After months in the doldrums, writes Science Mag, one of the worldʼs largest trials of COVID- 19 treatments is finally restarting. Solidarity, the global study led by the World Health Organization (WHO), is testing three new drugs in hospitalised COVID-19 patients: the cancer drug imatinib, the antibody infliximab, used to treat autoimmune diseases, and artesunate, an antimalarial.
The medicines have been shipped to Finland, the first country to have all approvals in place, says John-Arne Røttingen of the Norwegian Institute of Public Health, who chairs the studyʼs executive group. “I expect that the first patients will probably be recruited there any day,” he says. Other countries could soon join SolidarityPlus, as the new phase has been dubbed; more than 40 are in the process of getting ethical and regulatory approvals.
When the original Solidarity trial started in March 2020 it was a first: an effort to test drugs in dozens of countries simultaneously in the middle of a pandemic. By late in the year it had delivered verdicts on four treatments—none showed a benefit—but then became mired in negotiations with pharmaceutical companies and regulatory delays. “Itʼs great that Solidarity is proceeding with randomised clinical trials again, as they have already made an important contribution to our therapeutic approach during the pandemic,” says Eric Topol, director of the Scripps Research Translational Institute. “We canʼt be at all complacent about needing better therapies for patients with severe COVID.”
Although COVID-19 vaccine development has been a huge success story, only two drugs have proved to reduce COVID-19 mortality in hospitalised patients. In June 2020, the United Kingdomʼs Recovery trial found that dexamethasone, a cheap steroid, reduced deaths in that group by up to one-third. In February, Recovery investigators announced that tocilizumab, a monoclonal antibody that blocks the receptor for interleukin-6, reduced mortality a bit further.
Both drugs work by dampening the overshooting immune response in severely sick patients.
The new drugs also target the immune system rather than the virus itself. In the severely ill patients included in Solidarity, itʼs probably too late for an antiviral drug to work, Røttingen explains. (Monoclonal antibodies to SARS-CoV-2, for example, are most effective when given before serious disease develops.)
But sicker patients could benefit from additional drugs that target the immune system, says Anthony Gordon, a critical care specialist at Imperial College London. Although dexamethasone broadly dampens the immune response and tocilizumab powerfully shuts off one particular pathway, “There are still other pathways that we can block and maybe make a difference,” Gordon says.
Imatinib, an oral drug used to treat some leukaemias and other types of cancer, can also protect the epithelium lining the alveoli, where oxygen crosses from the lungs into the blood. A placebo-controlled trial in 400 hospitalised COVID-19 patients in the Netherlands, published in June (see study details below), showed patients on the drug spent less time on ventilators and were less likely to die. Although not statistically significant, the data were encouraging enough to spur larger studies, says Gordon, who is part of another international trial called REMAP-CAP that is also planning to test the drug.
Infliximab is an antibody given as a single infusion that blocks tumour necrosis factor alpha, a pivotal signalling molecule in the immune system, and is used to treat autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. Some observational data from large patient populations suggest the drug can also protect against COVID-19, Røttingen says.
Artesunate, an injected derivative of artemisinin and a powerful killer of malaria parasites, has also shown some antiviral activity in laboratory studies of SARS-CoV-2. But Solidarity is testing it because of another effect: the drug appears to reduce inflammation and counteract signals that attract immune cells into tissues. That could stop the immune reactions that damage the lungs in severe COVID-19.
Solidarityʼs revival was a long time coming. In October 2020, it published results from more than 11,000 patients in 400 hospitals that deflated hopes—and punctured hype—by showing no benefit for four treatments: the HIV combination therapy lopinavir/ritonavir, the malaria drug hydroxychloroquine, interferon-beta, and Gilead Sciencesʼs antiviral drug remdesivir. The remdesivir arm was continued for a while to gather more data—full results are expected in the coming weeks—but by late January all arms had been stopped.
An independent expert committee picked the three new drugs soon after. The delay is due partly to negotiations with the manufacturers to ensure that the drugs would be available at affordable prices worldwide if they turned out to work, Røttingen says, and partly due to the time needed for regulatory and ethical approvals in participating countries.
“We have definitely seen that there was a strong willingness to sort of work outside the normal system and really speed up processes in the beginning of the epidemic, and that seems to be less the case now,” Røttingen says. Thatʼs understandable, he adds. “But it also demonstrates that these processes are not fit for emergencies. We need fast-track systems for the future, in all countries.”
Study details
Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial
Published in The Lancet, 17 June 2021
Summary
Background
The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.
Methods
This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib.
Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10).
Findings
Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]).
After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.
Interpretation
The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings.
A giant trial of COVID-19 treatments is restarting. Here are the drugs it’s betting on (Open access)
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