- The World Health Organization (WHO) Solidarity trial provided information about four potential COVID-19 treatments at the beginning of the pandemic.
- After determining that none were effective, the researchers paused the trial at the end of 2020.
- The trial is now entering a new phase, with up to 50 countries expected to take part.
In the previous phase, scientists investigated four potential treatments but found that none were effective. In the new phase, the researchers will test another three drugs.
Since the emergence and global spread of SARS-CoV-2, the virus that causes COVID-19, scientists have focused on developing effective vaccines to minimize transmission and reduce the severity of the disease.
However, they have also tested potential treatments. This is important because many people have not yet been vaccinated,
And even where vaccination rates are high, scientists believe that the Delta variant of COVID-19 has reduced the effectiveness of the vaccines to 49% — meaning that many who are fully vaccinated could still develop the disease, and people who cannot receive vaccines are unlikely to be protected by herd immunity.
As a consequence, having effective treatments for severe COVID-19 could save a significant number of lives.
Speaking with Medical News Today, Dr. Rebecca Dezube, a specialist in pulmonology and assistant professor of medicine at Johns Hopkins University School of Medicine, in Baltimore, said that a number of treatments have already shown promise.
“The treatment with the most evidence for a mortality benefit in COVID-19 continues to be steroids, specifically dexamethasone.”
“Tocilizumab, an immune modulator directed toward the interleukin-6 receptor, was shown to have a mortality benefit in the RECOVERY trial and to decrease the time patients required organ support in critically ill patients in the REMAP-CAP trial.”
“In July 2021, the [
She went on to note that baricitinib, ruxolitinib, and fedratinib, which are Janus kinase inhibitors, and lenzilumab, which neutralizes a cytokine linked to COVID-19, also showed promise.
The restarted Solidarity trial will look at three potential treatments: artesunate, imatinib, and infliximab. A panel of experts selected these drugs because they had shown positive results in observational studies.
All three are repurposed medications that may modulate the inflammatory response, which can cause significant damage in people with severe COVID-19.
Artemisinin is a readily available, inexpensive malaria drug. Imatinib is used in cancer treatment, and it may offer protection against damage caused by inflammation in the lungs. Infliximab is used in the treatment of autoimmune diseases, such as inflammatory bowel disease.
The scientists are now exploring drugs that target the immune system, after having focused on antiviral medications in the last round of the Solidarity trial.
Speaking with MNT, Dr. John-Arne Røttingen, the chair of the Solidarity trial executive group and ambassador for global health at the Norwegian Ministry of Foreign Affairs, said:
“In the first phase, we attempted to use antiviral treatments. Now there’s a general consensus that that’s too late in the disease process, when people are already hospitalized. So then it’s really the pathogen-host interaction and the host’s response to the pathogen that is the most important target for drugs.”
“There are definitely many more drugs to […] consider. We decided on these based on the assessment of the therapeutics advisory group of the WHO, but of course, others are trying other drugs, as well.”
Dr. Shanthi Kappagoda, a clinical associate professor of medicine and infectious diseases at Stanford University, explained to MNT why it was crucial to identify drugs that affected the immune response.
“Every step in the virus’s life cycle — from attaching to our cells, to entering the cell, to reproducing new virus components and assembling them into a new infectious viral particle — is a potential drug target. But as the virus mutates, direct-acting antiviral drugs which target these steps may become less effective.”
“So, while I think direct-acting antiviral agents are important, targeting how the virus triggers acute respiratory distress syndrome is very important. I think this is likely why the WHO chose imatinib.”
Dr. Røttingen added that during drug trials, it often takes time to find an effective treatment, as with the negative findings of the initial Solidarity trial. However, he was nonetheless hopeful about the trial’s new phase.
“I think [not initially finding new treatments] is rather common, unfortunately. That’s why rigorous research and evaluations are important.”
“We see [quite solid evidence] from patient groups who use [these drugs] as chronic medication for the disease, and they seem to have better outcomes than others, but of course that can be confounded, so it’s really important to examine [them] in a large, randomized trial.”
“Artesunate is a very available drug. [However,] we don’t have solid clinical evidence but more lab indications and data. But given that it’s a globally available drug that is cheap, it’s definitely worth examining,” Dr. Røttingen said.
He also pointed out that critical care practice has developed to better respond to COVID-19, reducing the risk of mortality.
“The quality of […] acute care and how you use your best general means to optimize treatment in an intensive care setting is often overlooked. And we saw big variations in mortality outcomes across countries and across settings — even though we fully understand them, I think there’s definitely also differences in routine care and programs.”
For Dr. Røttingen, the next year is an important time to explore new COVID-19 treatments. This is because finding new treatments may become more difficult as the virus becomes endemic — which is more likely, now that the Delta variant of SARS-CoV-2 has made herd immunity less achievable.
“That’s now the most likely scenario, that this will be an endemic disease […] that we will need to live with in the coming years. But [now is the best opportunity] of doing robust, large randomized trials. [If the virus becomes endemic,] it’s more challenging because […] it will be harder to organize and structure those trials. It’s really important to do our best now, in the coming year.”
While new variants are a concern, he explained, they are unlikely to diminish the effectiveness of treatments that target the immune system, such as those currently under study in the Solidarity trial.
“Since most of the treatments, or at least those that seem to be effective in hospitalized patients, are based on modulating the immune response, I don’t expect [that] the new variants will be different, when it comes to treatment outcomes.”
– Dr. John-Arne Røttingen
“Where there will be impact is on the antiviral side, and in particular the monoclonal antibodies and the cocktail of antibodies that have been tested and are still being developed and optimized — particularly in high risk groups that can be diagnosed early and that can be given antibodies early.”
“That’s definitely a space where new antibodies need to be developed and adjusted to the circulating variant. But otherwise I would expect that treatment effects would be fairly similar.”
Dr. Kappagoda agreed:
“We have already seen how mutations in different parts of the virus — for example the spike protein — have made some monoclonal antibodies less effective, for example bamlanivimab and etesevimab.”
“Direct-acting antiviral medicines, which target enzymes or other proteins [that] the virus needs to reproduce or enter our cells are also likely to be impacted by the mutations in SARS-CoV2 variants.”
“This is less likely to be an issue in medicines that target our immune or inflammatory response, like dexamethasone or tocilizumab, since they do not directly work on the virus itself but on our immune response to it,” she explained.
Dr. Dezube also highlighted the risk that new variants pose to monoclonal antibody treatments:
“Multiple SARS-CoV-2 variants of concern have reduced susceptibility to certain monoclonal antibody products. This is worrisome, as monoclonal antibodies are the only treatment, for patients not in the hospital, with a proven benefit. Fortunately, casirivimab/imdevimab appears to be effective against our current known variants.”
Dr. Røttingen said that after the original Solidarity trial was paused, following negative results, it took longer than they had hoped to restart the trial.
“We had a too-long period […] before we could start again. That was first related to the need to scan the opportunities and the most viable potential [treatments]; then it was the agreeing on drugs to ensure we had a sufficient supply that could be distributed to countries in all regions, including [agreeing] with the potential manufacturers that they would be committed to sound access possibilities and availability of the drugs, in particular in low-income countries, if they proved to be successful.”
Dr. Røttingen told MNT more about how ethical and regulatory approvals were delayed, compared with the speedy approvals at the start of the pandemic.
“We managed to set up the first phase of Solidarity very quickly, a month or maybe a month and a half from protocols ready until we recruited the first patient. I think at that time, there was an understanding [from] all regulatory authorities that this is a crisis, and we need to go outside normal timelines. I think that understanding is now less pressing, and probably [regulatory authorities] are pushed on other fronts.
“We need to have more speedy processes. When there is an epidemic, when there is an outbreak, we need to test drugs — where the risk and the disease is time-dependent and the opportunity to do the trial is really critical and time-dependent.”
“That needs to be done in individual countries, but in addition, I think we should look for harmonized and coordinated approval processes, so that instead of needing to go and have approval in all individual countries, there would at least be some preapproval at an international level that could then be adopted by countries, in maybe a more expeditious and faster process.”
“We don’t have that system today, and that’s something that needs to be looked into.”
For Dr. Røttingen, it is important that new structures are put in place to ensure that approval can be granted safely but quickly. The initial goodwill from regulatory agencies, pharmaceutical companies, and the scientific community is not sustainable.
“We see that [the goodwill is] really still there, but I think now […] the system is a bit exhausted and has a need to go back to normal operations. And those are too slow.”
Dr. Kappagoda also highlighted lessons to be learned from the initial response to the pandemic.
“I think one silver lining of the pandemic is that ministries of health, hospitals, and universities have recognized the importance of making clinical research more nimble and efficient during an emergency.”
“Small changes, like having institutional review boards meet remotely, strengthening fast-tracking and prioritization systems for clinical research, and having systems in place to do informed consent via video chat should remain in place, ready for future pandemics.”
“Participating in trials such as Solidarity […] can build capacity for future clinical research at hospitals and medical centers which previously may not have been heavily involved in research,” she added.
“Clinical researchers newly involved in multicenter trials during this pandemic will be developing professional networks, which can help them navigate the clinical research process for future pandemics.”