In the quarantined Chinese city of Wuhan, health workers fighting the explosive outbreak of a new coronavirus have been improvising for weeks, trying to provide whatever care they can for Covid-19 patients whose symptoms range from a cough and fever to severe pneumonia, septic shock, and organ failure. In addition to treating these symptoms with oxygen therapy, ventilators, and antibiotics, doctors there have also resorted to experimentation. With no approved treatments for any of the illnesses caused by coronaviruses, health workers have been trying everything from steroids and antibodies to drugs normally intended for HIV and influenza. But because these treatments have been dispensed on a case-by-case basis, without any rigorous, centralized tracking of results, it’s hard to know if any of them are effective against the new disease.
Now, researchers in China are racing to launch more systematic tests of these repurposed medicines. Since January 28, scientists have registered 19 clinical trials in China, and at least a few have already begun dosing patients. With initial results expected as early as April, the swift leap into clinical research is an important one for frontline health workers desperate for hard evidence about which therapies work best. The trick will be making sure that evidence stacks up.
“When you have a treatment, you can measure different things in a patient,” said Marie-Paule Kieny, WHO’s assistant director general of health systems and innovation, at a press conference Wednesday. “What is important if you want to compare different treatments is that everybody measures the same.” Her remarks came at the conclusion of a two-day summit convened by the WHO that brought together major funders and more than 300 scientists to define the most pressing research priorities of the current outbreak.
Chinese scientists who attended in person or virtually pushed for two urgent, short-term requests, according to Kieny, who cochaired the summit. The first is creating simpler tests for diagnosing Covid-19 that doctors could use at patients’ bedsides or even out in the field as part of community screening programs. Currently, the only tests available require time-consuming lab work, which means that biological samples have to be shipped to qualified hospitals where backlogs can quickly build up. The second is for the global medical community to produce standardized treatment plans with a strong data-collection component. In other words, they want to know what’s working for the sickest patients.
WHO’s director general, Tedros Adhanom Ghebreyesus, said Wednesday that the organization is now in the process of developing a master plan for coordinating clinical trials. The framework is intended to create consistency across studies of different treatments so the data can be compared directly as it comes in.
A randomized, controlled trial is the gold standard of clinical research. But pulling one together for Covid-19 is complicated by the realities of working in hospital systems overwhelmed by the sheer size of the outbreak. One of the biggest issues is ensuring the same standard of care in every place where the drug is being tested, says Nahid Bhadelia, medical director of the Special Pathogens Unit at Boston University’s National Emerging Infectious Disease Laboratories. “You can’t determine if a drug works unless the rest of the treatment received by patients is also the same,” says Bhadelia.
That gets much harder during a public health emergency like the one hitting Hubei province, where more than 48,000 people have fallen ill. Reports from the region show hospitals pushed to the brink—long lines, crammed wards, people being turned away—as the crush of patients has not yet been alleviated by the rushed construction of field hospitals and temporary quarantine structures.
But what researchers there do have going for them is a deep and growing expertise in clinical trials. About 20 percent of all clinical trials are now conducted in China, up from 10 percent five years ago, Thompson Reuters recently reported. That includes nearly 500 ongoing trials in the city of Wuhan, which has been hardest hit by Covid-19. The outbreak has disrupted some of these studies, as the doctors and facilities once dedicated to them have become a front line in the epidemic. But it has provided no shortage of willing patients on which to test potential Covid-19 treatments.
Two trials, which The New York Times reported began recruiting patients last week, will test the efficacy of remdesivir, an experimental antiviral produced by American drugmaker Gilead. It works by blocking the enzyme that many viruses use to replicate inside human cells. It has not yet been approved for any use, but it does appear to be safe, according to the results of a 2018 clinical trial of Ebola patients in the Democratic Republic of the Congo. Though this will be its first test against coronaviruses in humans, scientists in China recently reported that remdesivir proved effective at preventing SARS-nCoV-2 (the virus that causes Covid-19) from infecting primate cells.
The trials, which are being conducted by researchers from China-Japan Hospital, will both compare remdesivir to a placebo. One will enroll patients with severe symptoms, the other with mild to moderate symptoms. Gilead has provided enough doses of the drug to treat up to 500 trial participants, according to company spokesperson Sonia Choi. Following the Ebola outbreaks in recent years, Gilead created a stockpile that it is now using to supply drugs for the two trials and for compassionate use requests, Choi wrote in an email. So far, the company has only disclosed treating one Covid-19 patient in the US: a 35-year-old man in Washington state.
More than 100 patients have so far been enrolled, with upwards of another 660 to be added. (Not all participants will receive the drug; some will receive the placebo.) “That really speaks to both the resource capacity in China and the dedication of the staff there,” says Richard T. Davey, medical director of the Special Clinical Studies Unit at the National Institute of Allergy and Infectious Diseases. He spearheaded the team of researchers who ran the 2018 trial of remdesivir in Ebola patients, which took place in an active war zone in a health care setting not used to conducting research. Compared to that, he says, China is in a much better position to act quickly. “They have subject matter experts and lots of people who’ve run trials before. We’re just sort of waiting to hear what, if anything, we can do to assist them.”
With such quick recruitment, results from the trials in China are expected as soon as April. If remdesivir proves effective, it’s unclear whether or not Gilead will have enough of the drug to treat the thousands of people likely to still be in need.
According to Choi, the company is taking steps to increase the available supply as quickly as possible. That includes making more than one formulation of remdesivir, initiating talks with new production partners in multiple regions, and boosting internal manufacturing capacity. “In anticipation of potential future needs, we have accelerated manufacturing timelines to increase our available supply as rapidly as possible,” Choi wrote. “We are doing this before knowing whether remdesivir will be determined to be safe and effective to treat patients with COVID-19.”
In addition to remdesivir, researchers have begun dosing patients in another trial, testing antiviral drugs lopinavir and ritonavir, which have been approved for HIV and come in generic formulations. These drugs also impede viruses by blocking an enzyme they use to replicate inside human cells. Soon, trials are expected to begin to test the effectiveness of oseltamivir and arbidol, influenza drugs already approved in China, which flight the flu by preventing its ability to shed copies of itself from the surface of host cells. The trial registry also includes a number of more unconventional—and perhaps dubious—approaches, including hormones, injections of stem cells, and even vitamin C infusions. And unfortunately, in an outbreak, the one thing there’s sure to be no shortage of are patients desperate to try anything.
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