By Barbara Casolla, MD, PhD
Univ. Lille, Inserm U1172,
Degenerative and Vascular Cognitive Disorders,
CHU Lille, Department of Neurology, France
Data obtained from clinical trials are the fundamentals of our clinical practice. Networks and collaborations are the keys for their success. During this dynamic ESO webinar, moderated by Silke Walter and Robin Lemmens, a panel of experts shared their experiences on the main goals and difficulties of setting up and keeping a clinical trial ongoing, especially during these times of health system massive crisis.
Professor Peter Kelly, from Ireland, introduced the ESOTA and its added values: to join forces in the consolidation of a “European super Network” represents an important challenge for promoting scientific knowledge sharing, resource optimization, increasing competitiveness for EU funds, supporting new networks to form and join. ESOTA is an active network with 3 randomized clinical trials actually planned in funding application phase (EPICS, ASPIRING and TICH3).
The first speaker, from Nottingham, was Professor Nicola Sprigg, who brought the experience of TICH2 and EUROHYP trials. What are the key steps for delivering a trial? Trial design, funding and approvals. These key issues are linked together and they can challenge the trial even before its starting point. First rule: research protocols need to be embedded into clinical practice, therefore, a simple and pragmatic design, as closest and aligned to clinical practice as possible, is essential for inclusion, consent, randomization, follow-up and data collection advancement. Concerning funding: this is a time-consuming step, “start small than build up” and “promote internal pilot studies with stop-go decision for progression” said Professor Sprigg. Regulatory approvals (insurance, contracts and payments) affects trial delivery and needs simple processes as well. The delivery phase depends on networks: some of the successful approaches of TICH-2 consisted of leaning on existing trial networks, promoting co-enrollment with other studies, embedding sub-studies and feeding the networks with work shop and on-line join training/investigator meetings. Indeed, inclusion failure is the main reason for trial failure. A multiple site recruitment may help by offering multiple opportunities in set-up and delivery, but it is challenging. Improving collaboration: but what is the reward? Answering important clinical questions for patient better outcome, but also balancing authorship and ownership of sub studies. Moreover, involvement of stroke survivors is crucial for motivation, consent input and for focusing on other potential clinically relevant outcome measures that we wouldn’t have thought of.
In these times of global pandemic, the challenge of making a clinical trial successful becomes major. COVID-19 pandemic has certainly impacted ongoing trials on multiple aspects: opening new trial sites, recruitment, involvement of participants in the trials and patient’s follow-up. What is the experience of the speakers?
Professor Terry Quinn, from Scotland, explained alternatives to replace face-to-face assessment for outcome. For instance, video-recordings, telephone assessments, self-questionnaires and existing data from observational records. Remote assessment options are possible but they require training. Certain modalities are better suited to certain outcomes and/or patient’s profile, and sometimes remote assessment may require modification of the existing assessments scale. Some examples? There is evidence supporting remote assessment of modified Rankin Scale (mRS) by video recordings, with advantages (flexibility and possibility of quality control) and limitations (digital exclusion for some patients, dependency on technology). Montreal Cognitive Assessment test (MoCA) can be obtained by telephone, however, available data on feasibility and acceptability are limited, and some cognitive domains, such as executive and spatial functions cannot be explored by phone. What about quality of life self-questionnaire? They have an easy access and limited costs, but they targeted population is limited by the degree of stroke impairments. Furthermore, variability in response rate should also be taken into account: to improve it, “short is good”. Secondary analysis of existing data is also feasible and can be strengthen by blending data sources, especially for mortality, home-time, stroke scales such as NIHSS and mRS outcomes.
Professor Urs Fischer, from Bern, shared the experience of his team on SWIFT-Direct, ELAN and SWITCH trials. What is the experience concerning the impact of COVID-19 on these acute phase trials? These 3 trials continued to recruit during the pandemic, with differences among countries. The keys of this success? Their pragmatic design and management, the flexibility and commitment of study team. Design is indeed in line with clinical routine and involves only few study-specific (and single) interventions, with easy randomization procedures and possibility of remote follow-up. Study data are centrally monitored and study initiation visits by zoom were organized even before the COVID-19 pandemic. The team of these trials provided recommendations at the beginning of the pandemic, including possibility of phone follow-up and consent of relatives, and also took contact with different sites to tailor activities depending on local situations. The study management continuously worked from home office and could be contacted at any time. Regular contacts with teams continued after the first wave, with an investigator meeting and many newsletters, e-mails, surprises and gifts to promote motivation of teams (including delicious Suisse chocolate!)
Moving to the post-acute phase, Professor Julia Bernhardt, from Melbourne, explained that, rehabilitation and recovery trials present differences compared to acute phase studies: patient must be fully engaged, investigator/patient interaction is more complex and include behavioral interventions that are usually derived face-to-face, with dose titration tailored to the patient, and multiple sessions along the trial. Outcomes are more complex, with potential confounding variables. Therefore, post-acute intervention were strongly affected with ward closures and shorter length of stay and trials recruiting from community and needing an in-hospital training or assessment were postponed, adapted or abandoned. Pr Bernhardt brought the example of AVERT DOSE, a large international, multi-arm and multi stage trial for the impact of COVID-19. Protocols were adapted, with online assessment version of some outcome (and decision about what assessment cannot be done, virtually), and shift from face-to-face meeting to virtual meeting and remote monitoring site data. Site specific policies were followed and sites that were still able to recruit were supported. The international dimension of the AVERT DOSE trial also underlined potential inter-country issues: tracking COVID-19 infected patients, especially in countries with many cases, such as India and Brazil, and evaluations on the impact of COVID-19 in key domains (treatment discontinuation, compliance to treatment, additional medications and data collection).
As a stroke community, we thank the organizers, the moderators and the speakers for their excellent talks: joining forces and building networks during these hard times seems to be even more important than before.