Community-based management of a five-arm randomised clinical trial in COVID-19 outpatients in South Africa: challenges and opportunities

Abstract

Background: Repeated COVID-19 waves and corresponding mitigation measures have impacted health systems globally with exceptional challenges. In response to the pandemic, researchers, regulators, and funders rapidly pivoted to COVID-19 research activities. However, many clinical drug studies were not completed, due to often complex and rapidly evolving research conditions.

Methods: We outline our experience of planning and managing a randomised, adaptive, open-label, phase 2 clinical trial to evaluate the safety and efficacy of four repurposed drug regimens versus standard-of-care (SOC) in outpatients with 'mild to moderate' COVID-19 in Johannesburg, South Africa, in the context of a partnership with multiple stakeholders. The study was conducted between 3 September 2020 and 23 August 2021 during changing COVID-19 restrictions, significant morbidity and mortality waves, and allied supply line, economic, and political instability.

Results: Our clinical study design was pragmatic, including low-risk patients who were treated open label. There was built-in flexibility, including provision for some sample size adjustment and a range of secondary efficacy outcomes. Barriers to recruitment included the timing of waves, staff shortages due to illness, late presentation of patients, COVID-19 misinformation, and political unrest. Mitigations were the use of community health workers, deployment of mobile clinical units, and simplification of screening. Trial management required a radical reorganisation of logistics and processes to accommodate COVID-19 restrictions. These included the delivery of staff training and monitoring remotely, electronic consent, patient training and support to collect samples and report data at home, and the introduction of tele-medicine. These measures were successful for data collection, safe, and well received by patients.

Conclusion: Completing a COVID-19 trial in outpatients during the height of the pandemic required multiple innovations in nearly every aspect of clinical trial management, a high commitment level from study staff and patients, and support from study sponsors. Our experience has generated a more robust clinical research infrastructure, building in efficiencies to clinical trial management beyond the pandemic.

Keywords: COVID-19; Clinical research management; Clinical trial design; Drug repurposing; Outpatient; South Africa.

Fig. 1

Location of the study area (shaded green) in Gauteng Province, South Africa. Redrawn and adapted from: File: Map of Gauteng with municipalities blank (2016).svg (https://commons.wikimedia.org/wiki/File:Map_of_Gauteng_with_municipalities_blank_(2016).svg)

Fig. 2

Study summary

Fig. 3

Timeline of the pandemic responses and trial recruitment. A Timing of COVID-19 alert levels across South Africa [39]. B Cumulative patient recruitment versus active COVID-19 cases in Gauteng province [40]