Dominique Costagliola is Deputy Director of the Pierre-Louis Institute of Epidemiology and Public Health (Sorbonne University, Inserm). She is a member of the French Academy of Sciences and participates in the scientific council of the consortium. REACTing. She's giving an update on the Covid-19 therapies still in the pipeline.
The results of the studies that have been conducted in Europe and around the world are beginning to be published. In the United Kingdom, the Recovery trial showed a positive effect of low-dose dexamethasone corticosteroid therapy, particularly in people who were in intensive care. This type of treatment is known to be effective: it was already being given to patients who developed acute respiratory distress syndrome (ARDS) in other settings, prior to infection with the SARS-CoV-2 coronavirus. It is not intended to be given to all patients, but to those who are already in an advanced stage: this has an important effect, since mortality is reduced after administration.
A few weeks ago, there had been a lot of talk about Remdesivir, a molecule that has been proven effective against various viruses (Ebola, Lassa...) because it disrupts the replication of their RNA. What about it?
Remdesivir has been the subject of three randomized studies. A Chinese study was the first published. It evaluated the use of Remdesivir administered for 10 days. The results were negative: no beneficial effects were found. But the inclusion of participants had to be stopped due to lack of patients, once the epidemic was under control in China.
Second, Gilead Pharmaceuticals conducted a trial comparing the use of Remdesivir for 5 days to its use for 10 days. The trial concluded that there was no significant difference in effect between the two durations of use; andHowever, it cannot be said that 5 days is not less than 10 days of treatment.
Finally, an NIH-led trial was stopped early because the use of Remdesivir shortened the length of hospital stay (by a median of 4 days). The length of hospitalization was reduced from 14 days to 11 days. However, no effect on mortality could be demonstrated in this study. Not all patients had reached one month of follow-up, which is the length of follow-up used in most inpatient studies. However, this early cessation after short follow-up for a significant proportion of participants may overestimate the effect and does not lead to a benefit on mortality. Despite these limitations, a recommendation for use in hospitalized patients has been issued in the U.S. and the product has just obtained a conditional marketing authorization in Europe, with a request for additional mortality data.
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Many clinicians are unconvinced by the criterion used to judge the shortening of the length of hospital stay. Furthermore, early discontinuation has not made it possible to know in which patients this treatment would be most useful. This is all the more annoying as the number of available doses is limited and the USA has pre-empted them. How do you know who to treat first?
The evaluation of Remdesivir is continuing to assess its possible impact on mortality in the WHO Solidarity international trial and its associated Discovery trial, conducted by Inserm in several European countries (France, Austria, Belgium, Luxembourg for the moment). The question of the interest of Remdesivir remains, all the more so as this drug is expensive and will not be a "cure-all". game changer "if it doesn't improve survival.
What leads have been dropped by the major ongoing clinical trials?
Of all the molecules that have been tested, hydroxychloroquine clearly does not work for hospitalized people. Lopinavir, an antiretroviral drug whose main use is the treatment of HIV infection, has also been abandoned by both the British Recovery and Solidarity trials. Data from Discovery, which is the only trial that tracks tolerance issues and adverse events in detail, also showed that the use of Lopinavir was problematic in terms of renal complications, particularly in people with severe forms. This effect was described in the summary of Lopinavir's characteristics, but in the context of HIV infection it is not common.
This point illustrates that the adverse events of a drug may be different depending on the pathology in which it is used, as the pathology itself may have a specific impact on certain organs. However, SARS-CoV-2 infection is suspected to affect many organs: the lungs of course, but also the heart, the kidney, potentially the nervous system...
And what therapies are still being evaluated?
The Solidarity trial is still testing azithromycin, an antibiotic of the azalid class (macrolide family) alone. This arm has not been stopped, results are still pending.
Among the interesting avenues for which we do not yet have a formal answer is the plasma of convalescent people. Studies of these types of therapies are more complex than testing a drug for which we are familiar with the manufacturing process. Plasma is collected from people who have had the disease, but not everyone does the same thing to screen donors. In France, for example, in the CORIPLASM test, the presence of neutralizing antibodies is checked. This is not necessarily the case in all the studies that are conducted and the time of administration can also play a role. Therefore, this should be taken into account when analyzing the results.
To date, some studies have suggested positive results in patients treated with convalescent plasma, but they were not randomized or comparative. Many trials around the world are evaluating this option (including the Recovery trial in the UK). Positive results could pave the way for testing combinations ofmonoclonal antibodies making it possible to envisage a simpler and more generalizable manufacturing process than convalescent plasma.
Another avenue being explored is to move from attacking the virus to attacking the inflammatory storm it triggers: this is the avenue of immunomodulators in general, and anti-interleukins in particular (Editor's note: interleukins are chemical messengers that are involved in the immune response and associated inflammation.). One such drug is Tocilizumab, an antibody that blocks the interleukin-6 receptor, used to treat rheumatoid arthritis. A team from the PA-HP communicated on the subject at the end of April and the results are currently being submitted for publication. Tocilizumab is also being tested in the Recovery trial.
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On the basis of recent publications or announcements, injectable or nebulized interferon is also a topical issue (editor's note: interferons are proteins involved in the immune response, particularly antiviral).
Many other hypotheses have also been formulated and are being evaluated, although it is not known whether the number of participant inclusions in these studies will be sufficient to draw conclusions.
Does this mean that too many clinical trials have been implemented?
The issue is complex, and on this point France and the United Kingdom have had two very different approaches. The British have been very drastic. They basically organized a very large, simple public trial, Recovery, in which they included about 12,000 people. It has already produced results, negative for hydroxychloroquine and Lopinavir, positive for low-dose corticosteroid therapy. More are to come.
In France, on the contrary, there has been a flurry of studies, with no initial coordination. In addition, the Franco-French hype surrounding hydroxychloroquine has led to an increase in the number of trials related to this molecule. This is due in particular to the way the system is organized. The more research that university hospitals conduct, the more funding they receive. They are the sponsors of public trials. And as long as a team has a sponsor, neither the National Agency for the Safety of Medicines and Health Products (ANSM) nor the Patient Protection Committee can oppose the start of its trial on the pretext that there would already be enough of them (provided that the trial follows the rules on the protection of participants, of course).
In addition, the research is organized in such a way as to value the principal investigator of the work. This system leads to a plethora of research projects and less value is placed on collaboration. More than 80 proposals were submitted to REACTing. Ideally, a single trial, as in the UK, would have been balanced against these 80 proposals... We could have limited ourselves to a few trials in cities and hospitals, for example. But that would have required people working with each other, and it would have required an organization to be able to legitimately prioritize the proposals.
And this would have brought out another difficulty: when you receive so many proposals, even if some of them have only a modest rational, how can you be sure to give priority to the good ones? It is not an easy exercise in this context.
Finally, it can also be noted that there has been little cooperation at European level. All this indicates that lessons will have to be learned from this crisis, both in terms of the organisation of clinical trials and national and international cooperation in the context of an emerging infectious disease. In particular in view of the continuing epidemic...
Dominique CostagliolaEpidemiologist and biostatistician, Deputy Director of the Pierre Louis Institute of Epidemiology and Public Health (Sorbonne University/Inserm), Research Director, Inserm