NINA-1

Department of Circulation and Imaging, NTNU

AHL Senteret St. Olavs, Trondheim, Norway,

Dept. secretary, Department of Circulation and Imaging, NTNU, 47 73595000, isb-post@medisin.ntnu.no

Dept. secretary, Department of Circulation and Imaging, NTNU, 47 73595000, isb-post@medisin.ntnu.no

No

No

No

Final

30 Oct 2020

Yes

06 Oct 2020

Yes

06 Oct 2020

No

Measure and evaluate clinical response to nasal naloxone in real opioid overdoses in the pre hospital environment.

Patients included in the NINA-1 trial were in several ways vulnerable patients. Opioid users are often considered a vulnerable group in society. The risk of overdose is particularly high for people injecting opioids (heroin), and our inclusion criteria selects out participants with high risk drug use. Article 20 of the Helsinki Declaration describes research on vulnerable participants. It states that “Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non- vulnerable group”. Nasal naloxone is a drug designed especially for the group at risk of opioid overdoses, as emergency treatment of a life threatening condition. Further the declaration states Article 30 regulates the situation of unconscious patients with no legal representative present within the time period research must happen. “Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary characteristic of the research group”. Our inclusion criteria describe exactly such a group- where unconsciousness (low GCS) is an inclusion criterion. This protection was mainly that all other treatment options were unchanged, the only aspect of treatment altered was the dose and route of administration of naloxone. Airway, breathing and follow up was the same for included and not included patients. Patients were included by trained ambulance personnel, with wide experience in treating opioid intoxicated patients. In addition to the existing professional training they all received study specific training in how to conduct the trial and ensure the well being and safety of participants. The trial was approved by the Ethics committee and an independent Data Monitoring and Safety Board was in place.

14 Jun 2018

No

Yes

Norway: 286

286

286

0

0

0

0

0

0

286

0

0

Overall trial (overall period)

Randomised - controlled

To ensure blinding, a double-dummy design is used. Participants are administered both a nasal spray and an intramuscular injection at the same time, of which one contains naloxone and the other an inactive substance. This ensures that all patients receive naloxone and that both the patient and study workers are blinded for the treatment which the patient is allocated. The blinding assembly, randomisation of kits was performed the pharmacy of the Central Norwegian Regional Health Authority

Yes

Nasal naloxone 1.4 mg/dose

ATC: V03AB15

Nalokson DnE Nasal Spray 14 mg/mL

Nasal spray, solution in single-dose container

Intranasal use

The investigational medicinal product (IMP) is a 1.4 mg naloxone hydrochloride nasal spray. This drug is administered as 1.4 mg/0.1 mL nasal spray using the Aptar Unit Dose Device (Louveciennes, France). Spray was produced by Sanivo Pharma, Oslo, Norway. Participants are administered both a nasal spray and an intramuscular injection at the same time, of which one contains naloxone and the other an inactive substance. This ensures that all patients receive naloxone and that both the patient and study workers are blinded for the treatment which the patient is allocated. The drugs will be administered as simultaneously as possible, and within 30 s of each other. The IN spray is administered first if unable to coordinate simultaneous administration on site

0,9% Sodium Chloride Injection

Solution for injection

Intramuscular use

Participants are administered both a nasal spray and an intramuscular injection at the same time, of which one contains naloxone and the other an inactive substance. This ensures that all patients receive naloxone and that both the patient and study workers are blinded for the treatment which the patient is allocated. The drugs will be administered as simultaneously as possible, and within 30 s of each other. The IN spray is administered first if unable to coordinate simultaneous administration on site. The IM placebo was administered as 2 ml intramuscular injection in the deltoid muscle

Naloxone Hydrochloride Injection, USP

Solution for injection

Intramuscular use

Participants are administered both a nasal spray and an intramuscular injection at the same time, of which one contains naloxone and the other an inactive substance. This ensures that all patients receive naloxone and that both the patient and study workers are blinded for the treatment which the patient is allocated. The drugs will be administered as simultaneously as possible, and within 30 s of each other. The IN spray is administered first if unable to coordinate simultaneous administration on site. The active comparator is 2 mL naloxone hydrochloride (0.4 mg/mL), with a total dose of 0.8 mg. The intramuscular injection should be given in the deltoid muscle.

Placebo nasal spray

Nasal spray, solution in single-dose container

Intranasal use

0.1 ml nasal spray in Aptar Unit Dose container. Produced by Sanivo Pharma. Contained Povidone, Glycerol, Disodium edetate Benzalkonium chloride, Citric acid monohydrate, Sodium citrate, Sodium hydroxide (for pH-adjustment) Hydrochloric acid (for pH-adjustment) Water for injections. Did not contain naloxone

Overall trial

Full Analysis Set (FAS)

In EudraCT we report Full analysis set (FAS): All events where the patient received study medicine and where the patient did not refuse or withdrew consent. Please note we report events, not individuals, these 208 events constitute 161 individuals, some included multiple times Other subject sets analysed were: • All randomized overdose events: All events that have been randomized whether or not the patient received treatment. • Safety Set: All events where the patient received study medicine (full or partial adherence to allocated treatment) and including anonymous data on from participants who have not consented • Per protocol set (PPS): All events where the patient received study medicine fully compliant with the study protocol and where the patient did not refuse or withdrew consent.

Per Protocol set

Per protocol set (PPS): All events where the patient received study medicine fully compliant with the study protocol and where the patient did not refuse or withdrew consent.

Safety Set

Safety Set: All events where the patient received study medicine (full or partial adherence to allocated treatment) and including anonymous data on from participants who have not consented

Intranasal naloxone

Intramuscular naloxone

Full Analysis Set (FAS)

In EudraCT we report Full analysis set (FAS): All events where the patient received study medicine and where the patient did not refuse or withdrew consent. Please note we report events, not individuals, these 208 events constitute 161 individuals, some included multiple times Other subject sets analysed were: • All randomized overdose events: All events that have been randomized whether or not the patient received treatment. • Safety Set: All events where the patient received study medicine (full or partial adherence to allocated treatment) and including anonymous data on from participants who have not consented • Per protocol set (PPS): All events where the patient received study medicine fully compliant with the study protocol and where the patient did not refuse or withdrew consent.

Per Protocol set

Per protocol set (PPS): All events where the patient received study medicine fully compliant with the study protocol and where the patient did not refuse or withdrew consent.

Safety Set

Safety Set: All events where the patient received study medicine (full or partial adherence to allocated treatment) and including anonymous data on from participants who have not consented

Ambulance staff should note the number of minutes from the administration of the study medicine to a spontaneous respiration rate of ≥10 breaths/min.

Primary

Within 10 minutes of being administered study drug.

The dichotomous treatment variable will be adjusted by study site. To account for the the same individual may be included several times the parameters in the model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the difference in the marginal predicted probabilities of returning to spontaneous breathing within 10 minutes will be calculated for each group.

Intranasal naloxone v Intramuscular naloxone

208

Pre-specified

17.3

2-sided

Changes in Glasgow Coma Scale from 0 to 10 minutes where 0 is time naloxone is administered

Secondary

0- 10 minutes

A linear regression model will be fitted to the data, with the change value (for GCS and oxygen saturation, respectively) as the dependent variable. The dichotomous treatment variable will be adjusted for by study site and the initial measurement before the trial. The model parameters will be fitted using GEE with exchangeable working correlation, to account for the clustering of the data (possibly more than one overdose in each individual).

Intramuscular naloxone v Intranasal naloxone

201

Pre-specified

1.86

2-sided

Oxygen saturation, SpO2 = oxygen saturation as measured by light absorptionn through a non-invasive pulse oximeter. It is the fraction of oxygen-saturated haemoglobin relative to total haemoglobin (unsaturated + saturated) in the blood. SpO2 is given as a percentage. The change in SpO2 as measured before the intervention (at baseline), to the SpO2 value measured at the end of the intervention (at 10 minutes). This is a continuous outcome.

Secondary

The change in SpO2 as measured before the intervention (at baseline), to the SpO2 value measured at the end of the intervention (at 10 minutes). This is a continuous outcome.

A linear regression model will be fitted to the data, with the change value (for GCS and oxygen saturation, respectively) as the dependent variable. The dichotomous treatment variable will be adjusted for by study site and the initial measurement before the trial. The model parameters will be fitted using GEE with exchangeable working correlation, to account for the clustering of the data (possibly more than one overdose in each individual).

Intranasal naloxone v Intramuscular naloxone

201

Pre-specified

-0.33

2-sided

Whether or not the patient has an overdose complication. This is recorded during the time of protocol therapy. This is a dichotomous outcome.

Secondary

From Naloxone administered until end of observation time

The dichotomous treatment variable will be adjusted by study site (the stratification factor used in the randomisation). To account for the possibility that the same individual may be included several times in the trial (i.e. the same person can have several overdoses), the parameters in the logistic regression model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the d

Intranasal naloxone v Intramuscular naloxone

201

Pre-specified

0.012

2-sided

Adverse reactions defined as opioid withdrawal syndromes (MedDra lowest level term (LLT) 10030882). It includes responses subjectively described as abstinence, agitation or aggression. Nausea and vomiting are excluded, and perorated separately as Adverse Events

Secondary

From administration of naloxone to end of observation

The will be adjusted by study site . To account for the possibility that the same individual may be included several times in the trial the parameters in the logistic regression model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the difference in the marginal predicted will be calculated for each group. There will be no assumption checks performed

Intranasal naloxone v Intramuscular naloxone

201

Pre-specified

0.012

2-sided

The will be adjusted by study site . To account for the possibility that the same individual may be included several times in the trial the parameters in the logistic regression model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the difference in the marginal predicted will be calculated for each group. There will be no assumption checks performed

Intranasal naloxone v Intramuscular naloxone

201

Post-hoc

6.8

2-sided

Whether or not the patient has an adverse reaction to the naloxone formulation. This is recorded during the time of protocol therapy. This is a dichotomous outcome. An adverse event deemed to have a certain, probable/likely or possible causal relationship to the IMP will be classified as an adverse reaction.

Secondary

From naloxone administration to end of observation

The will be adjusted by study site . To account for the possibility that the same individual may be included several times in the trial the parameters in the logistic regression model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the difference in the marginal predicted will be calculated for each group. There will be no assumption checks performed

Intramuscular naloxone v Intranasal naloxone

201

Pre-specified

-0.022

2-sided

This is defined as patients treated with non- IMP naloxone in addition to study drug during the study visit, or immediately after transfer to follow up. Some patients will be in clinical need of further naloxone, but not have this given for various reasons. Such reasons not to give rescue naloxone to non-responders will be recorded and listed.

Secondary

From naloxone administration until end of treatment

The will be adjusted by study site . To account for the possibility that the same individual may be included several times in the trial the parameters in the logistic regression model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the difference in the marginal predicted will be calculated for each group. There will be no assumption checks performed

Intranasal naloxone v Intramuscular naloxone

201

Pre-specified

-0.194

2-sided

Recurrence is defined as having received naloxone within 12 hours after discharge from study visit. This includes Take Home Naloxone known to Emergency medical Services, or naloxone administered by the ambulance service. It is assessed by analysing medical records in the Ambulance Service for ambulance callouts to individuals included with known national Identity Number for 12 hours following inclusion in this trial. However, patients who receive Take-Home Naloxone without involving the ambulance service will not be recorded. Patients suffering a fatal overdose in this 12-hour window may not be registered in the trial as the study database will not be linked to the Norwegian National Cause of Death Registry

Secondary

from naloxone administration and 12 hours onwards

The will be adjusted by study site . To account for the possibility that the same individual may be included several times in the trial the parameters in the logistic regression model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the difference in the marginal predicted will be calculated for each group. There will be no assumption checks performed

Intramuscular naloxone v Intranasal naloxone

201

Pre-specified

-0.002

2-sided

Risk of being followed-up at hospital or by primary care as opposed to being left at the scene without further health service follow up. Defined as the level of health care to which the patient is transferred after treatment by ambulance services, or if left at the scene. The variable contains the following categories: 1. Left at the scene of treatment. This represent patients who are not transported to further care or follow up after treatment with study drug. 2. Handed over to primary care. In Norway defined as general practitioners and Accident and Emergency Outpatient Clinic (Kommunal legevakt). 3. Handed over to hospital. Patient is transferred to tertiary care, defined as hospitals with facilities for advanced medical investigations and treatment. 4. Others. Some patients are transferred to places not fitting any of these categories, such as drug-user shelters.

Secondary

From naloxone administration until end of obervation

The will be adjusted by study site . To account for the possibility that the same individual may be included several times in the trial the parameters in the logistic regression model will be estimated by the means of generalized estimating equations (GEE) with exchangeable working correlation. Once the logistic regression model has been fitted to the data, the difference in the marginal predicted will be calculated for each group. There will be no assumption checks performed

Intranasal naloxone v Intramuscular naloxone

201

Pre-specified

-0.112

2-sided

Adverse events are reported for the treatment period of 10 minutes with a further observation time of up to 30 minutes. No adverse events are reported after ambulance service has left the patient.

20.1

Safety Set

Intranasal naloxone

Intramuscular naloxone