A team of researchers from the Saudi Critical Care Trials Group (SCCTG) has shown that a drug combination regimen  reduced mortality by a third in a group of hospitalized patients with the Middle East Respiratory Syndrome (MERS).

Caused by the MERS-CoV virus, MERS is fatal in over a third of infections, with 2519 confirmed cases and 866 deaths reported as of January 2020. The disease, which reportedly first spread from dromedary camels to humans in 2012, typically presents with severe respiratory symptoms including fever, cough, and shortness of breath. 

As with COVID-19, pre-existing conditions predispose patients to severe illness, and some individuals are mildly symptomatic or asymptomatic. Although MERS cases in humans are declining, the virus is still widespread in dromedaries, posing a potentially grave risk. “MERS, at present, is not easily transmissible between humans, unlike COVID-19,” says Yaseen Arabi, chairman of the Intensive Care Department at King Abdulaziz Medical City and professor at the College of Medicine at King Saud Bin Abdulaziz University for Health Sciences, who was the principal investigator of the new research. “The worry is always that maybe a mutation makes the virus more transmissible.”

A new trial for a stubborn disease

The team enrolled 95 patients from nine clinical sites in Saudi Arabia in a MERS clinical trial. Of the cohort, 43 were given a 14-day course of experimental therapy that combined interferon Beta-1b and lopinavir-ritonavir, and a second group of 52 patients received a course of placebo therapy. The team found that after 90 days, 44% of the placebo group had died from the disease, whereas the mortality rate was only 28% in the experimental treatment group. This represents a significant reduction in mortality for a disease that has so far been untreatable. 

The team found that to receive the clinical benefit, patients needed to start the regimen within seven days of symptom onset. “Early treatment makes a big difference. I think early recognition and treatment might help bring mortality down even lower,” says Arabi. The drugs used in the trial were chosen based on their efficacy in preclinical studies, which showed that lopinavir inhibited the replication of MERS-CoV and SARS-CoV (the causative virus of the SARS epidemic) in vitro, and lopinavir-ritonavir/interferon beta-1b was previously shown to improve the condition of infected marmosets. By using a therapy of two medications, one of which (lopinavir-ritonavir) is a two-drug combination, the team was able to target MERS-CoV at different levels, providing both immunomodulatory and antiviral effects.

One of the challenges in conducting the trial was that MERS is an uncommon virus with episodic infection flares. “We started recruiting patients in 2016, and the last one was recruited in early 2020,” says Arabi, highlighting the time needed to get a useful number of cases. While randomized controlled trials are typically based on pilot studies, Arabi and his team recognized that the low rate of new cases meant they would need to design an adaptive trial that incorporated multiple stages with interim assessments to guide the trial to research-validated findings. To ensure the design was robust, the team included a longer-term 90-day follow-up. The study found that the survival of the two groups “continued to diverge well beyond day 28”. 

A focus on intensive care research

The SCCTG represents a concerted effort by clinical academia within the Kingdom of Saudi Arabia to boost the country’s clinical trials portfolio and expertise in intensive care medicine. KAIMRC researchers are part of the SCCTG, and the institution also hosts Saudi Arabia’s National Command Center for Clinical Trials. Active for several years, the SCCTG has published multiple papers in high-impact journals, including a series of publications on MERS therapies. “All of these questions turned out to be really critical when COVID struck,” says Arabi. “People asked the same questions.”

Despite the horrors of MERS, it primed Saudi society for the onslaught of COVID-19. “Exposure to MERS over the last several years has helped a lot in building our prescience, advising the culture to the threat of viral infections. So, when COVID-19 came, people knew what the risks were and that we should take precautions,” says Arabi. And perhaps more importantly, the Saudi healthcare system was primed to respond, already having prepared response plans for viral infections and pandemics.

Just as the fight against MERS prepared society for the fight against COVID, the ongoing pandemic may in turn offer insights that help researchers combat MERS.  While Arabi believes some COVID treatments may warrant testing as MERS therapies, he and other MERS researchers will have to cope with the difficulty of evaluating multiple potential therapies with only a small group of patients. 

Even with the experimental therapy, mortality from MERS remained at 28% in the trial. This is a significant reduction from the generally reported mortality rate of 35%, but it simultaneously highlights the need for more work to reduce mortality further. 

The SCCTG is now looking at questions raised by the COVID-19 pandemic, and they have two clinical trials in the works. One investigates whether prone positioning in awake patients helps their oxygenation and clinical outcomes, as has been shown for patients on ventilators, while the other looks at the benefits of non-invasive helmet-based ventilation in COVID-19. Arabi and the SCCTG are also involved in the international REMAP-CAP trial, designed to simultaneously and efficiently evaluate a number of treatment options for COVID-19. 

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