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Bioavailability of Nasal Naloxone and Injected Naloxone Compared (OPI-15-002)

Primary Purpose

Drug Overdose

Status
Completed
Phase
Phase 1
Locations
Norway
Study Type
Interventional
Intervention
Intranasal (IN) naloxone 1x
Intranasal (IN) naloxone 2
Intravenous (IV) naloxone
Intramuscular (IM) naloxone
Sponsored by
Norwegian University of Science and Technology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Drug Overdose focused on measuring Emergency Treatment, Morphine Derivates, Heroin, Antidotes, Administration, Intravenous, Pharmacology, Naloxone, Healthy volunteers, Administration, intramuscular, Administration, intranasal

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

In order to participate in this study the subjects must meet all of the following inclusion criteria:

  • Provision of a signed written informed consent
  • ECG without any pathological abnormalities
  • Have a BMI range of 18.5- 26.0 kg/m
  • Female subject with child bearing potential must use high efficacy contraception. For the purpose of this study acceptable contraception is defined as sterilization, oral contraceptives, patch, implants, vaginal ring, hormonal IUD or copper IUD through out the study until the last visit.

  • Laboratory values within reference values for the following haematology and biochemistry tests:

    • Haemoglobin
    • Creatinine
    • ASAT
    • ALAT
    • Gamma GT

Exclusion Criteria:

In order to participate in the study subjects must not meet any of the following exclusion criteria:

  • using medication on a regular basis, including regular use of nasal spray of any form.
  • History of prior drug allergy
  • local nasal disease or nasal surgery for the last 2 months
  • Pregnant or breast feeding women. A serum HCG below 3 U/L must be demonstrated in females of child-bearing potential at Screening Visit.
  • Current drug or alcohol abuse, which in the opinion of the Investigator should preclude participation in the study.
  • Having received another new medical chemical entity (defined as a compound which has not been approved for marketing) or having participated in any other clinical study that included drug treatment within 3 months of the administration of investigational product in this study.
  • Hypersensitivity to naloxone or any of its excipients.
  • Investigator considers subject unlikely to comply with study procedures, restrictions and/or other requirements.

Sites / Locations

  • Department of Circulation and Medical Imaging

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Active Comparator

Active Comparator

Arm Label

Intranasal naloxone 1x

Intranasal naloxone 2x

Intravenous naloxone

Intramuscular naloxone

Arm Description

Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.

Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.

Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.

Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.

Outcomes

Primary Outcome Measures

Difference in Peak plasma concentration (Cmax)
Cmax will be compared for single dose IN, IM and IV naloxone
Difference in systemic exposure: Area under the plasma concentration versus time curve (AUC-0last)
AUC 0-last will be compared for single dose IN, IM and IV naloxone
Difference in dose adjusted systemic exposure: Area under the plasma concentration versus time curve (AUC-0inf)
AUC0-inf will be compared for single dose IN, IM and IV naloxone
Difference in time at which the Cmax is observed (Tmax)
Tmax will be compared for single dose IN, IM and IV naloxone

Secondary Outcome Measures

Dose proportionality
assessed by comparing systemic exposure (AUC0-last) following one and two doses of 1.4 mg of IN naloxone in the same nostril.
Absolute bioavailability
assessed by comparing dose adjusted systemic exposure (AUC0-last) of IN and IV naloxone
Relative bioavailability
assessed by comparing dose adjusted systemic exposure (AUC0-last) of IN and IM naloxone

Full Information

First Posted
November 2, 2015
Last Updated
February 2, 2017
Sponsor
Norwegian University of Science and Technology
Collaborators
St. Olavs Hospital, A/S Den norske Eterfabrikk, Smerud Medical Research International AS
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1. Study Identification

Unique Protocol Identification Number
NCT02598856
Brief Title
Bioavailability of Nasal Naloxone and Injected Naloxone Compared
Acronym
OPI-15-002
Official Title
Bioavailability of Nasal Naloxone and Injected Naloxone Compared. A Randomized, Open Label, 4-way Cross-over Study
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
March 2016 (undefined)
Primary Completion Date
December 2016 (Actual)
Study Completion Date
December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Norwegian University of Science and Technology
Collaborators
St. Olavs Hospital, A/S Den norske Eterfabrikk, Smerud Medical Research International AS

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Opioid overdoses have in the last decade counted for about 230 untimely deaths annually in Norway. The government is currently implementing a strategy for combating this epidemic. Among the actions promoted in this strategy is the distribution of naloxone for intranasal administration. Such administration of naloxone is currently being implemented and tried out around the world, but very little has been done to pharmacologically study this new route of administration of this well known drug, and only 3 open label randomized controlled trials (RCTs) have been conducted. A recent guideline from the WHO on community management of opioid overdoses is a comprehensive review of many of the aspects the investigators cover in our research. Regarding both dosage, routes of administration of naloxone and care of these patients in the pre hospital setting. The WHO calls for nasal formulations with a higher concentration, as well as focuses on the current wide spread off label use of nasal naloxone as a problem and identifies several research questions of critical importance and very low evidence.The current study, together with our research group's previous and future studies, aims to provide data for the development of a medicinal product with marketing authorisation for use in pre-hospital overdoses. This to contribute to public health measures for opioid users and those around them.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Drug Overdose
Keywords
Emergency Treatment, Morphine Derivates, Heroin, Antidotes, Administration, Intravenous, Pharmacology, Naloxone, Healthy volunteers, Administration, intramuscular, Administration, intranasal

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
22 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intranasal naloxone 1x
Arm Type
Experimental
Arm Description
Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.
Arm Title
Intranasal naloxone 2x
Arm Type
Active Comparator
Arm Description
Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.
Arm Title
Intravenous naloxone
Arm Type
Active Comparator
Arm Description
Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.
Arm Title
Intramuscular naloxone
Arm Type
Active Comparator
Arm Description
Each subject will receive one dose of IN naloxone 1.4 mg, IN naloxone 2 x 1.4 mg, IV naloxone 0.4 mg and IM naloxone 0.8 mg in a randomized order. The four doses will be given at four different visits with a washout period of at least 72 hours between. One follow-up visit will be conducted within one month after the last exposure.
Intervention Type
Drug
Intervention Name(s)
Intranasal (IN) naloxone 1x
Intervention Description
Administered as 100 μl 14.0 mg/ml (1.4 mg naloxone) by Aptar Unitdose device as one puff in one nostril
Intervention Type
Drug
Intervention Name(s)
Intranasal (IN) naloxone 2
Intervention Description
Administered as 2x 100 μl 14 mg/ml (2.8 mg naloxone) by Aptar Unitdose device as two puffs within the same nostril with 3 minutes interval
Intervention Type
Drug
Intervention Name(s)
Intravenous (IV) naloxone
Intervention Description
Administered as 1 ml Naloxon B Braun 0.4 mg/ml (0.4 mg naloxone), in an intravenous cannula in the opposite arm of which the blood samples are drawn from. IV bolus will be given rapidly (in less than 5 seconds)
Intervention Type
Drug
Intervention Name(s)
Intramuscular (IM) naloxone
Intervention Description
Naloxone administered as 2 ml Naloxon B Braun 0.4 mg/ml (0.8 mg naloxone) in a Braun Omnifix 2.5 ml syringe using a BD Microlance 3 21G (green) 0.8x40 mm needle in the deltoid muscle of the non-dominant arm
Primary Outcome Measure Information:
Title
Difference in Peak plasma concentration (Cmax)
Description
Cmax will be compared for single dose IN, IM and IV naloxone
Time Frame
4 days
Title
Difference in systemic exposure: Area under the plasma concentration versus time curve (AUC-0last)
Description
AUC 0-last will be compared for single dose IN, IM and IV naloxone
Time Frame
4 days
Title
Difference in dose adjusted systemic exposure: Area under the plasma concentration versus time curve (AUC-0inf)
Description
AUC0-inf will be compared for single dose IN, IM and IV naloxone
Time Frame
4 days
Title
Difference in time at which the Cmax is observed (Tmax)
Description
Tmax will be compared for single dose IN, IM and IV naloxone
Time Frame
4 days
Secondary Outcome Measure Information:
Title
Dose proportionality
Description
assessed by comparing systemic exposure (AUC0-last) following one and two doses of 1.4 mg of IN naloxone in the same nostril.
Time Frame
4 days
Title
Absolute bioavailability
Description
assessed by comparing dose adjusted systemic exposure (AUC0-last) of IN and IV naloxone
Time Frame
4 days
Title
Relative bioavailability
Description
assessed by comparing dose adjusted systemic exposure (AUC0-last) of IN and IM naloxone
Time Frame
4 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: In order to participate in this study the subjects must meet all of the following inclusion criteria: Provision of a signed written informed consent ECG without any pathological abnormalities Have a BMI range of 18.5- 26.0 kg/m Female subject with child bearing potential must use high efficacy contraception. For the purpose of this study acceptable contraception is defined as sterilization, oral contraceptives, patch, implants, vaginal ring, hormonal IUD or copper IUD through out the study until the last visit. Laboratory values within reference values for the following haematology and biochemistry tests: Haemoglobin Creatinine ASAT ALAT Gamma GT Exclusion Criteria: In order to participate in the study subjects must not meet any of the following exclusion criteria: using medication on a regular basis, including regular use of nasal spray of any form. History of prior drug allergy local nasal disease or nasal surgery for the last 2 months Pregnant or breast feeding women. A serum HCG below 3 U/L must be demonstrated in females of child-bearing potential at Screening Visit. Current drug or alcohol abuse, which in the opinion of the Investigator should preclude participation in the study. Having received another new medical chemical entity (defined as a compound which has not been approved for marketing) or having participated in any other clinical study that included drug treatment within 3 months of the administration of investigational product in this study. Hypersensitivity to naloxone or any of its excipients. Investigator considers subject unlikely to comply with study procedures, restrictions and/or other requirements.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Toril A Nagelhus Hernes, phd prof
Organizational Affiliation
Norwegian University of Science and Technology
Official's Role
Study Director
Facility Information:
Facility Name
Department of Circulation and Medical Imaging
City
Trondheim
Country
Norway

12. IPD Sharing Statement

Learn more about this trial

Bioavailability of Nasal Naloxone and Injected Naloxone Compared

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