The SALOME study: recruitment experiences in a clinical trial offering injectable diacetylmorphine and hydromorphone for opioid dependency

Opioid dependency remains to be a major public health concern in North America and worldwide. Abstinence oriented treatment has shown to benefit small proportions of people struggling with opioid-dependence [1]; opioid substitution and maintenance treatment continues to be the best approach to stop the use of illicit opioids [2]. Oral methadone is the most used and studied of these treatments with demonstrated effectiveness at reducing illicit drug use and improving health and psychosocial outcomes [3]. Few other opioids besides oral methadone have been studied for the treatment of opioid dependency. Among these other opioids, injectable diacetylmorphine (i.e., pharmaceutical-grade heroin [DAM]), dispensed in a controlled and medically supervised setting, has shown to be effective in the treatment of long-term opioid injectors not sufficiently benefitting from oral methadone [4].

Despite that several randomized clinical trials (RCT) in Europe and Canada have demonstrated the effectiveness of DAM, very few countries have adopted it as part of their addiction treatment system. There is a clear need for alternative treatments as effective as injectable DAM that health care systems could adopt to attract and retain long-term street opioid injectors into treatment. One such alternative could be HDM [5] and the SALOME (Study to Assess Long-term Opioid Medication Effectiveness) study was designed to test this. SALOME is a randomized double blind controlled trial testing if injectable HDM (a licenced pain medication) is as effective as DAM for the treatment of long-term opioid-dependent individuals who are not benefitting sufficiently from conventional treatments, and if a transition to the oral equivalent of HDM and DAM after six-months is as effective as the injection form.

Recruiting participants for clinical trials can be slow and difficult, and much effort is dedicated to reach the required sample size within a reasonable timescale and budget [6‐8]. For example, a review of RCTs across a wide array of medical conditions in the United Kingdom showed that nearly half of the trials received an extension of some kind due to the struggle to recruit the planned sample size [9]. Although it is unclear why some trials recruit more effectively than others, it has been suggested that studies providing treatments that are desired and/or only available through the trial, or studies comparing two similar treatments, might have fewer challenges with recruitment [10‐13].

Methodological and empirical studies regarding recruitment in clinical trials for addiction are sparse. Some evidence suggests that RCTs in this field face similar challenges to those aforementioned in medical research [14]. However, addiction treatment trialists also encounter barriers specific to this field [15]. For example, motivation to participate may be more challenging when recruiting participants who have generally unstable daily living conditions and difficulties attending appointments [16]. Studies with similar populations have addressed the importance of building trust with the target population, support them to keep appointments, and provide ancillary services for other needs as part of their recruitment strategies [17]. Moreover, traditionally employed strategies for motivating participation, such as telephone reminders [18], may not be feasible with this population. These unique factors necessitate discussion amongst addictions researchers to better inform strategies tailored to benefit recruitment in forthcoming addiction trials.

Context specific challenges related to recruitment for RCTs with DAM treatment have also been documented. Every RCT testing DAM has had longer than expected recruitments and in some cases had to enrol fewer participants than planned [19]. A variety of context-specific reasons explain this. For example, in Spain, by the time the study was able to start enrolling participants, injection street heroin use had dropped drastically (heroin users were smoking it instead) and the sample size could not be reached [20]. In a Belgian study, one of the main reasons street heroin users did not apply was the concern over the limited length of access to the study medications [19]. In our prior study, NAOMI (North American Opiate Medication Initiative), the site in Vancouver received more than 1,000 applications; however, the study criteria did not reflect the realities of the intended sample population and most applicants did not even meet minimal requirements at first contact [21].

SALOME compared two treatments appealing to the target population that were only available through the study. Despite the advantages that this scenario presents for recruitment, experience in prior RCTs testing DAM suggested that offering desirable treatments might not be sufficient to meet the planned sample size within a reasonable time. The aim of the present study is to describe the recruitment experiences of the SALOME trial and discuss the strategies that were employed. This paper could inform the development of recruitment strategies for upcoming clinical trials in addictions research, a field that faces unique barriers.

From December 2011 to December 2013, a total of 598 (196 female, 397 male, 4 transgender-female and 1 with missing gender) applications were received for the SALOME trial. Figure 1a and 1b show the progress of the applications over the two-year period. On the first day 130 individuals applied to the study (Figure 1a). These applicants were randomly assigned a number that was used to determine their processing order. Individuals who applied after these 130 applicants were added to this list in chronological order. After the first day the number of applicants continued to increase steadily over the two-year period at a pace faster than the study had capacity to enrol. Therefore, efforts to actively promote recruitment (e.g., recruitment posters, recruitment tables) were halted.Figure 2 shows the flow of the applications through to randomization. From the total number of applicants, 485 (81.1% of total 598 who applied) met the prerequisites on the pre-screening checklist. Among those eligible for screening at this stage, 159 were female, 321 were male, 4 were transgender-female and one applicant’s gender was missing. For various reasons shown in Figure 2, we could not re-assess 185 of these 485 applicants (e.g., could not be found, passed away, etc.) and an additional 29 applicants were excluded for no longer meeting study prerequisites or no longer being interested in participating. The rate of applicants not meeting the prerequisites on the pre-screening checklist throughout the two-year recruitment period remained constant (Figure 1a).A total of 253 (52.2% of those who met prerequisites on the pre-screening checklist; 76 female, 174 male, 3 transgender-female) candidates signed the informed consent and initiated screening. Due to the limited clinic capacity and the external situations that halted recruitment, the average time lapse between the point of first application and first screening visit was 8.3 (SD = 4.44; Q1 = 6.33; median = 8.67; Q3 = 11.03) months. Their average age was 44.76 (SD = 9.61; Q1 = 38.0; median = 45.0; Q3 = 52.0). Thirty candidates (11.8% of those who started screening; 11 female, 19 male) were excluded due to not meeting at least one of the inclusion or exclusion criteria. In addition, 14 (5 female, 9 male) candidates started the screening process but did not continue for unknown reasons and 7 (1 female, 6 male) expressed that they were no longer interested in participating in the study. The primary reasons for exclusion of the 30 candidates was the regularity of current opioid injection (n = 15) and not sufficiently attempted OST or other types of addiction treatment (n = 9). For those eligible candidates, the average number of days between the first screening visit and randomization date was 25.95 (SD = 37.48; Q1 = 9.0; median = 15.0; Q3 = 23.0; Figure 1b). For 28 participants, the time lapse between first consent and randomization was more than 30 days, mainly because of challenges maintaining contact and rescheduling of missed appointments.

As in prior trials offering injectable DAM within a supervised model, recruiting participants for this study took seven months longer. However, this additional time can be attributed to the extraneous events and limited clinic capacity. Without these events and with a larger clinic, recruitment into the trial would have been even faster than expected.

The challenges that the research team had to overcome for recruitment into SALOME were due to the high number of applicants compared with the limited number that could be randomized and treated. Our recruitment plan was based on recommendations from recruitment into clinical trials in general, the addictions field and prior experiences of this research team [21]. The recruitment strategies that were instrumental in overcoming these challenges included the community engagement process [13, 22], the consistent, accessible and experienced team [13] and a participant-centered screening process [12, 14].

The community engagement process was highly valuable in forming partnerships with key agencies working with the study population and the patients. A very important long-term aim of the community engagement plan was to lay the foundation for future continuation of supervised injectable treatment. With these partnerships and their vested interest in this, we had the opportunity to establish this groundwork. In addition, the CAB was an important forum for communicating information about arising barriers as well as devising collaborative strategies for overcoming them. Throughout the study, there was open and ongoing communication between the research team and the community. For example, when a physician contacted any team member with concerns regarding a patient being included into the study, meetings were promptly held to discuss these concerns, while upholding mutual goals to protect participant/patient autonomy and the scientific integrity of the study.

The commitment of the community and stakeholders strengthened our ability to recruit the necessary number of participants despite the many external barriers affecting recruitment. In addition, having an experienced team improved communication and the consistency of research procedures. The team’s cohesion proved beneficial as the recruitment processes remained constant and the team’s skills matured over time as barriers continued to arise. Messages and information relayed about the study were also homogeneous through media, information materials and our team. Each message was tailored for the intended (i.e., participant, health care provider) audience, yet was consistent to minimize the negative impact arising barriers might pose to ongoing recruitment. For example, when we experienced the hydromorphone shortage, we quickly developed a plan for addressing this issue and a script for communication. This reduced uncertainty and maintained community engagement and support.

As in many RCTs, the stages of screening can be a burden on candidates and SALOME was no exception to this. In an effort to reduce the loss of candidates during the screening stages while maintaining scientific rigor, our procedures aimed to be participant-centered. Overall interactions with candidates were supportive and understanding of the daily struggles applicants had. Most candidates required additional support from the research team or other agencies to, for example, attend the multiple appointments required for screening. Sometimes a team member met candidates at their residence to accompany them to appointments. If the candidate had a social worker or advocate, the research team worked closely with that person to support the candidate throughout the process. The team understood this process as an opportunity to engage candidates not just in the study but also with the health care system, attending to their particular needs and barriers.

Precise estimates regarding how many applicants were needed to reach the planned sample size was difficult to achieve. For example, in many occasions we would have to go down the ordered applicant list because many consecutive applicants could not be found. Other times, they no longer met the prerequisites, were not interested or were doing well on other treatments. Due to this unpredictability, the research team continued to accept new applications until the final sample size was reached. This decision was made in collaboration with the clinical team and community advisory board. Like other trials [17], it was agreed that the opportunity to make contact with applicants, provide information about the trial and other treatments was favorable despite the possibility that recruitment might be complete before we could enrol them. In our communication with these applicants, they were informed of their application number, the number we were presently contacting and our best estimate of the time lapse or the likelihood of being contacted before reaching the sample size. Applicants’ desire to apply to the study despite this and the patience they demonstrated is indicative of their willingness to access alternative treatments for their long-term opioid dependency.

While our recruitment strategies were effective in reaching the target sample and allowing us to overcome extraneous challenges, a limitation of the data collected in this study is the impossibility to ascertain which strategy or combination of strategies was most influential or cost-effective. Given that our main strategy for recruitment was based on a strong community engagement plan, it is difficult to determine which of these activities contributed to the overall effectiveness of this strategy. For example, word of mouth was the primary response received when applicants were asked how they heard about the study. With such a response, we are not able to determine if the sample could have been reached, for example, by focusing efforts on information sessions to drug user groups only, without contacting health care workers. Also, the extensive time lapse caused by the external events makes comparison with refusal rates from other RCTs problematic. Nevertheless, it is important to note that approximately one-third of applicants meeting prerequisites were not invited to initiate screening because we were unable to find them or because recruitment ended before their number was reached. Since the pre-screening checklist data was provided prior to consent, the information collected was very limited and so we have little data about those we were unable to contact.

This study contributes to the building evidence [14, 15, 17, 19, 23] regarding the recruitment experiences and strategies used by addictions trialists who face barriers unique to this field. The recruitment strategy yielded the necessary sample size but also provided the foundation for constructive discussion regarding continuation of treatment. The strategies put in place in the SALOME trial and the positive outcomes emphasize the importance of the time investment in three particular areas. Well before the trial began, a core team was dedicated to establishing respectful relationships with the community, which created a supportive system in the face of unpredictable circumstances that affected the recruitment timeline. A consistent and committed recruitment team was dedicated and maintained through the study for this task. Finally, frontline research and clinical staff worked toward ensuring applicants had the support they needed to complete the screening process and were successfully allocated into the trial. Our experiences reflected in this manuscript could help other researchers in the planning and implementation of future RCTs in the addictions field with the potential for improving recruitment timelines and retention outcomes.

SALOME is searching for evidence-based treatments that can attract and retain individuals struggling with long-term opioid dependency into treatment. Although we reached the target sample size, SALOME recruitment faced serious challenges specific to the study context. These challenges were successfully managed through open communication with the community, a consistent and accessible team and a participant-centered screening process. Our study emphasizes the value of integrating these strategies into clinical addiction research to overcome study-specific barriers.