By Deborah Borfitz 

March 9, 2022 | A fully remote randomized clinical trial, born of necessity in the early days of the pandemic, provides evidence that the study model is viable even when testing drugs with potential heart rhythm effects. Whether the concept will be as well embraced post-pandemic remains anyone’s guess, says Arun Sridhar, M.D., assistant professor of cardiology at the University of Washington School of Medicine and one of the investigators on the study of hydroxychloroquine and azithromycin for the treatment of mild COVID-19 disease. 

Conducted by researchers at five U.S.-based healthcare systems and led by the University of Washington, the study enrolled 218 patients and found no signs of efficacy from either of the two test drugs, he says. But operationally, the remote trial was remarkably successful. 

The only real challenge was tele-educating patients on how to use the handheld rhythm-monitoring device (KardiaMobile 6L, AliveCor Inc.), which generally took two to three hours per patient, Sridhar says. Adherence to the ECG protocol also waned after two weeks when the study drugs were discontinued.

Going in, the main concern of investigators was the drugs’ potential to cause a type of heart rhythm disorder called a prolonged QT interval, he continues. If allowed to persist, long QT can cause life-threatening cardiac arrhythmias. 

COVID-19 concerns precluded participants from coming to the clinic for their ECGs, so they needed to learn how to perform the test at home and transmit the results via an app on their smartphone, says Sridhar.  A lack of digital literacy among some of the older trial participants was remedied by family members who stepped in to assist, as was communication barriers with a few who were native Spanish speakers.

Remote Features

As reported recently in Communications Medicine (DOI: 10.1038/s43856-021-00052-w), remote components of the trial included enrollment by phone or mail with consent confirmed by secure video teleconference. This step was also handled by the University of Washington, Sridhar says. Per the study’s inclusion criteria, participants all had access to the internet for participation in video conference visits and to complete study data. 

A courier delivered study drugs as well as nasal swabs for SARS-CoV-2 RT-PCR testing and self-monitoring kits containing a six-lead ECG monitor, oxygen saturation monitor, and an oral thermometer.

Artificial intelligence was used to determine the QT interval, as was recently shown to be feasible (DOI: 10.1161/CIRCULATIONAHA.120.050231), which helped accelerate turnaround time by focusing human attention on abnormal ECG readings, Sridhar notes. An ECG result indicating QT prolongation necessitated study drug hold and participants were contacted to collect a follow-up ECG. If a prolonged QT interval was confirmed, the study medication was permanently discontinued.

Study results indicate a total of 3,245 ECGs (median of 17 per participant) were uploaded and adjudicated by the Mayo Clinic. Mean daily adherence to the ECG testing protocol was about 85%, mirroring that for the survey and mid-nasal swab elements of the trial.

Feedback Loop 

One of the most notable features of the study was a feedback loop ensuring ECG information was sent to investigators within one hour, says Sridhar. Since ECG results were being transmitted in a timely fashion, investigators could quickly react to avert problems by having patients alter their dosage or stop taking the drug. 

As it turned out, hydroxychloroquine and azithromycin were associated with a relatively low adverse event rate, he adds. QT prolongation meeting criteria for an adverse event occurred in 28 (12.1%) participants, including two in the placebo group, 19 in the hydroxychloroquine group, and seven in those taking both study drugs. 

The study was approved by the Western Institutional Review Board with reliance agreements from the collaborating institutions. In the absence of a pandemic, an innovative trial of this type would have progressed at a much slower pace, Sridhar says. 

Clinical Excitement 

It is likely that many multi-center clinical trials in the future will be at least partially decentralized and remotely operated, he predicts, primarily to accommodate participants who don’t live near any of the bricks-and-mortar study sites or have limited mobility. This would include patients at risk of QT interval prolongation, such as those who receive certain chemotherapeutic agents, antibiotics, or antiviral agents. 

Sridhar says he believes the nonadherence issue seen in the recent COVID-19 drug trial could be overcome with more frequent patient contact and coaching—virtual or otherwise—and perhaps some modest financial incentives. Standard practice is to send patients to the hospital for the procedure, which adds time and travel cost burdens to clinical trial participation. 

“There is a lot of excitement among cardiologists for these kinds of trials,” says Sridhar. More than 100 prescribed medications, and many more in the development pipeline, can potentially lengthen the QT interval in otherwise healthy people. The list includes antibiotics, antifungal medications, diuretics, heart rhythm drugs, cancer drugs, antidepressant and antipsychotic medications, and anti-nausea drugs.