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

1: Identify patients immediately affected by the extenuating circumstances. Consider intervention delivery and safety, and primary outcome

Identified patients still in the ICU at highest risk for protocol deviations as they required the intervention, as well as those in hospital still requiring the primary outcome

Once high-risk points in the protocol were identified, site teams could develop strategies to mitigate missing data and losses to follow-up

2: Develop standardized communication tools to gather pertinent site information that is relevant to study conduct (e.g., staff capacity, patient status, data cleaning progress, etc.)

Developed structured email templates with focused questions regarding patient status and staff capacity

These templates allowed the Methods Centre to obtain precise information required to develop individualized strategies to promote protocol fidelity and retention

3: Develop standardized internal tools focused on the high-risk points in the protocol to facilitate real-time monitoring and timely identification of threats to study retention and fidelity

Revised existing tracking documents (e.g., data entry and validation to include a column indicating whether or not research personnel at each site has remote access to the database) to monitor and track patient progress by site

Tracking documents focused on high-risk points for patient status to mitigate missing data and losses to follow-up. Documenting the status of data entry and validation allowed the Methods Centre to continue to monitor the study for safety and protocol adherence and prepare for the interim analysis as scheduled

4: Continue as many trial activities as possible in preparation for future trial resumption at participating sites and the Methods Centre

Identified future trial milestones, such as data cleaning for the interim analysis, and future trial education. We worked with sites towards data entry, cleaning, and validation for the interim analysis. At the Methods Centre, we prepared for the interim analysis with our biostatistician for the data safety and monitoring committee. We modified in-person educational materials to virtual interactive sessions for future teaching

Maximizing the enrolment downtime provided opportunity to keep background work moving in a timely manner, and also facilitated ongoing Methods Centre personnel employment for study-related activities

5: Provide guidance for sites in preparation for trial resumption

Identified important considerations for protocol fidelity and cohort retention to help sites prepare to resume enrolment. We developed standardized communication tools for the site to prepare to restart research.

This allowed the Methods Centre to help sites optimize protocol fidelity in the context of uncertain future waves and potential resource challenges

6: Determine if major trial modifications are required or not required, considering current circumstances, and report rationale

Decision not to enroll patients with COVID-19 upon initial trial resumption due to infection control considerations for the equipment and strained therapy resources. We did not make major trial modifications

Reporting decision-making rationale will help readers assess the impact of the response to extenuating circumstances

7: Disseminate and share the lessons learned via peer-review publications

Collaborated with sites to carefully document the challenges and the solutions developed to mitigate them

Share best practices and experiences with the research community to inform future study management