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

Abstract

Introduction: Intranasal (IN) naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared with injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers, while off-label nasal sprays with low bioavailability have been studied in patients. Randomised clinical trials are needed to investigate efficacy and safety of approved IN naloxone in patients suffering overdose. This study investigates whether the administration of 1.4 mg naloxone in 0.1 mL per dose is non-inferior to 0.8 mg intramuscular injection in patients treated for opioid overdose.

Methods and analysis: Sponsor is the Norwegian University of Science and Technology. The study has been developed in collaboration with user representatives. The primary endpoint is the restoration of spontaneous respiration≥10 breaths/min based on a sample of 200 opioid overdose cases. Double-dummy design ensures blinding, which will be maintained until the database is locked.

Ethics and dissemination: The study was approved by the Norwegian Medicines Agency and Regional Ethics Committees (REC: 2016/2000). It adheres to the Good Clinical Practice guidelines as set out by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.Informed consent will be sought through a differentiated model. This allows for deferred consent after inclusion for patients who have regained the ability to consent. Patients who are unable to consent prior to discharge by emergency services are given written information and can withdraw at a later date in line with user recommendations. Metadata will be published in the Norwegian University of Science and Technology Open repository. Deidentified individual participant data will be made available to recipients conditional of data processor agreement being entered.

Trial registration numbers: EudraCT Registry (2016-004072-22) and Clinicaltrials.gov Registry (NCT03518021).

Keywords: accident & emergency medicine; clinical pharmacology; medical ethics; statistics & research methods; toxicology.

Conflict of interest statement

Competing interests: The contents and production of study kits are funded by dne pharma as, Oslo, Norway. Norwegian University of Science and Technology (NTNU) and its subsidiary Technical Transfer Office have signed cooperative and licensing contracts with dne pharma as to seek commercialisation of this nasal naloxone formulation. This regulates potential royalties for OD through NTNU. dne pharma as has compensated OD for business travel from Trondheim to Oslo and to Lisbon. AKS spoke at a seminar arranged by dne pharma as in Lisbon in October 2019 without an honorarium or other compensation. The other authors declare no conflicts of interest. The funding sources have no role in the study design, data collection, data analysis, data interpretation or writing of the clinical study report.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study kit contents. (A) Hypodermic needles for aspiration and intramuscular administration. (B) Active or placebo for intramuscular injection. (C) Freeze watch. (D) Alcohol swab. (E) Syringe, 2.5 mL. (F) Active or placebo nasal spray. (G) Stopwatch illustration by Øystein Horgmo, Oslo University Hospital.

Figure 2

Flow chart for study visit. ABC, Airway, Breathing, Circulation; EMS, Emergency Medical Services; GCS, Glasgow Coma Scale; IM, intramuscular; IN, intranasal.

Figure 3

Flow chart over procedure for consent.