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

NCT03518021 | Completed Phase 3 DMC

• 2 other identifiers: 2016-004072-222016/2000
• Study Type: interventional
• Target: 286
• Locations: 1 country
• Sites: 2

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.

Conditions

Overdose; Drug Abuse

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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

  40 minutes

Secondary Outcomes (11)

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

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

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

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

• Overdose complications

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

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

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

• Opioid withdrawal reaction to naloxone reversal

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

Study Arms (4)

Naloxone, intranasal

EXPERIMENTAL

Drug: Naloxone, intranasal

Naloxone, intramuscular

ACTIVE COMPARATOR

Drug: Naloxone, intramuscular

placebo, intranasal

PLACEBO COMPARATOR

Drug: placebo, intranasal

placebo, intramuscular

PLACEBO COMPARATOR

Drug: placebo, intramuscular

Interventions

Naloxone, intranasal DRUG

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.

Naloxone, intranasal

placebo, intranasal DRUG

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.

placebo, intranasal

Naloxone, intramuscular DRUG

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

Naloxone, intramuscular

placebo, intramuscular DRUG

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

placebo, intramuscular

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Norwegian University of Science and Technology: lead
• St. Olavs Hospital: collaborator
• Oslo University Hospital: collaborator

Study Sites (2)

Oslo University Hospital, Prehospital devision

Oslo, Norway

Location

St Olavs Hospital, Department for Emergency Medicine and Prehospital Services

Trondheim, Norway

Location

Related Publications (2)

• Skulberg AK, Tylleskar I, Valberg M, Braarud AC, Dale J, Heyerdahl F, Skalhegg T, Barstein J, Mellesmo S, Dale O. Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double-dummy, randomised, controlled trial. Addiction. 2022 Jun;117(6):1658-1667. doi: 10.1111/add.15806. Epub 2022 Feb 8.

  PMID: 35137493 DERIVED

• 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.

  PMID: 33184084 DERIVED

MeSH Terms

Conditions

Drug Overdose; Substance-Related Disorders

Interventions

Naloxone; Injections, Intramuscular

Condition Hierarchy (Ancestors)

Prescription Drug Misuse; Drug Misuse; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Injections; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Øystein Risa

  Norwegian University of Science and Technology

  STUDY DIRECTOR

• Arne K Skulberg, MD PhD

  Norwegian University of Science and Technology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Double blinded, double dummy, randomized controlled trial

Study Record Dates

• First Submitted: May 3, 2018
• First Posted: May 8, 2018
• Study Start: May 15, 2018
• Primary Completion: October 6, 2020
• Study Completion: October 6, 2020
• Last Updated: October 8, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Updated regularly, but no later than one year after publication of main results
• 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.

Locations

NO (2)