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

• ClinicalTrials.gov Identifier: NCT03518021
• Recruitment Status: Recruiting
• First Posted: May 8, 2018
• Last Update Posted: April 29, 2020
• Sponsor: Norwegian University of Science and Technology
• Collaborators: St. Olavs Hospital; Oslo University Hospital
• Information provided by (Responsible Party): Norwegian University of Science and Technology

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.

Condition or disease	Intervention/treatment	Phase
Overdose; Drug Abuse	Drug: Naloxone, intranasal; Drug: placebo, intranasal; Drug: Naloxone, intramuscular; Drug: placebo, intramuscular	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Double blinded, double dummy, randomized controlled trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.
• Primary Purpose: Treatment
• Official Title: NTNU Intranasal Naloxone Trial - a Double Blinded, Double Dummy, Randomized Controlled Trial of Intranasal Naloxone for Pre-hospital Use
• Actual Study Start Date: May 15, 2018
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Naloxone, intranasal	Drug: Naloxone, intranasal; 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.
Active Comparator: Naloxone, intramuscular	Drug: Naloxone, intramuscular; 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
Placebo Comparator: placebo, intranasal	Drug: placebo, intranasal; 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 Comparator: placebo, intramuscular	Drug: placebo, intramuscular; Intramuscular Sodium Chloride Injection 9mg/ml, will be administered as a 2 ml intramuscular injection in the deltoid muscle

Outcome Measures

Primary Outcome Measures :

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 [ Time Frame: 40 minutes ]

Secondary Outcome Measures :

1. 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 ]
2. 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 ]
3. Overdose complications [ Time Frame: The time participants are in the care of ambulance personnel, estimated 40 minutes ]
   aspiration, cardiac arrest, death
4. 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 ]
5. Opioid withdrawal reaction to naloxone reversal [ Time Frame: The time participants are in the care of ambulance personnel, estimated 40 minutes ]
6. Suitability of spray device in pre-hospital setting [ Time Frame: The time participants are in the care of ambulance personnel, estimated 40 minutes ]
7. Adverse reactions to naloxone formulation [ Time Frame: The time participants are in the care of ambulance personnel, estimated 40 minutes ]
8. 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 ]
9. Recurrence of opioid overdose/ need for further pre-hospital naloxone within 12 hours of inclusion [ Time Frame: 12 hours ]
10. reasons not to give rescue naloxone to non-responders [ Time Frame: The time participants are in the care of ambulance personnel, estimated 40 minutes ]
11. follow-up after care [ Time Frame: The time participants are in the care of ambulance personnel, estimated 40 minutes ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Arne K Skulberg, MD PhD; +47 93083544; Arne.skulberg@ntnu.no

Locations

Norway

Oslo University Hospital, Prehospital devision; Recruiting

Oslo, Norway

Contact: Anne Cathrine Braarud, md phd +47 95251010 ANNNAE@ous-hf.no

St Olavs Hospital, Department for Emergency Medicine and Prehospital Services; Recruiting

Trondheim, Norway

Contact: Jostein K Dale, md jostein.dale@stolav.no

Sponsors and Collaborators

Norwegian University of Science and Technology

St. Olavs Hospital

Oslo University Hospital

Investigators

• Study Director: Øystein Risa; Norwegian University of Science and Technology
• Principal Investigator: Arne K Skulberg, MD PhD; Norwegian University of Science and Technology

More Information

• Responsible Party: Norwegian University of Science and Technology
• ClinicalTrials.gov Identifier: NCT03518021
• Other Study ID Numbers: 2016-004072-22; 2016/2000 ( Other Identifier: REK ); 2016-004072-22 ( EudraCT Number )
• First Posted: May 8, 2018
• Last Update Posted: April 29, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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.
• URL: https://dataverse.no/dataset.xhtml?persistentId=doi:10.18710/ABRUWW

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Norwegian University of Science and Technology:

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

Additional relevant MeSH terms:

Substance-Related Disorders; Drug Overdose; Chemically-Induced Disorders; Mental Disorders; Naloxone; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents