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International megatrial of coronavirus treatments is at a standstill

Clinicians care for a COVID-19 patient in Tehran. Iran is one of more than 40 countries taking part in the Solidarity trial testing coronavirus treatments.

MORTEZA NIKOUBAZL/NURPHOTO/GETTY IMAGES

Science‘s COVID-19 reporting is supported by the Heising-Simons Foundation.

The only global trial of potential COVID-19 treatments is languishing. The World Health Organization’s (WHO’s) Solidarity trial, set up last year to quickly test potential COVID-19 therapies with tens of thousands of patients, produced headlines in October 2020 when it showed that four candidate treatments offer little benefit. But since then, it hasn’t launched any new tests. On 27 January, John-Arne Røttingen, who works at Norway’s foreign ministry and chairs the trial’s executive group, pulled the plug on the study’s only remaining arm, which tested the antiviral remdesivir. “The Solidarity trial is now on pause,” he says.

The executive group discussed potential new targets at a meeting on 24 February, and Røttingen hopes to restart the trial in a few weeks. But observers are dismayed at the pause in the challenging but important trial. “It would be such a shame for this extraordinary network of clinical researchers to not maintain their momentum of discovery,” says Eric Topol, director of the Scripps Research Translational Institute. “They have had a strong influence on global patient care during the pandemic.”

Solidarity and the United Kingdom’s Recovery trial, which both launched in March 2020, are the largest COVID-19 treatment trials worldwide. Hundreds of smaller studies of experimental COVID-19 therapies have not included enough patients to convincingly rule in or out any drugs. “We’re trying to distinguish reliably between a moderate but worthwhile effect, and no worthwhile effect. And for that, you need big numbers,” says Richard Peto, a University of Oxford epidemiologist who helped design Solidarity and analyze the data.

Solidarity was set up to make it easy for doctors around the world to take part, by randomizing patients to one of the study treatments and recording minimal data. It quickly launched tests of four treatments: remdesivir, hydroxychloroquine (a drug touted by former U.S. President Donald Trump and others), interferon beta, and the HIV drug combination lopinavir and ritonavir. Results published from more than 11,000 patients in 400 hospitals showed none of the therapies led to a significant reduction in deaths. A smaller U.S. trial had shown remdesivir reduced the time patients needed to recover. So Solidarity continued to randomize patients to receive remdesivir or standard of care, to hunt for any small effect, particularly in patients who need little or no supplemental oxygen. When the arm finally stopped, about 4500 patients had received the drug. “We believe that we will have solid data that should convincingly demonstrate whether remdesivir has any value,” Røttingen says.

The Recovery trial also produced important results, including showing in June 2020 that the cheap steroid dexamethasone could cut deaths from COVID-19 by one-third. And unlike Solidarity, it has continued to add patients and test new candidate drugs. The trial has randomized more than 38,000 participants and is testing five drugs: aspirin; colchicine, a gout treatment; a COVID-19–targeted antibody cocktail made by Regeneron Pharmaceuticals; baricitinib, which treats rheumatoid arthritis; and dimethyl fumarate, a treatment for multiple sclerosis. With about 7000 patients treated with aspirin and 5500 with colchicine, results could come soon, says Martin Landray, a principal investigator of Recovery at the University of Oxford.

The United States has tried to create a similar clinical trial program, but its efforts have been “slow moving, cumbersome, and basically not … simple like Recovery and Solidarity,” Topol says. Meanwhile, Recovery has recently expanded to include patients in Indonesia and Nepal, a move to build capacity to run clinical trials in those countries.

Solidarity, spread across dozens of countries, has been harder to manage than Recovery and has had some bad luck. Immediately after the results on the first four drugs were published, Solidarity negotiated with Astra-Zeneca to test its cancer drug acalabrutinib, which dampens the immune system. Investigators changed treatment protocols to include the medicine, but then the company decided not to give the green light. Solidarity was also hoping to test monoclonal antibodies, but it became clear that the patients most likely to benefit are those with early stage infections, and Solidarity was designed to test drugs in hospitalized patients. So the companies that make the antibodies pulled back, says Soumya Swaminathan, chief scientist at WHO. “Some of those things fell through, and we did lose some time.”

And there was no real plan B or C. “In retrospect, we should have had a pipeline of other drugs that we could add,” Swaminathan says. One problem was that the ad hoc group set up to choose the first batch of drugs for testing was not a permanent body. Only in November 2020 did WHO set up a permanent drug-selecting group.

Another mistake was waiting for a particularly promising drug after the first four all disappointed, Røttingen says. “We maybe were too cautious,” he says. “I think we should have rather started with some cheap generic product while waiting for potentially stronger candidates to come.”

Among the new candidates the executive group discussed last week is the malaria drug artesunate, which has both an anti-inflammatory and an antiviral effect. The researchers also hope to test an inhibitor of tumor necrosis factor, which is involved in inflammation, and another drug that inhibits the complement system, an arm of the immune system. But other parties also need to sign on. “Timing depends on agreements with companies [that make the drugs] and approvals in countries,” Røttingen says.

In future emergencies, Swaminathan says, the process for prioritizing drugs to be tested should be streamlined. “Some kind of global coordination, where you also then make decisions as to which trials are going to look at what, would make sense,” she says.

Despite its doldrums, Solidarity is still a success story, Peto argues. “We are talking about the second most successful trial in the world in terms of recruitment,” he says. “We’ve got 38,000 randomized in Recovery; we’ve got 15,000 randomized in Solidarity. And the next biggest one that I know of is about 1000.

Source: Science Mag