investigator believed would have interfered with the ability to provide informed consent or comply with study instructions, or that could confound the interpretation of the study results or put the subject at undue risk. Used any opioids for 30 days prior to Day 1. Required treatment with monoamine oxidase inhibitors (MAOIs) within 30 days prior to Day 1 and during the study. Presence of an ongoing upper respiratory infection, rhinitis, rhinorrhea, or nasal congestion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Treatment Sequence A-B-C<br>Participants received Treatment A on Day 1 of Period 1, Treatment B on Day 1 of Period 2, and Treatment C on Day 1 of Period 3. | Drug: Treatment A: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment B: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment C: Naloxone HCL Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|
| Experimental: Cohort 2: Treatment Sequence B-C-A<br>Participants received Treatment B on Day 1 of Period 1, Treatment C on Day 1 of Period 2, and Treatment A on Day 1 of Period 3. | Drug: Treatment A: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment B: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment C: Naloxone HCL Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|
| Experimental: Cohort 3: Treatment Sequence C-A-B<br>Participants received Treatment C on Day 1 of Period 1, Treatment A on Day 1 of Period 2, and Treatment B on Day 1 of Period 3. | Drug: Treatment A: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment B: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment C: Naloxone HCL Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|
| Experimental: Cohort 4: Treatment Sequence A-C-B<br>Participants received Treatment A on Day 1 of Period 1, Treatment C on Day 1 of Period 2, and Treatment B on Day 1 of Period 3. | Drug: Treatment A: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment B: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment C: Naloxone HCL Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|
| Experimental: Cohort 5: Treatment Sequence C-B-A<br>Participants received Treatment C on Day 1 of Period 1, Treatment B on Day 1 of Period 2, and Treatment A on Day 1 of Period 3. | Drug: Treatment A: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment B: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment C: Naloxone HCL Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|
| Experimental: Cohort 6: Treatment Sequence B-A-C<br>Participants received Treatment B on Day 1 of Period 1, Treatment A on Day 1 of Period 2, and Treatment C on Day 1 of Period 3. | Drug: Treatment A: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment B: Naloxone Nasal Spray<br>* Participants received naloxone nasal spray following a 10 hour fast.<br>Drug: Treatment C: Naloxone HCL Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 1 hour post-dose | 
| Partial Area Under the Concentration Curve (AUC) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 1 hour post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve from Time 0 to the Last Measured Concentration (AUC0-t) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Area Under the Curve from Time 0 to Infinity (AUC0-inf) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Percentage of AUC0-inf Obtained by Extrapolation (AUCextrap) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Maximum Plasma Concentration (Cmax) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Last Quantifiable Concentration (Clast) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Time of the Last Quantifiable Concentration (Tlast) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Time Prior to the First Measurable (Non-Zero) Concentration (Tlag) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Elimination Rate Constant (λz) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Elimination Half-Life (t1/2) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. A serious AE (SAE) is any AE that results in death, is life threatening, requires hospitalization or prolongs existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is medically significant or requires intervention. | Day 1 up to Day 10 |