Implementation of a fully remote randomized clinical trial with cardiac monitoring

Abstract

Background: The coronavirus disease 2019 (COVID-19) pandemic has challenged researchers performing clinical trials to develop innovative approaches to mitigate infectious risk while maintaining rigorous safety monitoring.

Methods: In this report we describe the implementation of a novel exclusively remote randomized clinical trial (ClinicalTrials.gov NCT04354428) of hydroxychloroquine and azithromycin for the treatment of the SARS-CoV-2-mediated COVID-19 disease which included cardiovascular safety monitoring. All study activities were conducted remotely. Self-collected vital signs (temperature, respiratory rate, heart rate, and oxygen saturation) and electrocardiographic (ECG) measurements were transmitted digitally to investigators while mid-nasal swabs for SARS-CoV-2 testing were shipped. ECG collection relied on a consumer device (KardiaMobile 6L, AliveCor Inc.) that recorded and transmitted six-lead ECGs via participants' internet-enabled devices to a central core laboratory, which measured and reported QTc intervals that were then used to monitor safety.

Results: Two hundred and thirty-one participants uploaded 3245 ECGs. Mean daily adherence to the ECG protocol was 85.2% and was similar to the survey and mid-nasal swab elements of the study. Adherence rates did not differ by age or sex assigned at birth and were high across all reported race and ethnicities. QTc prolongation meeting criteria for an adverse event occurred in 28 (12.1%) participants, with 2 occurring in the placebo group, 19 in the hydroxychloroquine group, and 7 in the hydroxychloroquine + azithromycin group.

Conclusions: Our report demonstrates that digital health technologies can be leveraged to conduct rigorous, safe, and entirely remote clinical trials.

Keywords: Cardiology; Randomized controlled trials.

Fig. 1. Timeline of participant study drug administration and data collection with schematic demonstrating data processing and storage.

Visual representation of the study protocol. Study drugs were taken on protocol days 1–10. ECGs, mid-nasal viral swabs, symptom surveys, and vital signs were self-collected on protocol days 1–14, while only ECGs, symptom surveys, and vital signs were obtained on days 21 and 28. On days 2, 4, 9, 14, and 28, planned investigator-initiated contact was undertaken to collect subjective data and encourage adherence. Vital signs were collected twice daily. ECGs were uploaded to the secure web portal where study coordinators pushed them to the core ECG laboratory and then recorded the returned interpretation, as described in the “Methods” section. Viral swabs were sent to the core virology laboratory. All data were warehoused in REDCap.

Fig. 2. Electrocardiogram acquisition and workflow.

Six-lead electrocardiogram acquisition by the patient using the AliveCor® KardiaMobile 6L device (A). Note: rotating the device 180° results in limb lead reversal. Implementation of remote QTc monitoring (B). ECG is collected by the participant, uploaded to a secure web portal, and transmitted by study coordinators for adjudication at a core laboratory. QTc results are transmitted to study coordinators for safety ascertainment by study clinicians.

Fig. 3. Graphical overview of recruitment, screening, logistics, and data acquisition.

A multipronged recruitment effort was utilized, and screening leveraged secure digital health technologies.

Fig. 4. Percent of participants who submitted an ECG per protocol day.

Red bars represent days that were specified for ECG submission in the protocol, while gray bars represent days when ECG upload was not required.

Fig. 5. Comparative daily percent adherence to survey completion, mid-nasal swab submission, and ECG upload by protocol day.

ECG protocol adherence was noted to reduce to <70% after the study drugs were discontinued after day 14.