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Naloxone Nasal Spray Compared With Naloxone Injection for Opioid Overdoses Outside the Hospital (NINA-1)

Primary Purpose

Overdose, Drug Abuse

Status

Completed

Phase

Phase 3

Locations

Norway

Study Type

Interventional

Intervention

Naloxone, intranasal

placebo, intranasal

Naloxone, intramuscular

placebo, intramuscular

About this trial

This is an interventional treatment trial for Overdose focused on measuring Naloxone, Administration, Intranasal, Injections, Intramuscular, Narcotic Antagonists

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Suspected opioid overdose clinically diagnosed by emergency medical service (EMS) based on the following criteria
1. Reduced (below and equal to 8 breaths per minute) or absent spontaneous respiration
2. Miosis
3. Glasgow Coma Scale (GCS) below 12
Palpable carotid or radial arterial pulse

Exclusion Criteria:

Cardiac arrest
Failure to assist ventilation using mask-bag technique
Facial trauma or epistaxis or visible nasal blockage
Iatrogenic opioid overdose when opioid is administered in- hospital, or by EMS or other health care workers in the pre- hospital setting
Suspected or visibly pregnant participant
Has received naloxone by any route in the current overdose
in prison or custody by police
EMS staff without training as study workers
No study drug available
Study drug frozen as indicated by Freeze Watch in kit or past its expiry date
Deemed unfit for inclusion due to any other cause by study personnel at the scene; such as unsafe work environment for EMS

Sites / Locations

Oslo University Hospital, Prehospital devision
St Olavs Hospital, Department for Emergency Medicine and Prehospital Services

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

Naloxone, intranasal

Naloxone, intramuscular

placebo, intranasal

placebo, intramuscular

Arm Description

Outcomes

Primary Outcome Measures

Proportion of patients with return of spontaneous respiration (above or equal to 10 breaths per minute) within 10 minutes of naloxone administration in pre-hospital opioid overdose

Secondary Outcome Measures

Changes in Glasgow Coma Scale (GCS) in patients treated with study medicine for opioid overdose

Changes in oxygen saturation (SaO2) in patients treated with study medicine for opioid overdose

Overdose complications

aspiration, cardiac arrest, death

Time from administration of naloxone to respiration above or equal to 10 breaths per minute

Opioid withdrawal reaction to naloxone reversal

Suitability of spray device in pre-hospital setting

Adverse reactions to naloxone formulation

Need for rescue naloxone, dose and route of administration during study visit

Recurrence of opioid overdose/ need for further pre-hospital naloxone within 12 hours of inclusion

reasons not to give rescue naloxone to non-responders

follow-up after care

Full Information

NCT ID

NCT03518021

First Posted

May 3, 2018

Last Updated

October 7, 2020

Sponsor

Norwegian University of Science and Technology

Collaborators

St. Olavs Hospital, Oslo University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03518021

Brief Title

Naloxone Nasal Spray Compared With Naloxone Injection for Opioid Overdoses Outside the Hospital

Acronym

NINA-1

Official Title

NTNU Intranasal Naloxone Trial - a Double Blinded, Double Dummy, Randomized Controlled Trial of Intranasal Naloxone for Pre-hospital Use

Study Type

Interventional

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Completed

Study Start Date

May 15, 2018 (Actual)

Primary Completion Date

October 6, 2020 (Actual)

Study Completion Date

October 6, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Norwegian University of Science and Technology

Collaborators

St. Olavs Hospital, Oslo University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This trial will compare the clinical response to intramuscular and intranasal naloxone in pre-hospital opioid overdoses. Objective of the study is to measure and evaluate clinical response (return of spontaneous respiration within 10 minutes of naloxone administration) to a new nasal naloxone formulation in real opioid overdoses in the pre-hospital environment. The aim is to demonstrate that intranasal administration of naloxone is not clinically inferior to intramuscular administration, which is now standard treatment of care.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Overdose, Drug Abuse

Keywords

Naloxone, Administration, Intranasal, Injections, Intramuscular, Narcotic Antagonists

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Model Description

Double blinded, double dummy, randomized controlled trial

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

The whole study team, including the statistician, will be blinded until after database lock and the primary analysis are done. The allocation list will be stored by by the Hospital Pharmacy Trondheim. There will not be automatic unblinding of SAEs. Study personnel do not have any access to the allocation list. An emergency option for individual unblinding is available to medical monitor in case of SAE/ SUSAR Study workers are blinded to the different preparations. This is carefully performed by covering the vials with neutral and opaque labels for "study drug". The risk of for unintentional unblinding is very small. The procedure for securing credible blinding is described in the study protocol and approved by the Norwegian Medicines Agency.

Allocation

Randomized

Enrollment

286 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Naloxone, intranasal

Arm Type

Experimental

Arm Title

Naloxone, intramuscular

Arm Type

Active Comparator

Arm Title

placebo, intranasal

Arm Type

Placebo Comparator

Arm Title

placebo, intramuscular

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Naloxone, intranasal

Intervention Description

Active compound naloxone 14 mg/ml, (±10%). Nasal spray will be administered with one puff (100 microL ±10%) in one nostril (1.4 mg dose) using the Aptar Unitdose device. The spray device should be inserted about 1 cm into a nostril, pointing towards the ipsilateral ear and the plunger pushed in a firm and gentle manner for the formulation to be sprayed into the nose. After the plunger is inserted the device is immediately removed from the nose and assisted ventilation continued.

Intervention Type

Drug

Intervention Name(s)

placebo, intranasal

Intervention Description

Same spray but without naloxone. Nasal spray will be administered with one puff (100 microL +/- 10%) in one nostril using the Aptar Unitdose device. The spray device should be inserted about 1 cm into a nostril, pointing towards the ipsilateral ear and the plunger pushed in a firm and gentle manner for the formulation to be sprayed into the nose. After the plunger is inserted the device is immediately removed from the nose and assisted ventilation continued.

Intervention Type

Drug

Intervention Name(s)

Naloxone, intramuscular

Intervention Description

Intramuscular comparator Naloxone Hydrochloride 0.4 mg/ml will be administered as a 2 ml intramuscular (IM) injection in the deltoid muscle, total dose of 0,8 mg naloxone IM

Intervention Type

Drug

Intervention Name(s)

placebo, intramuscular

Intervention Description

Intramuscular Sodium Chloride Injection 9mg/ml, will be administered as a 2 ml intramuscular injection in the deltoid muscle

Primary Outcome Measure Information:

Title

Proportion of patients with return of spontaneous respiration (above or equal to 10 breaths per minute) within 10 minutes of naloxone administration in pre-hospital opioid overdose

Time Frame

40 minutes

Secondary Outcome Measure Information:

Title

Changes in Glasgow Coma Scale (GCS) in patients treated with study medicine for opioid overdose

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Changes in oxygen saturation (SaO2) in patients treated with study medicine for opioid overdose

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Overdose complications

Description

aspiration, cardiac arrest, death

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Time from administration of naloxone to respiration above or equal to 10 breaths per minute

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Opioid withdrawal reaction to naloxone reversal

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Suitability of spray device in pre-hospital setting

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Adverse reactions to naloxone formulation

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Need for rescue naloxone, dose and route of administration during study visit

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

Recurrence of opioid overdose/ need for further pre-hospital naloxone within 12 hours of inclusion

Time Frame

12 hours

Title

reasons not to give rescue naloxone to non-responders

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

Title

follow-up after care

Time Frame

The time participants are in the care of ambulance personnel, estimated 40 minutes

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Suspected opioid overdose clinically diagnosed by emergency medical service (EMS) based on the following criteria Reduced (below and equal to 8 breaths per minute) or absent spontaneous respiration Miosis Glasgow Coma Scale (GCS) below 12 Palpable carotid or radial arterial pulse Exclusion Criteria: Cardiac arrest Failure to assist ventilation using mask-bag technique Facial trauma or epistaxis or visible nasal blockage Iatrogenic opioid overdose when opioid is administered in- hospital, or by EMS or other health care workers in the pre- hospital setting Suspected or visibly pregnant participant Has received naloxone by any route in the current overdose in prison or custody by police EMS staff without training as study workers No study drug available Study drug frozen as indicated by Freeze Watch in kit or past its expiry date Deemed unfit for inclusion due to any other cause by study personnel at the scene; such as unsafe work environment for EMS

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Øystein Risa

Organizational Affiliation

Norwegian University of Science and Technology

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Arne K Skulberg, MD PhD

Organizational Affiliation

Norwegian University of Science and Technology

Official's Role

Principal Investigator

Facility Information:

Facility Name

Oslo University Hospital, Prehospital devision

City

Oslo

Country

Norway

Facility Name

St Olavs Hospital, Department for Emergency Medicine and Prehospital Services

City

Trondheim

Country

Norway

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

NTNU has complete ownership and publishing rights of all results, regardless of outcome. The full protocol, Statistical Analysis Plan, information letter for consent and other trial documents will be published open access in the NTNU Open repository. The Clinical Study report and Statistical Analysis Report will also be made openly available, but open versions may be censored to ensure that it will not be possible to identify individual study participants. The datasets analysed during the current study will be made available from NTNU upon reasonable request and a methodological sound proposal based on the consent given by participants.

IPD Sharing Time Frame

Updated regularly, but no later than one year after publication of main results

IPD Sharing Access Criteria

NTNU will require data processor agreements for recipients conform to standards set out in Norwegian Law and the European General Data Protection Regulation. Any shared datasets will have pseudonymisation of personal data. If doubt NTNU will seek advice from Ethics Committee.

IPD Sharing URL

https://dataverse.no/dataset.xhtml?persistentId=doi:10.18710/ABRUWW

Citations:

PubMed Identifier

33184084

Citation

Skulberg AK, Tylleskar I, Braarud AC, Dale J, Heyerdahl F, Mellesmo S, Valberg M, Dale O. NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use. BMJ Open. 2020 Nov 12;10(11):e041556. doi: 10.1136/bmjopen-2020-041556.

Results Reference

derived

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Naloxone Nasal Spray Compared With Naloxone Injection for Opioid Overdoses Outside the Hospital

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