Buccal Versus Injectable Naloxone: a Phase I Healthy Volunteer Study

Study Overview
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Brief Summary
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Naloxone is the standard treatment in response to cases of suspected opiate overdose. Buccal formulation of naloxone is a novel alternative to the licensed naloxone injection which, by removing the risk of accidental needle-stick, may be safer and easier to administer. Current UK policy allows the emergency administration of naloxone by any member of the general public (Strang, Kelleher, Best, Mayet, & Manning, 2006), and the preventative provision of naloxone to drug users and their family members (take-home naloxone) is possible on a prescription basis. Thus, buccal naloxone may be particularly suitable for administration by family members who are providing interim overdose management care while awaiting the arrival of an ambulance. The aim of this study is to examine the bioavailability and dose proportionality of buccal naloxone compared with the licensed injection standards (intravenous, intramuscular). The investigators hypothesise that buccal naloxone is not inferior to the injection reference in absorption kinetics, i.e. time elapsed till peak concentration (Tmax; primary outcome), peak plasma concentration (Cmax), overall absorption (AUC), bioavailability (F%) and, duration of action (mean terminal half-life; T1/2). The investigators propose a pharmacokinetic pilot investigation with within-subjects (crossover) design, comparing two doses (0.8 mg; 1.6 mg) of buccal naloxone hydrochloride solution to the licensed intramuscular (IM; 0.8 mg) and intravenous (IV; 0.8 mg) routes of injection. The investigators will invite four healthy (i.e., non-opioid using) male volunteers (n=4, not powered), each of whom will attend four experimental sessions at counterbalanced sequence. Each volunteer will receive naloxone hydrochloride doses of 0.8 mg IM, 0.8 mg IV, 0.8 mg buccal, and 1.6 mg buccal, with only one dose administered per session. Blood concentrations will be measured at selected times during each session to establish speed of naloxone absorption, time to peak concentration, estimated half-life, and overall bioavailability. This dose-ranging pilot will inform future work by providing preliminary data on buccal naloxone absorption into the bloodstream and by establishing feasibility of the buccal route for naloxone delivery.

Detailed Description
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Blood samples (3 ml) will be collected at -5, +1, 2, 3, 4, 6, 8, 10, 12.5, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 300, 360, 420, and 480 minutes.

Official Title
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A Pilot, Phase 1, Open-Labelled, 4 Period, Randomised, Crossover Study to Evaluate the Pharmacokinetics of Naloxone When Given by the IV, IM and Buccal Routes of Administration in Healthy Male Subjects

Conditions
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Drug Overdose, Opioid-Related Disorders

Intervention / Treatment
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* Drug: Naloxone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males aged 18 to 64 years inclusive and between 19 and 29.9 kg/m2 body mass index (BMI). Subjects who are healthy as determined by pre-study medical history and physical examination. Subjects who are able and willing to give written informed consent. Medical history must be verified by either a personal physician or medical practitioner as appropriate. Exclusion Criteria: Subjects who do not conform to the above inclusion criteria. Subjects who have a clinical condition (such as abnormal liver function, renal or cardiac issues) which, in the opinion of their personal physician or other examining medical practitioner, makes participation in the study inappropriate. Subjects who have a clinically relevant surgical history. Subjects who have a clinically relevant family history. Subjects who have a history of relevant atopy. Subjects who have a history of drug hypersensitivity relevant to naloxone. Subjects who have a history of alcoholism. Subjects who have a history of drug abuse. Subjects who consume more than 42 units of alcohol a week. (unit = 1 glass of wine (125 mL) = 1 measure of spirits = ½ pint of beer) Subjects who have an acute infection (such as influenza) or relevant lesion (such as oral tract) at the time of screening or admission. Subjects can be rescreened once they have recovered. At re-screening, a urine test of drugs of abuse and alcohol parameters will need to be repeated. Subjects who have used prescription drugs within 4 weeks of first dosing. Subjects who have used over the counter medications containing codeine or other opiates within 7 days of first dosing, unless agreed as not clinically relevant by the Principal Investigator. Details will be documented in source data. Subjects who have used any investigational drug in any clinical trial within 3 months of receiving the last dose. Subjects who have received the last dose of IMP greater than 3 months ago but who are on extended follow-up Subjects who cannot communicate reliably with the Investigator. Subjects who are unlikely to co-operate with the requirements of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Male

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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMP: buccal naloxone (single dose)<br>0.8 mg buccal (solution) of 1 mg/ml Naloxone Hydrochloride Injection | Drug: Naloxone<br> <br> * Other names: naloxone-hydrochloride;|
| Experimental: IMP: buccal naloxone (double dose)<br>1.6 mg buccal (solution) of 1 mg/ml Naloxone Hydrochloride Injection | Drug: Naloxone<br> <br> * Other names: naloxone-hydrochloride;|
| Active Comparator: Intramuscular (IM) reference<br>0.8 mg IM injection of 1 mg/ml Naloxone Hydrochloride Injection | Drug: Naloxone<br> <br> * Other names: naloxone-hydrochloride;|
| Active Comparator: Intravenous (IV) reference<br>0.8 mg IV injection of 1 mg/ml Naloxone Hydrochloride Injection | Drug: Naloxone<br> <br> * Other names: naloxone-hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax | Time elapsed till peak concentration | Within 8-hour sampling period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration is assessed as Cmax | Peak concentration | Within 8-hour sampling period | 
| Absorption of the active ingredient is determined as Area under the Curve (AUC) | Overall absorption (AUC = Area Under the Curve) | Within 8-hour sampling period | 
| Absolute bioavailability of buccal naloxone relative to intravenous naloxone is assessed as F% | Absolute bioavailability relative to the IV reference (dose-corrected AUC for non-intravenous Buccal AUC divided by intravenous AUC multiplied by 100 | Within 8-hour sampling period | 
| Mean terminal half-life is assessed for all participants as T1/2 | mean terminal half-life | Within 8-hour sampling period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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opiate, heroin, opioid, overdose, naloxone