Randomised controlled trial results

Our results are reported in line with the CONSORT extension for reporting feasibility studies.69

Setting and recruitment

Site 2 AS was the first site to open to recruitment on 13 May 2019; Site 1 AS was the last on 10 October 2019.

Site 1 AS suspended recruitment on 28 November 2019 with concerns that paramedics could not supply THN under the agreed PGD – ‘our Pharmaceutical Advisor has raised the issue with her colleagues in the Specialist Pharmacy Service and been advised that administration under PGD by paramedics is not supported by the current legal framework’. Site 2 AS then paused recruitment as well. The Trial Office wrote to the MHRA to reassure the ASs that paramedics could supply THN under a PGD, and received this response on 4 December 2019: ‘Paramedics can supply Naloxone under a PGD. Naloxone is not usually supplied on a named patient basis. Once the Naloxone has been supplied an exemption in Section 17 of the Human Medicines Regulations 2012 would allow it to be administered by anyone in a medical emergency’. Site 2 AS recommenced recruitment the following day. Site 1 AS recommenced recruitment on 18 December 2019.

The recruitment period for TIME was also disrupted by COVID-19; all recruitment was paused on 17 March 2020 (except for Site 2 ED where study activity paused on 23 March 2020). Table 15 shows when each site originally opened; opened after the pause for COVID-19; and then closed to recruitment. Site 2 ED took the longest time to reopen as their research nurse had been redeployed during COVID-19 and recruitment could not recommence until he was reinstated.

Clinical staff trained

In total, 299 staff were trained to supply THN kits to eligible patients (Site 1 ED: 107, Site 2 ED: 25, Site 1 AS: 121, Site 2 AS: 46).

Trial recruitment

In total, 277 patients were identified as eligible to receive a THN kit and training in this trial (see Figure 1). Sixty THN kits were supplied to eligible patients during the recruitment period (Site 1 ED = 36, Site 2 ED = 16, Site 1 AS = 4, Site 2 AS = 4). In 16 cases (all in Site 1 ED), the patient agreed to the THN kit and accompanying training but ultimately did not receive the kit (n = 4) or declined the THN kit because they already had one (n = 12). In 37 cases, the patient declined the THN kit for reasons other than already having one Site 1 ED = 25, Site 2 ED = 9, Site 1 AS = 1, Site 2 AS = 2. Eligible patients were not offered THN kits 164 times (Site 1 ED = 159, Site 1 AS = 2, Site 2 AS = 3). Reasons reported for not offering eligible patients kits were: staff forgot (n = 136); no kit available (n = 2); staff too busy (n = 15); suspected intentional overdose (n = 3); already given by drugs nurse (n = 4); and other (n = 3).

FIGURE 1 CONSORT flow diagram. a, We are unable to report patient numbers by site due to small numbers of cases at some sites. (Figure not reproduced here; see the original article.)

Over 90% of cases in Site 1 ED and Site 2 AS occurred between July 2019 and March 2020 – that is, before the start of the COVID-19 pandemic. In contrast, only a third of cases at Site 2 ED occurred before the pandemic, with two-thirds between February 2021 and July 2021. At Site 1 AS, equal numbers of cases were reported before and after the start of the pandemic, over the period from November 2019 to October 2020. We are unable to provide further details or more precise numbers due to the small numbers of cases at some sites.

We had no direct access to identifiable or other demographic data on patients presenting with opioid overdose or problems related to opioid use. Instead, some sites sent data to NHS Digital with the intention of generating demographic data from linked data. As no data linkage was undertaken, we are unable to report any characteristics of these patients.

Staff recorded 626 people as being considered for inclusion but found not to be eligible (Site 1 ED = 532; Site 2 ED = 4; Site 1 AS = 49; Site 2 AS = 41). Reasons given were: uncooperative including being abusive towards staff (n = 55); lack of capacity (n = 35); reduced consciousness level (n = 41); patient in custody (n = 21); patient admitted to hospital (n = 194, see Protocol deviations); 6); staff not trained (n = 29); locum staff (n = 14); already recruited (n = 64); other (n = 12).

Completeness of data

The data recorded and uploaded by each site were not uniform. Each site was supposed to record information about THN eligibility, offered, patients trained, received, declined and presenting complaint. There was no eligibility information recorded by Site 2 ED but the other three sites identified a total of 278 patients eligible to receive the intervention [Site 1 ED (n = 264), Site 1 AS (n = 8), Site 2 AS (n = 6)]. Site 1 ED documented 504 ineligible patients as these were either admitted (25%), self-discharged (20%), aggressive (3.4%) or were in police custody (1.4%). The majority of patients (n = 49) were identified to be ineligible by Site 1 AS with over 50% having reduced consciousness and few lacking the capacity or being abusive. Everyone recorded as having attended by Site 2 ED was deemed eligible.

Site 1 ED trained 37 patients receiving the kit and offered training to 25 but was declined due to reasons unknown while further 12 declined as they already had kits. Other sites did not record how many were trained.

Sample size and recruitment required for a full trial

To extend this study into a full trial we were required to identify at least 75% of people presented to ED or attended by the AS with an opioid overdose or use-related problem. Across the 4 sites we identified 848 people presented to ED or attended by the AS using the routine data; however, only 453 were reported to us.

Additionally, we were required to issue kits to 50% of the eligible patients, we identified 277 patients as eligible; however, we only issued kits to 60.

Adverse events

No adverse events were reported.

Fulfilment of progression criteria

1. Sign-up of four sites, including ≥ 50% eligible staff to complete training in delivering the intervention at each intervention site.
   • Assessment: RED: Four sites did recruit patients to the TIME trial. At the time of staff training, there were 132 eligible staff in Site 1 ED; 197 in Site 2 ED; 222 in Site 1 AS; and 136 in Site 2 AS. Both Site 1 ED and Site 1 AS trained more than 50% of their eligible staff (82.6% and 54.5%, respectively). Site 2 AS, however, trained only 33.8% (46/136) and Site 2 ED only trained 8.1% (16/197) of eligible staff. This progression criterion was not met.
2. Identification of ≥ 75% of people who have presented to ED or AS with opioid overdose or an opioid use-related problem over a 12-month period.
   • We were unable to identify all those who presented to ED or the AS with opioid overdose or other related problem, so were not able to ascertain whether this criterion was met.
3. Take-home naloxone kits issued to ≥ 50% eligible patients over a 12-month period at intervention sites.
   • RED: Sixty kits were given to eligible patients, out of n = 277 identified by trial staff as eligible. As this is just 21.7% of eligible patients, we did not meet this progression criterion.
4. Serious adverse event rate (to be defined in agreement with DMEC) of no more than 10% difference in intervention sites to control sites at the conclusion of recruitment.
   • GREEN: No serious adverse events were reported; therefore, this criterion was met.

Trial method feasibility

1. Identification and inclusion for follow-up of ≥ 75% of people who died of opioid poisoning in the following year in the study areas according to ONS mortality data (previous ONS data suggest between 140 and 180 such deaths across the 4 participating sites during the study period).
   • RED: We were unable to identify this population to include in the 1-year follow-up.
2. Matching and data linkage of quantitative data collected.
   • RED: The linkage of quantitative data was no longer pursued due to issues with NHS Digital approvals resulting in significant delays that did not allow for linkage and analysis to be possible within the timeframe of this project, as well as low distribution of THN kits at intervention sites. Therefore, we did not meet this criterion.
3. Retrieval of primary and secondary outcomes from NHS Digital and National Welsh Informatics Service within 6 months of projected timeline.
   • RED: We did not retrieve primary and secondary outcomes from NHS Digital and NWIS within 6 months of our projected timeline; therefore, we did not meet this criterion.

Protocol deviations

There were 201 protocol deviations reported during the trial. One protocol deviation was reported to the Research Ethics Committee (REC) and Sponsor, both on 23 February 2021. There was miscommunication between the Trial Office and Site 1 ED, with the Trial Office being under the impression that Site 1 ED had stopped recruiting on 2 December 2020 as agreed. Site 1 ED actually continued to recruit until 5 February 2021 (a total of 61 weeks instead of 52). The underlying reasons for this miscommunication were reported as related to the COVID-19 pandemic (with research staff at site having not met in December 2020 or January 2021 as planned), and a change in Trial Manager at Swansea University (a new Trial Manager was appointed in December 2020). No further action was taken regarding this.

Other protocol deviations reported to the Trial Office were:

1. Site 1 ED: 194 protocol deviations were recorded for patients who were going to be admitted and were not offered a THN kit; this was not one of our exclusion criteria.
2. Site 1 AS: TIME Patient Information Leaflet not left with the patient 5 November 2019.
3. Site 2 AS: Reduced frequency of THN kit audit following reopening of recruitment after the pause for COVID-19. Prior to the pandemic, Site 2 AS audited there THN kits every fortnight. Subsequently, this was done once at reopening and once at closure (8 weeks apart). This was due to availability of staff members.
4. Site 2 AS: on three occasions, THN kits were not accounted for during audit. One of these was eventually located, two were not.
5. Site 2 AS: a THN kit was used on a patient on one occasion.