This two-arm RCT compares ED site-directed care (control) to the Relay intervention for patients presenting to the ED with a suspected opioid-involved overdose (see Section 2.3 for details). As per standard Relay processes, when patients present to the ED with a suspected opioid-involved overdose, ED staff call the Relay hotline. The hotline operator then notifies the research team, and a research assistant (RA) meets the patient in the ED to assess the patient for study eligibility. Study participants are randomly assigned to the site-directed care or Relay arm; a Relay Wellness Advocate is dispatched for participants assigned to the Relay arm. Fig. 1 shows a schematic of the study design. The study was approved by the Institutional Review Board (IRB) at NYU Grossman School of Medicine.

At the time of study initiation, Relay operated in 13 NYC EDs. The study is being conducted at four of those EDs: St. Barnabas Hospital (in the Bronx), NYU Langone Health-Tisch (on Manhattan’s east side), NYU Langone Hospital-Brooklyn (in southern Brooklyn), and Mount Sinai Beth Israel (in Manhattan’s East Village neighborhood). These EDs were selected with consideration for their volume of calls to the Relay program, research capacity, and geographic diversity. Each study ED had participated in Relay for at least a year prior to the start of the study. Each Relay hospital has a designated “ED Champion,” an ED staff member who works with Relay staff to provide training on Relay, both at launch and on an ongoing basis by conducting pop-in visits, staff huddles, and presentations. Relay staff also distribute promotional items to ED staff, including pens, lanyards, and mousepads with the Relay phone number.

When a study hospital ED provider calls the Relay hotline, the operator immediately contacts the appropriate study team member. Study RA shifts generally span weekdays 7:00 am to 1:00 am and weekends 7:00 am to 6:00 pm. If a Relay hotline call is received from a study ED at a time when no RA is available, the hotline operator activates a Relay Wellness Advocate directly to see the patient (i.e., the patient is not assessed for study eligibility).

Patients for whom the study team receives an alert from the Relay hotline are assessed for eligibility. Eligibility criteria include: age 18 years or older; English-or Spanish-speaking; living in NYC; and presenting to the ED with a suspected opioid-involved overdose. An opioid-involved overdose includes any overdose severity involving at least one suspected opioid, whether or not it was the primary drug used, whether or not use of the opioid was intentional (i.e., patients who overdose after using non-opioid drugs suspected to be contaminated with an opioid are eligible), and whether or not naloxone was administered.

In their eligibility assessment, RAs ascertain patient self-report of having had an opioid-involved overdose with the following question: “The next question is about taking too much drugs or medications/pills, and/or drinking too much alcohol. This is sometimes called ‘poisoning,’ ‘passing out,’ ‘nodding out,’ ‘blacking out,’ or an ‘overdose’ or ‘OD.’ Did you have an experience like this today that involved any opioid?” “Opioids” are described as including opioid medications for pain or addiction treatment in addition to illicit opioids, and patients are instructed, “please let me know if you used any opioid today, even if you don’t think the opioid was the cause of the overdose.” This question was adapted from research conducted by Bohnert, et al. with ED patients [29]. If the patient answers “no,” RAs ask the patient’s ED care provider whether they believe based on clinical presentation (e.g., physical exam findings, response to naloxone) that the patient had an opioid-involved overdose. If either the patient or their ED provider reports a suspected opioid-involved overdose, the patient is potentially eligible for study participation.

Study exclusion criteria include: unable to provide informed consent; currently incarcerated or in police custody; known to be pregnant; already participating in the study; or currently engaged in Relay. Additionally, one of the study EDs, which has a relatively lower volume of Spanish-speaking patients, does not have Spanish-speaking RAs so patients who cannot speak English are excluded at that site.

The study team member receiving the Relay hotline referral generally arrives at the ED within one hour to assesses the patient for study eligibility. RAs follow a standardized series of eligibility screening questions and procedures and obtain written informed consent. If the patient is too sedated (e.g., due to overdose) or agitated (e.g., due to opioid withdrawal) at the time of initial RA assessment, RAs remain in the ED to reassess the patient at regular intervals. If there is any question about a patient’s capacity to provide informed consent, RAs consult the ED treating team (e.g., attending physician) and/or complete a brief consent capacity quiz [30]. If the patient is ineligible or declines study participation, RAs call the Relay hotline to activate a Wellness Advocate for the patient.

Enrolled patients are randomly assigned to the site-directed care or Relay arm. Randomization uses a 1:1 ratio and is stratified by site; permuted blocks with variable block sizes are used to maintain balance over time and prevent prediction of assignment by RAs. Given the nature of the intervention, blinding is not possible for study participants or staff.

Participants randomized to the site-directed care arm receive a standard set of education and materials provided by RAs: 1) overdose education and naloxone distribution (OEND), 2) list of local addiction treatment programs, and 3) flyer with information about Relay. OEND includes RAs providing participants with 1–2 naloxone kits and overdose education materials (including naloxone use instructions). RAs also give participants a printed list of local addiction treatment programs and a flyer with information about Relay including a telephone number participants can call to receive Relay services if desired after their ED visit. DOHMH and research staff track any Relay services provided in this participant-initiated manner. Clinical equipoise exists to justify an RCT, as there has not yet been research demonstrating a convincing benefit of peer navigator approaches for ED patients presenting after opioid overdose compared to standard ED care. After 12-month study follow-up for the primary outcome, DOHMH will attempt to contact participants who have been assigned to the site-directed care arm to offer Relay services.

As is the case across the U.S., standard care at a given ED for patients presenting after overdose is variable. Study EDs have implemented their own protocols and initiatives for patients who present with opioid use disorder or after overdose, which vary by site and are provided independent of the study. For example, one study ED provides fentanyl test strips and two study EDs have pharmacist-driven naloxone distribution for relevant patients. The study team will track the overdose prevention-related ED care that study participants receive with a baseline visit exit survey.

Relay is delivered by trained peer navigators (“Wellness Advocates”) who have lived experience with substance use (see Appendix for details on Wellness Advocate training). After being dispatched to an ED, a Wellness Advocate attempts to contact the patient within one hour, usually by meeting them in person in the ED, or by talking with them by phone if meeting in person is not feasible (e.g., patient expected to leave the ED before the Wellness Advocate would arrive). Usually when patients present to an ED after a nonfatal overdose there is a period of several hours when they are assessed, observed, and possibly complete additional testing (e.g., laboratory studies). Thus, Wellness Advocates have an opportunity to meet with patients while they are still in the ED, which is particularly important because many patients have unreliable telephone access or practical barriers to attending scheduled follow-up visits. The initial meeting focuses on patient engagement and providing peer support, using a person-centered harm reduction approach [31]. The Wellness Advocate describes Relay, obtains consent for participation in Relay, and collects patient contact information. They provide brief, tailored overdose risk reduction education; opioid overdose rescue training and naloxone kit distribution for the patient and any friends or family members; referrals and navigation to harm reduction, drug treatment, or other services (if this is of interest to the patient); and support in the ED (e.g., helping mediate communication between the patient and ED treatment team). The Wellness Advocate also offers a care bag which includes a toothbrush and toothpaste, socks, a water bottle, a snack, a public transportation ticket, and educational materials.

After the initial ED encounter, a Wellness Advocate follows up with the participant within 24–48 h of discharge to discuss further how Relay can assist the participant in avoiding future overdose. The Wellness Advocate continues to follow up and provide support and connections to services for up to 90 days, with occasional extensions to 120 days permitted on a case-by-case basis. These follow-up contacts can occur by telephone (including text message) or in person. Contact frequency is dependent on participant needs and desires, with follow-up intensity decreasing over the course of three phases following a Critical Time Intervention approach [32–34] (see Appendix for details). Wellness Advocates are assigned no >20 participants at one time.

Both in the ED and at follow-up visits, Wellness Advocates serve as positive role models while providing tangible and instrumental support to foster motivation, reduce stigma, and build individuals’ capacity to change risk behaviors and initiate treatment.

An overview is shown in Fig. 1. Procedures conducted at the baseline ED visit following eligibility assessment and informed consent are: baseline questionnaire, site-directed care or Relay intervention, collection of identifying and locator form information, exit survey, and incentive payment. Follow-up questionnaires are administered at 1-month, 3-month, and 6-months. For all questionnaires, RAs read questions and response choices aloud and record responses using REDCap [35].

The baseline visit exit survey (Section 2.8.3) assesses the interventions relevant to overdose that the participant received in the ED, from the Wellness Advocate (for participants assigned to the Relay arm) or ED providers. RAs also complete a check-list confirming they have delivered the elements of the site-directed care arm (Section 2.6). Participants are asked at follow-up assessments (Section 2.8.4) about any additional Relay contacts they have received in the interval since the last assessment. Relay Wellness Advocates also document each participant encounter in an electronic database; data collected include the type of interaction (e.g., in-person, telephone), services provided, and activities performed during the session. This data will be used for analyses at the conclusion of the study to consider intervention dose and fidelity, including fidelity to the Relay program model (see Appendix for details).

Study outcomes are summarized in Table 1 and detailed in the sections that follow.

The primary outcome analysis will use a Poisson generalized linear regression model to evaluate the intervention effect on the total number of opioid-related adverse events. We will include adjustment for study site, as well as baseline factors that may be unbalanced across arms. The primary effect measure will be the incidence rate ratio comparing Relay to site-directed care. If there is overdispersion of the count outcome due to some participants being routinely high utilizers of the ED, we will use a negative binomial model instead of a Poisson model.

For analysis of secondary and exploratory outcomes we will compare the Relay and site-directed care arms using models as appropriate for count vs. categorical variables, and again adjusting for factors that may be unbalanced across study arms. We will perform additional exploratory analyses examining differences in outcomes by study site.

The target sample size is 350 participants. Please see the Appendix for sample size calculations.

An external Data and Safety Monitoring Board (DSMB) meets twice yearly. The trial has a stopping rule based on fatal opioid overdose; the study will be stopped if we observe a rate ratio of overdose deaths in the site-directed care arm versus the Relay arm of ≥3.0 and a one-sided p-value of <0.01, or a one-sided p-value of <0.01 when the rate ratio is undefined due to zero deaths in the Relay arm.

RCT participants receive $75 after the baseline visit, $30 after each of the 1- and 3-month follow-up assessments, and $50 after the 6-month follow-up assessment. At the baseline visit participants are given a Greenphire ClinCard, which can be used either as a prepaid credit card or as a debit card to withdraw money from an ATM (which incurs a fee) or to receive money from a bank teller (which does not incur a fee but requires proof of identification). RAs load onto the participant’s ClinCard the compensation amounts for follow-up assessments upon completion of each assessment. Participants who have lost their ClinCard are mailed a new one.

The study’s start was delayed due to the COVID-19 pandemic. In-person Relay responses to the ED were paused early in the pandemic through summer 2020. Study enrollment began in October 2020. Research staff wear appropriate personal protective equipment (PPE), depending on the requirements of the specific ED. The pandemic has created changes in ED volume and processes, as well as changes, at times, related to the Relay intervention itself. For example, during the pandemic, post-ED follow-up visits with Wellness Advocates have shifted to primarily be telephonic. Pandemic-related effects on the study are being monitored and will be described in future publications.