Background

The novel coronavirus, SARS-CoV-2, first identified in Wuhan, China, in late December 2019 led to the World Health Organization (WHO) declaring a global pandemic on March 11, 2020. Concerns about personal protective equipment (PPE) supply and already strained health human resources challenged healthcare systems to minimize the demands on available resources, thus impacting the ability to conduct non-COVID-related research with patients. The anticipation of sharp increases in COVID-19 cases and hospitalizations raised further concerns about the availability and capacity to care for increased numbers of patients, the need for redeployment of research staff to meet clinical needs and/or prioritize COVID-related research, and mandates to transition to remote work.

COVID-19 imposed extenuating circumstances on clinical trials beyond the control of study investigators, sponsors, or funders. The CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstance) 2021 statement was developed to extend the CONSORT (Consolidated Standards of Reporting Trials) [1, 2] and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) [3] reporting guidelines to ensure the quality, completeness, and transparency of important protocol modifications due to extenuating circumstances for trials and trial protocols [4]. This guidance document encourages the research community to report how extenuating circumstances were managed, examine their overall impact, and take these modifications into account when interpreting trial results. Herein we report use of the CONSERVE-CONSORT Extension [4] as a framework to describe the CYCLE RCT (Critical Care Cycling to Improve Lower Extremity Strength; NCT03471247) study management during the first seven months of the pandemic. The CYCLE trial is currently underway.

CYCLE is an international multicenter randomized controlled trial (RCT) examining in-bed cycling in critically ill, mechanically ventilated adults (target N = 360). CYCLE involves a complex in-hospital rehabilitation intervention provided in the ICU and relies on a multidisciplinary team of frontline healthcare providers and research personnel to implement the protocol. Patients are randomized to either 30-minutes of daily in-bed cycling and routine physical rehabilitation (PR) or routine PR alone, delivered by ICU physical and occupational therapists (hereafter called “interventionists”) 5 days per week until ICU discharge or 28 days, whichever comes first. Physical outcome measures are administered at 4 time points through the index ICU and hospital admission; the primary outcome is the Physical Function ICU Test (scored) [5], a performance-based physical function measure assessed at 3-days post-ICU discharge by acute care therapists (physical and occupational therapists, and therapy assistants, hereafter called “assessors”) blinded to treatment allocation. Patient-reported outcomes, administered by research coordinators (RCs), are assessed at 3 time points through the index ICU and hospital admission and at 90-days post-randomization. Figure 1 outlines the study schema. Since study initiation in 2016, CYCLE has been enrolling patients in 17 sites in 3 countries (Canada, USA, Australia) and 2 languages (English and French). Further information about the protocol is located at https://clinicaltrials.gov/ct2/show/NCT03471247, and a protocol paper is in preparation. The CYCLE Methods Centre, comprised of the Principal Investigator, lead research coordinators, and research assistants, is based at St. Joseph’s Healthcare (Hamilton, Canada), the primary CYCLE study site.

Fig. 1
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CYCLE study schema

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With the global pandemic declaration, CYCLE recruitment was interrupted. At the time of the interruption, the CYCLE trial was actively enrolling patients and conducting follow-up assessments. The Methods Centre personnel were also preparing for a pre-planned 180-patient interim analysis (half of the target 360-patient enrollment). Immediately following interruption, the Methods Centre identified 3 main impacts to CYCLE’s internal validity, including (1) in-hospital randomized intervention delivery (cycling and routine PR), (2) obtaining in-hospital primary outcome data, and (3) accurate, timely data entry and validation for patient safety monitoring in preparation for the pending interim analysis. Our aims were to honor our research commitment to patients enrolled before the pandemic, optimize cohort retention, minimize missing data, and continue to conduct the trial where ever it was feasible and safe. This report describes the CYCLE trial management Methods Centre response to the pandemic up to September 30, 2020.

Methods

The CYCLE Methods Centre developed several risk mitigation strategies to minimize impact of the COVID pandemic on the internal validity of the CYCLE RCT and report these using the framework of the CONSERVE-CONSORT Extension guidance [4]. The CONSERVE-CONSORT checklist can be found in Additional File 1: Appendix 1. To account for randomized patients (item 13: participant flow—number of participants randomized, losses and exclusions after randomization), we first developed structured communication using a standardized email (Additional File 1: Appendix 2) to determine (1) patient status and identify patients at risk of not receiving the allocated intervention, those pending primary outcome assessment, and 90-day assessments scheduled to occur by April 30, 2020, and (2) site staffing and availability (i.e., interventionists, assessors, and RCs for tracking patients, coordinating blinded outcomes assessments, and administering patient-reported outcome measures in-hospital and at the 90-day follow-up).

We developed internal Methods Centre communications to track patients, data progress, and personnel (research and clinical) across sites with the goals of providing support and guidance as required. We used these same communication strategies to reactivate sites when non-COVID-19 research resumed in some centers in late Spring 2020.

To track protocol fidelity, we focused on attempts to conduct study procedures, allowing us to discern pre-specified reasons for not completing a study procedure from reasons imposed by the pandemic. An “attempt” included any time an interventionist, assessor, or RC tried to deliver the intervention, collect the physical function or patient-reported assessments, or collect the 90-day assessments, as per study protocol. An attempt may or may not have resulted in successful conduct of the planned task. For example, if a patient was too sick to receive the assigned intervention, this was consistent with our protocol and therefore not considered a protocol deviation. If a task was not attempted due to pandemic-related factors (e.g., lack of staffing, PPE supply), we classified this as deviation from the initial protocol and documented specific reasons.

Our study focuses on four metrics we deemed critical to study internal validity. The first three related to participant flow (CONSERVE item 13). We documented the following attempts: in the hospital, randomized intervention delivery in the ICU and collection of the primary physical function outcome at 3 days following ICU discharge; post-hospital discharge, 90-day assessments scheduled up to April 30, 2020, within the prescribed timeframe (i.e., from 83–120 days post-randomization). We chose randomized intervention delivery as a measure of protocol fidelity and the primary outcome because of its highest importance among all other outcomes. We selected the April 30 timeline based on 2 factors: (1) initial reports planned for lockdowns of only 2-weeks duration and (2) allowing time for the Methods Centre to develop processes for ongoing remote data collection should lockdowns persist. The final metric, related to statistical methods (CONSERVE item 12), was timely data collection and entry to ensure completion of the interim analysis.

We analyzed all data descriptively and present figures where relevant.

Results

By February 21, 2020, CYCLE had trained 17 sites and enrolled 50% of the 360-patient target, triggering the initiation of a planned 180-patient interim analysis. On March 17, 2020, the province of Ontario (home to the main research ethics board for CYCLE) declared a provincial state of emergency. At this time, 197 (54.7%) patients had been enrolled, and all actively enrolling sites (15 of 17 sites, including 12 academic and 3 community) were forced to pause recruitment into any non-COVID studies, including CYCLE. Figure 2 is a timeline of key events, both globally and related to the CYCLE trial. For patients already enrolled, study procedures continued according to each institution’s policy.

Fig. 2
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Timeline showing global, national, and CYCLE-related events during the COVID-19 pandemic from March-September 2020

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Site characteristics

Research personnel at all sites were required to work from home; at all but one site, interventionists and assessors were permitted to complete in-hospital activities for enrolled patients. Among the 15 active sites, we identified 26 unique patients (13.2% of total CYCLE cohort) still actively on the study protocol: 10 patients in hospital (5 patients still receiving study intervention in the ICU, 6 requiring primary outcome assessment), and 17 requiring 90-day follow-up assessments by April 30, 2020. Table 1 details progression through the protocol by site for these 26 patients. Figure 3 summarizes the activities of all CYCLE sites and the Methods Centre from January to September 30, 2020.

Table 1 Active patients and their study protocol status by site
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Fig. 3
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Timeline of CYCLE study sites from January to September 2020 with representation of patients of immediate concern during the first wave of COVID-19

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Participant flow—intervention delivery

Five study patients were in ICU requiring the intervention; for all 5 patients, the allocated interventions were attempted at least once during the remainder of their respective intervention periods. Table 2 shows the number of attempted intervention days compared to the number completed, with reasons not done.

Table 2 Attempted versus completed tasks by intervention delivery in the ICU, primary outcome, and 90-day follow-up
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Participant flow—outcome assessments

Of the 10 study patients in hospital, 6 were pending primary outcome at 3-days post-ICU, and 5/6 (83%) were attempted. The primary outcome for one patient was not attempted due to an institutional policy prohibiting research staff from being on-site. Of 17 patients pending their 90-day follow-up assessments, 100% were attempted. Table 2 shows the number of attempted, successful, and missed outcomes, with reasons.

RCs identified 2 concerns for completing the 90-day follow-up assessments due to institutional directives to work remotely: (1) patient confidentiality (i.e., potential for identifying documentation in the homes of research personnel rather than in secured offices) and (2) research staff privacy (i.e., using personal phones to conduct follow-ups). In response, we developed a written guidance document to protect patient and research staff privacy and ensure data confidentiality (Additional file 1: Appendix 3).

Statistical analysis—data entry and validation

For research staff working from home, the Methods Centre provided guidance for how to access and use the database remotely. The Methods Centre provided one-on-one support for data entry and cleaning. Working with sites, we validated data for the first 180-patients and the interim analysis was completed on-time in September 2020.

Recruitment—site reactivation

Using a similar communication strategy to the start of the pandemic, we developed a standardized reactivation email template that each site completed before resuming screening and enrolment (Additional file 1: Appendix 4). Through this template, we sought to ensure there was sufficient interventionist, assessor, and research personnel capacity to optimize protocol fidelity in the moment and through potential future waves. We also advised sites to exclude ICU patients with COVID-19 because of the unknown risks of disease transmission via bike equipment surfaces, strained therapy resources (i.e., due to increased clinical responsibilities to care for patients with COVID-19, or staff unable to work because of illness or quarantine), and PPE supply concerns. Figure 4 depicts the CYCLE enrollment graph from study initiation to the end of September 2020. By September 30, 2020, 10 sites (67%) had been reactivated, though recruitment was slower than pre-pandemic. With the commencement of the second wave in Fall 2020, 1 site was paused again at the direction of local leadership.

Fig. 4
figure 4

CYCLE RCT enrolment graph from start-up to end of September 2020. As of September 30, 2020, 221 patients had been enrolled accounting for 61% of the targeted enrollment

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In Tables 3 and 4, we summarize key tips we learned for Methods Centres and study sites, respectively to optimize cohort retention under extenuating circumstances.

Table 3 Strategies for Methods Centres to address extenuating circumstances in an ongoing clinical trial
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Table 4 Strategies for Sites to address extenuating circumstances in an ongoing clinical trial
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Discussion

Optimizing participant flow, cohort retention, and continuing with timely data entry and validation while assuring the safety of patients, interventionists, assessors, and research personnel were our primary goals in navigating the CYCLE trial through the COVID-19 pandemic. Our implementation priorities were driven by patients’ progress in the protocol at the beginning of the pandemic. Throughout the COVID-19 pandemic, we learned important lessons and implemented crucial processes to ensure research integrity, and patient and staff safety. In this report, we documented our approaches to address extenuating circumstances and patient retention for a complex rehabilitation intervention in critically ill patients requiring multiple personnel with distinct research and clinical roles, which will enrich the interpretation of the trial results. Moreover, lessons learned may help Methods Centres and sites navigate extenuating circumstances, such as the COVID-19 pandemic. In addition, these strategies may support future capacity-building efforts in rehabilitation science and enhance the rigor and quality of clinical trials outside of extenuating circumstances.

At the start of the pandemic, researchers expressed many concerns about the conduct of non-COVID-19 clinical trials. Members of our group collaboratively developed guidelines for continuing or restarting non-pandemic focused research [6] as many clinical trials were interrupted or halted by the pandemic [7]. A myriad of challenges from these interruptions have included lost treatment opportunities for patients [8, 9], threatened trial equipment supply chains [9], missed medication doses in vulnerable populations [10], uncertainties about re-starting trials [11], and challenges with data integrity and interpretability due to intercurrent complications (e.g., unavailable study drug, treatment discontinuation due to COVID-19 illness, and missing data) [12,13,14]. Few publications have described specific trial experiences in the context of the current pandemic. Shiely et al. reported management of 8 commercial clinical trials of investigational medicinal products during COVID-19 [15], underscoring challenges related to site communication, intervention delivery, participant retention, and data collection. For example, these investigators implemented protocol modifications to optimize intervention delivery away from in-hospital to home settings (e.g., to administer medication infusions to immunocompromised patients), and outcome assessments from in-person to telephone follow-ups. The authors also shifted from paper to electronic case report forms to facilitate remote collection and entry. However, not all trial interventions or outcomes assessments can pivot to virtual platforms or in-home visits, either due to the intervention and outcomes themselves, or the target population; for example, in-bed cycling with critically ill patients must be delivered in-person in the ICU and performance-based outcome measures cannot occur virtually.

Changing the modes of intervention delivery and outcome assessment may affect the internal validity of the study. For example, transitioning from in-person to telephone outcomes may alter the psychometric properties of a measure. In contrast, changes to the mode of data collection from paper to electronic case report forms are less likely to negatively impact internal validity, though this change should still be documented. Finally, pausing recruitment and enrolment to ensure participant and personnel safety may not have significant impacts on the scientific rigor of studies in progress, but will extend the duration of planned enrolment, and associated costs [16]. Notwithstanding, investigators will need to assess whether the trial management strategies implemented due to extenuating circumstances such as the COVID-19 pandemic affect the validity of trial results. For example, we collected 3 out of the 6 patients requiring primary outcome assessments. While our initial sample size calculation estimated that we needed to enroll 360 patients after accounting for ICU mortality and missing data, we plan to re-evaluate the effect of the pandemic in terms of the scope of any additional missing primary outcome data on the overall trial cohort as we develop our final statistical analysis plan.

The authors of CONSERVE 2021 define extenuating circumstances as, “Unavoidable situations that prompt modifications to a trial. These are not usually under the control of study investigators, sponsors, or funders.” [4] CONSERVE, which recommends reporting details about trial modifications, how the modifications are important, the potential impacts of modifications, and a timeline, suggests this extension only be used when the extenuating circumstances result in important modifications that could have a potentially meaningful effect on a study’s research question, ethics, internal validity and generalizability, feasibility, or analytical methods and statistical power [4]. In March 2020, the duration and impact of the circumstances imposed by the pandemic were unknown. To honor our commitment to enrolled patients and to continue to advance our research agenda in the midst of unknown circumstances, we recognized that a systematic evaluation of our study processes was needed to determine which, if any, would require modifications and how to effectively mitigate potential pandemic impacts. For example, we elected not to enroll patients with COVID-19 for infection control concerns and the possibility of transmitting the virus through the equipment; furthermore, strained therapy resources could impair trial fidelity. We focused on mitigating the impact of the pandemic to patients already enrolled in the trial. The pandemic pause in enrollment has resulted in delayed recruitment leading to a later trial closure date, although randomization has restarted. Clinically, given the emerging evidence on Long COVID outcomes, future studies of ICU rehabilitation in patients with COVID-19 will be critical, but this discussion is beyond the scope of this study.

After careful evaluation, we did not make important modifications to the CYCLE intervention or outcomes assessments and conducted our interim analysis as planned. However, we did implement extensive mitigation strategies to protect participant flow and statistical analyses. For these reasons, we suggest the use of the CONSERVE reporting guidance for all trials that experienced extenuating circumstances as defined above—notably, all trials occurring during the COVID-19 pandemic. This is supported by CONSERVE authors [4] who state that while it was intended to capture important modifications, there may be opportunity to enhance reporting within a broader context. Understanding how trialists implement and evaluate mitigation strategies and their rationale for any important modifications will help future trialists respond and adjust to other unforeseen circumstances causing research disruptions. Given the known gap in evidence for trial management [17], the universal implementation of CONSERVE 2021 reporting in all instances of extenuating circumstances will enhance transparency in reporting and decision-making. In Fig. 5, we outline the stages in a study at which CONSERVE 2021 could be applied.

Fig. 5
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Depiction of the stages at which CONSERVE could be applied to a trial in progress

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Strengths and limitations

Strengths of this study include focus on the conduct of an international multi-center trial of a complex rehabilitation intervention in acute care during the pandemic. We addressed key issues of data integrity, data completeness, and research ethics using the CONSERVE 2021 statement as a reporting framework for our trial in-progress. We reported our specific Methods Centre processes in the context of the COVID-19 pandemic, including practical examples and resources which could be generalizable to other complex interventions or studies including remote telephone follow-up. Our report also has limitations. First, it is focused on one trial underway in the ICU setting with follow-up in-hospital and beyond. Second, it does not address other parts of CONSERVE 2021, such as changing recruitment strategies or statistical analysis plans due to extenuating circumstances.

Conclusions

The pandemic has been a catalyst to identify guiding principles and develop contingency plans and mitigating strategies to optimize study recruitment, retention, fidelity and reporting in the face of unintended interruptions. Despite a complete pause in enrolment in this rehabilitation trial and an immediate transition to working from home for many research personnel, data integrity was maintained, the interim analysis was completed, and the study has since resumed enrolment at 10 of 15 sites.