Despite the efficacy of antiretroviral therapy (ART) at suppressing HIV replication and preventing progression to AIDS, people with HIV (PWH) have ongoing systemic immune activation and chronic inflammation and suffer from a spectrum of non-AIDS-related comorbidities, even in the context of suppressed HIV viral load [1,2,3,4]. Alleviating chronic inflammation could potentially help to prevent the onset of non-AIDS-related comorbidities in PWH on ART [5,6,7,8]. Furthermore, cannabis is often used by PWH for both medical reasons such as chronic pain, anxiety and depression, but also for recreational reasons, and to improve quality of life [9,10,11,12,13]. The primary cannabinoids in the cannabis plant, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), demonstrate potent anti-inflammatory and anti-fibrotic effects in both experimental models [14,15,16,17,18,19,20,21,22], as well as in human studies [23,24,25]. Studies from observational cohorts have demonstrated that PWH who use cannabis or cannabinoid-based medicines (CBMs) have lower levels of inflammation than non-cannabis users, although a causal relationship cannot be ascertained due to the risk of confounding in such study designs [6].

In order to establish the effect of cannabis on systemic inflammation in PWH, clinical trials are needed. However, there is a lack of preclinical and pharmacokinetic data on CBMs to guide dosing recommendations in PWH7, thereby raising safety and tolerability concerns [26,27]. Between August 2021 (study initiation)–April 2022, we aimed to enroll 26 PWH > 18 years of age on ART for randomization to either CBD ± THC capsules, titrating doses as tolerated, for 12 weeks in a pilot clinical trial to assess safety, tolerability and feasibility [7]. The impacts on safety, tolerability, systemic inflammation and HIV reservoir size were previously published [28,29]. The feasibility of executing a CBM RCT in Canada’s regulatory landscape, where medical cannabis has been legal since 2014 and recreational cannabis has been legal since 2018 [30], has never been previously described. Here we report on timeliness to study initiation, enrolment, compliance and retention outcomes, in addition to feedback from study participants and staff at close-out.

A study timeline is depicted in Figure 2. The first form of financial support was obtained in 2017. In 2018, Canada implemented the Cannabis Act, legalizing the use of cannabis for recreational purposes and enabling individuals to purchase and possess cannabis without a medical prescription. Along with this change in legislation came the need for researchers to possess a Cannabis Research License through Health Canada, which required 11 months to obtain. In 2019, the Cannabis Research License was obtained.

The COVID-19 pandemic, beginning in 2019, resulted in a near-complete shut-down of all research activities except those directly related to COVID-19 for approximately 6 months. When non-COVID-19 research was permitted to resume, changes were required to our study protocol and informed consent forms, prior to the study to initiation, to enable some tasks to be completed remotely, via telephone, in order to minimize the need for participants to come to our hospital-based clinic. This process took approximately 3 months. Furthermore, the supplier informed us that one of the products we had initially intended to use (capsules containing THC:CBD in a 1:9 ratio) failed a quality control test and there were concerns regarding its stability. To manufacture a new batch of capsules and have them undergo quality control checks would have taken several additional months. Therefore, we opted to use a capsule of 200 mg CBD only, which was already available and in use in other research studies. However, this change also required a change in our protocol and informed consent, and approvals from both our institutional REB and Health Canada (HC), resulting in additional delays to study initiation.

During the study time period, the expiration of our study capsules (shelf live 9 months) was approaching. Although the plant form of cannabis does not have a known “expiration date”, the stability of the manufactured capsules was set at 12 months. However, by the time the capsules are manufactured, complete quality control checks and are shipped to the research site, often 3 months has passed, leaving sites a 9-month window to recruit and distribute capsules and for participant consumption before expiration. Furthermore, during the course of our study, Tilray merged with another company and announced the closure of their manufacturing facility in Nanaimo, British Columbia, Canada, thus the production of cannabinoid capsules using the exact same protocols with which we initiated the study could not be guaranteed. If we had wanted to prolong the period of study recruitment and manufacture more capsules, this would require a new HC application as the product would essentially be new. The study opened to enrolment in Aug 2021 and closed to enrolment in April 2022. The site was not able to enrol any participants in March and April 2022. The study was closed to enrolment at the end of April due to product expiry. The main barriers and facilitators to the study are summarized in Table 1.

Pilot studies are effective in reducing waste in medical research by assisting researchers in identifying how they can adjust study procedures and reduce waste. Pilot studies are especially useful in fields where participants are difficult to recruit and retain, such as in HIV research [38]. Feasibility assessments help determine region- or institution-specific practices which impact study completion [38]. In the current pilot clinical trial, we evaluated the safety, tolerability and feasibility of administering oral cannabinoid capsules to PWH, with feasibility outcomes as the focus of the current manuscript. In addition to the timeliness of initiating this clinical trial, feasibility outcomes included consent rate, retention and compliance, along with verbal feedback solicited from participants and the study team. We report on factors impacting the timeliness of study initiation, including changing cannabis legislation within Canada during the study period, and the impact of the COVID-19 pandemic on non-COVID-19-related research. As we were unable to enroll sufficient participants, this meant that we could not confidently make conclusions about the effects of the cannabinoids on markers of inflammation, gut microbial translocation and reservoir size. Although trends may have been observed, we must be cautious in interpreting the findings due to the small sample size. Our primary objectives (safety and tolerability) could only be examined in a small number of individuals. Furthermore, we had originally wanted to examine the outcomes stratified by treatment group (i.e., CBD-only or THC/CBD combined capsule). Because of the small sample size, we decided to group all of our participants together.

The two largest barriers in this study were timeliness to study initiation and completion and challenges with recruitment. Globally, more than 80% of trials are unable to enroll on time, requiring study extension and potentially addition of new sites [39]. A major barrier to beginning the current study was the requirement to obtain a Cannabis Research License, which resulted in an 11-month delay from the time of application to the time we received the license from Health Canada. As researchers must wait in the same queue as licensed producers when seeking approvals from Health Canada, this may result in lengthy waiting times and delaying study initiation [40]. We have previously reviewed changes in the Canadian legislation landscape and their impacts on cannabis and cannabinoid research [40]. The COVID-19 pandemic also had an impact on the timeliness to study initiation, requiring us to amend the protocol to enable remote follow-up when feasible. It has been reported that more than 40% of clinical trials amend their protocol before the first participant visit, resulting in a delay of 4 months from protocol implementation to participant enrolment [41].

Recruitment was the most challenging aspect of conducting this study and we were unable to include more than 10 participants in this pilot study, and therefore we did not reach our first target sample size. This is consistent with what is reported in the literature for clinical trials, in which 35% of delays in conducting clinical trials are attributed to delays in recruitment [42]. In a review of all studies completed between 2014 and 2018 at a center in Mumbai, India, Bose et al. evaluated four pre-identified criteria for screen failures and dropouts: risk, nature of funding, study design and nature of participants [43]. They reported that high-risk and interventional studies were predictors for both screen failures and dropouts, whereas pharmaceutical industry-funded studies and healthy participants were predictors for only screen failures [43]. In a comprehensive review of RCTs funded by the United Kingdom National Institute for Health Research (NIHR) and published in the online NIHR Journals Library between January 1997–December 2020, Jacques et al. identified 388 RCCTs and 379 reports in the NIHR Journals Library [44]. They found that the final recruitment target sample size was achieved in 63% of the RCTs and that the original recruitment target was revised in 30% of trials (downwards in 67%) [44].

Studies involving CBMs require additional feasibility considerations given that cannabis/CBMs have additional regulatory requirements and may be associated with stigma. In Canada, the federal government considers cannabis/CBMs controlled substances, meaning that they are categorized as having a higher-than-average potential for abuse or addiction. Such drugs are divided into categories based on their potential for abuse or addiction [45]. Status as controlled substances results in additional regulatory considerations, contributing to more paperwork, and the need for particular storage and handling by the pharmacy and team [46].

Relatively few pilot feasibility studies involving CBMs have been conducted. To our knowledge, none of the feasibility pilot studies involving CBMs have been in Canada nor in PWH. The populations in the CBM feasibility studies were very diverse and included individuals with long COVID (United Kingdom) [47], cancer patients with cancer-related symptoms (Australia) [48], dialysis patients with chronic pain (Israel) [49], individuals with crack use disorder (Brazil) [50] and children with autism spectrum disorder (ASD) (Israel) [51]. In a single-arm, open-label feasibility trial in the United Kingdom of the safety and tolerability of a full-spectrum CBD-dominant CBM product for treating symptoms of long COVID, Thurgur et al. treated 12 participants with up to 3 mL of 5% CBD Oil (50 mg CBD/mL, <2 mg THC/mL) per day orally for a total of 21 weeks, followed by ~3 weeks without the study drug [47]. Participants adhered to the treatment protocol, there were no serious adverse events and response rates for the research assessments were high (>90% completion of patient-reported outcome measures and daily self-report). However, they also experienced challenges related to recruitment strategy and their initial proposal to recruit participants was amended [47]. Meanwhile, Good et al. conducted a prospective two-arm open-label pilot trial of escalating doses of CBD and THC oil in participants with advanced cancer and cancer-related symptoms in an Australian palliative and supportive care service of a cancer center to assess the feasibility of using global symptom burden measures to assess response to medicinal CBMs, to determine median tolerated doses of CBD and THC and to document adverse events [48]. One of the main outcome measures was the number of participants screened and randomized over the time frame and the number of participants completing days 14 and 28 and providing total symptom distress scores (TSDSs) [48]. Of the 21 participants enrolled (CBD, n = 16; THC, n = 5), 18 (86%) completed the primary outcome measure on day 14 and eight completed day 28 [48]. In another randomized trial of medical cannabis in patients with stage IV cancers in Israel to assess feasibility, dose requirements, impact on pain and opioid use, safety and overall patient satisfaction, Zylla et al. randomized 30 participants 1:1 to early cannabis (EC, n = 15) versus delayed start cannabis (DC, n = 15) [52]. The EC group obtained 3 months (3 M) of CBM through a state program at no charge, while the DC group received standard oncology care without CBMs for the first 3 months [52]. Participants met with licensed pharmacists at one of two CBM dispensaries to determine a suggested CBM dosing, formulation and route. Patients completed surveys on pain levels, opioid/MC use, side effects and overall satisfaction with the study [52]. In contrast to our study and that by Thurgur et al., Zylla et al. were more successful with recruitment as 36% of patients who met the eligibility criteria ultimately enrolled [52]. A higher proportion of EC patients achieved a reduction in opioid use and improved pain control [52].

The feasibility of CBMs has also been examined in studies involving different patient populations. In another feasibility study in Israel, Kliuk-Ben Bassat et al. examined feasibility and safety of sublingual oil-based medical cannabis for chronic pain management in hemodialysis (HD) patients [49]. In this prospective randomized, double-blind, cross-over design, participants were assigned to one of three arms: BOL-DP-o-04-WPE whole-plant extract (WPE), BOL-DP-o-04 cannabinoid extraction (API) or placebo. WPE and API contained THC and CBD in a 1:6 ratio (1:6, THC:CBD) [49]. Participants were treated for 8 weeks, with a subsequent 2-week washout, followed by a cross-over to a different arm. The primary endpoint was safety. Out of 18 patients recruited, 15 were randomized. Three did not complete the drug titration period due to AEs and one patient died during titration due to sepsis (WPE). Of those who completed at least one treatment period, seven patients were in the WPE arm, five in the API and nine received placebo [49]. Most AEs were mild to moderate and resolved spontaneously. In contrast to our study, liver enzymes were stable during cannabis treatment for all participants. Thus, they concluded that short-term medical cannabis use in patients treated with HD was generally well tolerated, and the investigators concluded that the safety data support further studies to assess the overall risk–benefit of a treatment paradigm utilizing medical cannabis to control pain in this patient population [49]. Feasibility has also been examined in persons with crack use disorder and in pediatrics for children with autism spectrum disorder (ASD). In a retrospective study, Aran et al. assessed the tolerability and efficacy of cannabidiol-rich cannabis in 60 children with ASD and severe behavioral problems (age = 11.8 ± 3.5, range 5.0–17.5; 77% low functioning; 83% boys) [51]. Efficacy was assessed using the Caregiver Global Impression of Change scale. Adverse events included sleep disturbances (14%), irritability (9%) and loss of appetite (9%). One girl who used higher THC had a transient serious psychotic event which required treatment with an antipsychotic. Following the cannabis treatment, behavioral outbreaks were much improved or very much improved in 61% of patients. The investigators concluded that their preliminary study supports the feasibility of CBD-based cannabis trials in children with ASD in Israel [51]. However, these findings may not be applicable to other countries and researchers must take into account the regulatory environment surrounding CBMs, literacy of the target population and issues surrounding stigma with the use of CBMs for medicinal purposes. Both healthcare providers and the public in Israel may be more open toward CBMs than physicians and the public in other countries [53,54].

The COVID-19 pandemic was a factor impacting timeliness to study initiation and recruitment, as many individuals did not want to come to the clinic, based in a tertiary care center, more than necessary in order to limit exposure. It is possible that PWH perceived themselves to be at greater risk of COVID-19 acquisition due to being considered “immunocompromised”, at older age and with a large burden of comorbidities. During the pandemic, PWH in Canada reported frequent practices of preventative behaviors including masking, physical distancing and limiting contact with at-risk individuals [55] and thus it is plausible recruitment was impacted due to the frequent study visits. As our clinic is very active in research in clinical trials and other research studies, it is possible that eligible participants may have been interested in our study but had already committed to being enrolled in another study, precluding participation. In a review of critical issues and challenges in the recruitment and retention of participants in clinical studies, Desai also comments on the competition for potential patients with multiple studies simultaneously recruiting participants at the same center [39]. In discussions with some study staff at our site, the view was expressed that studies focused on antiretroviral medications should take higher priority given the need of all PWH to take these medications and that studies for cannabis, while valid, would not have the same priority level. When initiating this study, there was discomfort related to cannabis’ classification as a controlled substanceat both the staff and study staff level, as well as amongst some PWH approached for potential participation. In a survey of Canadian healthcare providers, many were unfamiliar with topics related to CBMs and uncomfortable due to the lack of pre-existing clinical trials for efficacy and safety [39]. Ongoing work is also required to reduce the stigma associated with CBMs.

Differences across feasibility studies should also take into account different definitions used. Although numerous articles describe guidelines for the conduct of clinical studies, few have included specific feasibility indicators or strategies for evaluating multiple aspects of feasibility [56]. In their review, Teresi et al. present examples of indicators (recruitment, retention, intervention fidelity, acceptability, adherence and engagement) for feasibility assessment of data collection methods and intervention implementation and underscore the importance of examining feasibility when adapting an intervention tested in mainstream populations to more diverse groups [56]. It must be underscored that current feasibility studies use different definitions to define indicators, which makes comparison across studies challenging. For example, the recruitment rate may be defined as the proportion of all eligible participants who are enrolled/randomized or the proportion of participants approached who agree to undergo enrollment/randomization. Similarly, retention rate may be defined as enrolled participants with valid primary outcome data or the proportion of enrolled participants who are present throughout the length of the study until the final study visit [44,47,48,56].

The participants we did enroll in our study are not necessarily representative of many of our clinic patients, nor of the HIV epidemic in Canada. In our study, the majority of participants did not hold regular employment, 80% were male and 60% were white North Americans. In contrast, 40% of our clinic clients are Caucasian [57] whereas in Canada, there are increasing cases of HIV amongst women and non-Caucasian migrants [58]. In the aforementioned pilot feasibility study on CBMs for individuals with long COVID, Thurgur et al. also had a participant pool which was somewhat homogeneous and consisted mostly of white British women [47]. Collecting reasons for non-enrollment may help to determine what factors could be improved in future studies and to determine how participants enrolling in the study differ from the general clinic or patient population.

This study was resource-intensive. Due to significant delays in study initiation and roll-out, the costs associated with the study were much higher than calculated (mainly due to costs associated with study staff). There were delays associated with hiring and training of new staff as the study start was delayed and increased costs associated with amending protocols and ICF to account for activities which could be carried out remotely during the COVID-19 pandemic. Staff found the frequency of study visits onerous but recognized their importance for monitoring purposes, especially in the context of transaminitis. Participants that experienced unexpected adverse events attended additional study visits for follow-up There were also costs associated with pharmacist consultations and additional record-keeping required for cannabis as a controlled substance. Physical space requirements in the pharmacy must also be taken into account since bottles of capsules must be stored in locked cabinets. For this study, we obtained regulatory support as an in-kind contribution from the CTN. However, costs associated with submissions to Health Canada, including all protocol amendments, must be factored into the budget for studies involving cannabinoids. Moreover, participants who were using cannabinoids regularly prior to study enrolment found it difficult to stop using cannabis, especially when they were achieving positive effects for symptom control. Some participants who found the study capsules helpful expressed disappointment at not being able to access the study capsules following study termination.

The summary of recommendation for future studies, based on our experience, can be found in Table 3.

Recruitment was the most challenging aspect of conducting this study, with a low consent rate. Ongoing work is required to reduce stigma related to CBMs. Future studies should find a balance between requirements for safety monitoring and frequency of study visits. Interestingly, the need to refrain from using one’s own cannabis and to undergo a washout period was a major factor precluding participation for many individuals approached. Plans to enable participants to experience beneficial effects from study interventions should be in place to enable them to obtain the treatments following study completion. Information obtained from pilot studies is helpful to inform the design and implementation of large-scale studies, especially for non-conventional therapies with complex regulatory statuses.