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

Study Overview
=================
Brief Summary
-----------------
The main objective of this study was to compare the bioavailability of two test formulations of Naloxone Nasal Spray with the reference formulations of Naloxone HCl IV and IM injection under fasted conditions.

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

Conditions
-----------------
Healthy Volunteer

Intervention / Treatment
-----------------
* Drug: Treatment A: Naloxone Nasal Spray
* Drug: Treatment B: Naloxone Nasal Spray
* Drug: Treatment C: Naloxone HCl Intravenous (IV) Injection
* Drug: Treatment D: Naloxone HCl Intramuscular (IM) Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A minimum body weight of 50 kg. Body mass index (BMI) between 18.0 and 32.0 kg/m2 A seated blood pressure between 90 and 140 mmHg systolic/50 and 90 mmHg diastolic 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 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 congestions

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

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-D-C-B<br>Participants received Treatment A on Day 1 of Period 1, Treatment D on Day 1 of Period 2, Treatment C on Day 1 of Period 3 and Treatment B on Day 1 of Period 4. | 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 Intravenous (IV) Injection<br>* Participants received naloxone HCl IV injection following a 10 hour fast.<br>Drug: Treatment D: 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-D-A<br>Participants received Treatment B on Day 1 of Period 1, Treatment C on Day 1 of Period 2, Treatment D on Day 1 of Period 3 and Treatment A on Day 1 of Period 4. | 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 Intravenous (IV) Injection<br>* Participants received naloxone HCl IV injection following a 10 hour fast.<br>Drug: Treatment D: 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-D<br>Participants received Treatment C on Day 1 of Period 1, Treatment A on Day 1 of Period 2, Treatment B on Day 1 of Period 3 and Treatment D on Day 1 of Period 4. | 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 Intravenous (IV) Injection<br>* Participants received naloxone HCl IV injection following a 10 hour fast.<br>Drug: Treatment D: Naloxone HCl Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|
| Experimental: Cohort 4: Treatment Sequence D-B-A-C<br>Participants received Treatment D on Day 1 of Period 1, Treatment B on Day 1 of Period 2, Treatment A on Day 1 of Period 3 and Treatment C on Day 1 of Period 4. | 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 Intravenous (IV) Injection<br>* Participants received naloxone HCl IV injection following a 10 hour fast.<br>Drug: Treatment D: Naloxone HCl Intramuscular (IM) Injection<br>* Participants received naloxone HCl IM injection following a 10 hour fast.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time 0 to the Last Measured Concentration (AUC0-t) for Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| AUC Extrapolated to Infinity (AUC0-inf) for Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Maximum Plasma Concentration (Cmax) for Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Time to Reach Maximum Plasma Concentration (Tmax) for 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) for Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 
| Elimination Rate Constant (λz) for 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 | 
| Partial Area Under the Concentration Curve (AUC) of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Unconjugated Naloxone |  | Pre-dose and at multiple time points up to 2 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 to Day 14 |