Modified clinical trial protocol created in response to urgency of COVID-19 pandemic

May 19, 2020

May 19, 2020-- A new paper published online in the Annals of the American Thoracic Society describes a nimble, pragmatic and rigorous multicenter clinical trial design to meet urgent community needs in the face of the COVID-19 pandemic.

In "Hydroxychloroquine vs. Azithromycin for Hospitalized Patients With Suspected or Confirmed COVID-19 (HAHPS): Protocol for a Pragmatic, Open Label, Active Comparator Trial," Samuel Brown, MD, MS, and co-authors report on the design of a clinical trial, now underway, that they were able to quickly establish and adopt in community and academic hospitals throughout Utah comparing hydroxychloroquine and azithromycin as potential COVID-19 treatments.

"We developed the trial in response to local pressures for widespread, off-label use of these medications," said Dr. Brown, director of pulmonary and critical care research at Intermountain Healthcare in Salt Lake City, who oversees the Center for Humanizing Critical Care at Intermountain Medical Center. "This, and past experience with Ebola, underscored the need for nimble, timely, rigorous controlled trials in a pandemic setting."

The researchers hope to recruit up to 300 study participants with varying degrees of COVID-19 severity from within the Intermountain Healthcare and University of Utah health systems.

The study design differs from that of other randomized, controlled trials in that it does not have a placebo arm. "Placebos can take weeks or months to manufacture and distribute and generally require a research pharmacy to manage," Dr. Brown explained. "We were able to launch quickly because we didn't have to wait for the placebo manufacture. We were also able to start the trial at hospitals that don't have research pharmacies, including many community hospitals. It's really been an all-hands-on-deck effort."

In place of a placebo, the investigators chose to use a comparator drug - the antibiotic azithromycin. Because the drug showed anti-inflammatory pulmonary effects and other potential benefits in some previous trials, they felt it might have efficacy, and have a very low likelihood of harm due to its established safety profile.

The study is a prospective, randomized, open-label, active comparator trial of hydroxychloroquine versus azithromycin among hospitalized patients with confirmed or suspected COVID-19. Study participants in the hydroxychloroquine arm receive 400mg twice a day for one day, followed by 200mg twice daily for four days.

Participants in the azithromycin study arm receive 500mg on the first day, plus 250mg daily on days two through five. These patients are monitored remotely on a daily basis while receiving the study medication for adverse events and possible introduction of other medications that may result in cardiac problems.

Study participants are observed for 14 days, at which point their progress or decline are assessed (primary endpoint) based on the WHO COVID Ordinal Outcomes Scale. Secondary endpoints are calculated at 28 days based on whether they are hospital-free, ventilator-free and ICU-free.

A formal statistical analysis plan will be written prior to the initial formal interim analysis. New information may come to light that makes it necessary to modify the study protocol and analyses, due to the rapidly evolving state of knowledge about the COVID-19 pandemic.

The authors concluded: "Faced with the prospect of massive statewide expansion of clinical use of untested therapies with unknown risk/benefit profiles in COVID-19 and operating within the context of global placebo-controlled trials being launched in parallel, we initiated a pragmatic trial intended to both provide treatment options in a structured environment, with informed consent and formal safety monitoring, and to contribute to knowledge about which treatment strategies may be of use in subsequent waves of COVID-19 activity."
About the Annals of the American Thoracic Society

The AnnalsATS is a peer-reviewed journal published by the American Thoracic Society. The Journal delivers up-to-date and authoritative coverage of adult and pediatric pulmonary and respiratory sleep medicine and adult critical care. The scope of the Journal encompasses content that is applicable to clinical practice, the formative and continuing education of clinical specialists and the advancement of public health. The journal's impact factor is 4.026.

Editor: Colin Cooke, MD, MS, associate professor in the department of internal medicine at the University of Michigan.

About the American Thoracic Society

Founded in 1905, the American Thoracic Society is the world's leading medical association dedicated to advancing pulmonary, critical care and sleep medicine. The Society's 15,000 members prevent and fight respiratory disease around the globe through research, education, patient care and advocacy. The ATS publishes four journals, the American Journal of Respiratory and Critical Care Medicine, the American Journal of Respiratory Cell and Molecular Biology, the Annals of the American Thoracic Society, and ATS Scholar.

American Thoracic Society

Related Placebo Articles from Brightsurf:

Effect of fluvoxamine vs placebo on clinical deterioration in outpatients with symptomatic COVID-19
This randomized trial compares the effects of fluvoxamine, a selective serotonin reuptake inhibitor with immunomodulatory effects, versus placebo on a composite of dyspnea or pneumonia and oxygen desaturation among adult outpatients with polymerase chain reaction-confirmed mild COVID-19 illness.

Hydroxychloroquine no more effective than placebo in preventing COVID-19
Clinical trial with COVID-19 testing of participants shows health care workers in contact with coronavirus patients who took hydroxychloroquine each day did not reduce their rate of infection.

Compared to placebo, vitamin D has no benefit for severe asthma attacks
Contrary to earlier observational results, vitamin D supplements do not prevent severe asthma attacks in at-risk children, according to the first placebo-controlled clinical trial to test this relationship.

UMN trial shows hydroxychloroquine has no benefit over placebo in preventing COVID-19
Today, University of Minnesota Medical School researchers published the results from the first randomized clinical trial testing hydroxychloroquine for the post-exposure prevention of COVID-19.

The placebo effect and psychedelic drugs: tripping on nothing?
A new study from McGill suggests that, in the right context, some people may experience psychedelic-like effects from placebos alone.

Methotrexate reduces joint damage progression over placebo in erosive hand OA
According to new research findings presented at the 2019 ACR/ARP Annual Meeting, methotrexate did not demonstrate superior efficacy over placebo for pain relief and function evolution at three and 12 months in patients with erosive hand osteoarthritis, but did significantly reduce the progression of joint damage over placebo and seems to facilitate bone remodeling in these patients.

Botulinum toxin reduces chronic migraine attacks, compared to placebo
A growing body of evidence supports the effectiveness of botulinum toxin injections in reducing the frequency of chronic migraine headaches, concludes an updated review and analysis in the January issue of Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons (ASPS).

Opioids vs. placebo, nonopioid alternatives for chronic noncancer pain
An estimated 50 million adults in the United States were living with chronic noncancer pain in 2016 and many of them were prescribed opioid medications, even though a clinical benefit is uncertain.

Probiotic no better than placebo for acute gastroenteritis in children
While probiotics are often used to treat acute gastroenteritis (also known as infectious diarrhea) in children, the latest evidence shows no significant differences in outcomes, compared to a placebo.

Most common shoulder operation is no more beneficial than placebo surgery
In a landmark study published this week in the BMJ, Finnish researchers show that one of the most common surgical procedures in the Western world is probably unnecessary.

Read More: Placebo News and Placebo Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to