Buccal Versus Injectable Naloxone: a Phase I Healthy Volunteer Study

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

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.

Study Overview

• Status: Unknown
• Conditions: Opioid-Related Disorders; Drug Overdose
• Intervention / Treatment: Drug: Naloxone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 4
• Phase: Phase 1

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Adult males aged 18 to 64 years inclusive and between 19 and 29.9 kg/m2 body mass index (BMI).
2. Subjects who are healthy as determined by pre-study medical history and physical examination.
3. Subjects who are able and willing to give written informed consent.
4. Medical history must be verified by either a personal physician or medical practitioner as appropriate.

Exclusion Criteria:

1. Subjects who do not conform to the above inclusion criteria.
2. 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.
3. Subjects who have a clinically relevant surgical history.
4. Subjects who have a clinically relevant family history.
5. Subjects who have a history of relevant atopy.
6. Subjects who have a history of drug hypersensitivity relevant to naloxone.
7. Subjects who have a history of alcoholism.
8. Subjects who have a history of drug abuse.
9. 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)
10. 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.
11. Subjects who have used prescription drugs within 4 weeks of first dosing.
12. 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.
13. Subjects who have used any investigational drug in any clinical trial within 3 months of receiving the last dose.
14. Subjects who have received the last dose of IMP greater than 3 months ago but who are on extended follow-up
15. Subjects who cannot communicate reliably with the Investigator.
16. Subjects who are unlikely to co-operate with the requirements of the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: King's College London
• Investigators: Principal Investigator: John Strang, MBBS, MD, King's College London

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Anticipated): June 1, 2017
• Study Completion (Anticipated): June 1, 2017

Study Registration Dates

• First Submitted: March 8, 2016
• First Submitted That Met QC Criteria: April 5, 2016
• First Posted (Estimate): April 12, 2016

Study Record Updates

• Last Update Posted (Estimate): May 17, 2016
• Last Update Submitted That Met QC Criteria: May 16, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: opioid; naloxone; overdose; heroin; opiate
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Narcotic-Related Disorders; Opioid-Related Disorders; Drug Overdose; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Naloxone
• Other Study ID Numbers: KCL/NALOX/01/14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: There is no plan to provide access to to raw data.