ABSTRACT
Background. Early in the COVID-19 pandemic, no evidence-proven therapeutics were approved, and thus participation in a clinical trial was often the only way to access experimental medications. However, in the US, participation in medical research is low. Patient-stated factors impacting enrollment decisions are poorly characterized. Thus, the aim of this study was to identify patient-reported reasons for declining enrollment in a COVID-19 clinical trial. Methods. As part of an open-label, pragmatic randomized trial across five VAs from 4/10/20 - 2/3/21, SARS-COV-2 positive inpatients with moderate to severe disease were screened for eligibility. Potentially eligible patients received an informed consent packet with a letter explaining the study and were then contacted remotely to assess willingness to participate. If eligible patients declined to participate, if willing, they were asked an open-ended question about the reasons behind their decision. If they were not able to provide a specific answer, then general categories were offered. Qualitative responses were analyzed using a directed content analysis approach;responses were categorized using previously defined factors that have contributed to decisions not to enroll in other clinical therapeutics trials, primarily conducted in oncology. Results. Among 417 patients screened, 162 met eligibility criteria. Of these, 53 consented (32.7%), 102 declined to participate (62.9%), and 7 were unable to give consent. Themes and examples of reasons for declining participation are presented in Table 1. Among the patients who declined to participate, the four most cited factors were limited perceived benefit, competing priorities, physician or family influence and presence of comorbidities. Several patients reported that their decision was influenced by physician or family recommendation to decline, which was reported as physician lack of support for participation due to the presence of comorbidities or physician perceived lack of benefit given clinical improvement prior to study enrollment. Conclusion. Understanding reasons and attitudes driving enrollment may help investigators address them during the recruitment process and increase participation in clinical trials in the US.
ABSTRACT
Background. The aim of this pragmatic, embedded adaptive trial was to measure the effectiveness of subcutaneous sarilumab in addition to an evolving standard of care for clinical management of inpatients with moderate to severe COVID-19 disease (NCT04359901). The study is also a real-world demonstration of the realization of a prospective learning healthcare system. Methods. Two-arm, randomized, open-label controlled 5-center trial comparing standard care alone to standard care (SOC), which evolved over time, with addition of subcutaneous sarilumab (200 mg or 400 mg anti-IL6R) among hospitalized patients with moderate to severe COVID-19 not requiring mechanical ventilation. The primary outcome was 14-day incidence of intubation or death. The trial used a randomized play-the-winner design and was fully embedded within the EHR system, including the adaptive randomization process. Results. Among 417 patients screened, 162 were eligible based on chart review, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death ( >30% of eligible patients enrolled) (Figure 1). After the second interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. Conclusion. This randomized trial of patients hospitalized with COVID-19 and requiring supplemental oxygen but not mechanical ventilation found no evidence of benefit from subcutaneous sarilumab in addition to an evolving standard-of-care. The numbers of patients and events were too low to allow independent conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6 inhibition in the treatment of patients hospitalized with COVID-19. The major innovation of this trial was the advancement of embedded, point-of-care clinical trials for FDA-approved drugs;this represents a realization of the learning healthcare system. Methods developed and piloted during the conduct of this trial can be used in future investigations to speed the advancement of clinical science.