Researchers seek better scientific evidence to face the pandemic
Preliminary results of the first study on chloroquine against covid-19 pointed out risks to the lives of patients who received high doses of the substance09/05/2020
Conducted by more than 70 Brazilian researchers, who belong to the staff of important research institutions such as the Oswaldo Cruz Foundation (Fiocruz), the University of São Paulo (USP), the University of Brasilia (UnB), the Tropical Medicine Foundation Dr. Heitor Vieira Dourado (FMT-HVD), State University of Amazonas (UEA), the initial results of the CloroCovid-19 study, show that severe patients with covid-19 should not use high doses of chloroquine. The research, which aims to assess the safety and efficacy of two different dosages of the drug and analyzed 81 patients with covid-19 and severe acute respiratory syndrome (SARS). The results presented serve as a warning, offering more robust evidence for Covid-19 treatment protocols.
There is enormous pressure to use chloroquine in the treatment, however, the researchers found that the application of higher doses (600 milligrams) twice daily for ten days, had an unfavorable effect and generated side effects, such as cardiac arrhythmia or even death. The study remains ongoing and is being developed by a team that has been conducting research studies on malaria, HIV/AIDS, tuberculosis and other emerging diseases for years, with worldwide recognition and participation in international organizations, including the World Health Organization (WHO) . The research was approved by the National Research Ethics Commission (Conep), under CAAE 30504220.5.0000.0005. The committee is composed of Brazilian and foreign specialist phisicians, who started to monitor the results daily. An independent monitoring and security committee was set up.
To learn more about the subject, the Communication Office of the Brazilian Society of Tropical Medicine (BSTM), interviewed infectious diseases specialist, Dr. André Siqueira, researcher at the National Institute of Infectious Diseases Evandro Chagas (INI/Fiocruz) and member of the board of the Brazilian Society of Tropical Medicine (BSTM) and who was part of the study CloroCovid-19.
Find the full interview below:
BSTM: The misinterpretation of the CloroCovid-19 study by activist, investor and CEO at Yuko Social, Michael Coudrey, responsible for media control for politicians and organizations, published on Twitter, generated a wave of ideological reactions. And what was the repercussion in the scientific community?
Dr. André Siqueira: The study ChlorCovid-19, as it has been widely debated, proposed to study two doses of chloroquine in the treatment of coronavirus: the dose recommended by the Ministry of Health, up to 450 mg per day, and the Chinese dose of 1200 mg per day, the highest dose used in humans safely, which is used to treat patients with pancreatic cancer. There was a scientific and practical need to evaluate high doses that can reach high concentrations in the lungs due to the lethality of the disease in severe cases. So the repercussion was quite large in the press and also with some groups. The reaction of the scientific community is positive in terms of the need for this study and of having followed appropriate ethical and methodological criteria. Criticism always exists in the scientific process.
SBMT: Something that has been little commented on about this study is the conflict of interest between the federal government and clinical research. What do you think about it?
Dr. André Siqueira: One of the important questions in clinical research giving an idea of the unit is the relationship with the sponsor and those who carry out research. So we obviously know that many clinical trials are funded by the producer of the drug. So it is essential to analyze the role of the funder, if he participated in the design, analysis, writing of the manu . These are the factors that lead us to judge the possibility of a conflict of interest. In our case, the interest has always been the well-being of the patients, so that the monitoring committee acted promptly at the slightest sign of toxicity when using the highest dose.
SBMT: The reason for the criticism could be a matter of conflict of interest, since the research was funded by Amazonas State Government, Oswaldo Cruz Foundation (Farmanguinhos), Manaus Free Trade Zone Superintendence (SUFRAMA), Higher Education Personnel Improvement Coordination (CAPES), Amazonas State Research Support Foundation (FAPEAM) and federal funds granted by a coalition of Brazilian senators and the president of the republic has already publicly spoken out in favor of the use of chloroquine?
Dr. André Siqueira: The research was funded by this group of entities that had no participation in the design, execution and analysis of the data. Again, the interest was to conduct the study, following the appropriate ethical and methodological standards to respond as quickly as possible to the pandemic.
SBMT: We are experiencing an emergency situation that demands quick responses from science. At the same time, we do not have the right to demand from society the expertise to evaluate the quality of the CloroCovid-19 study and we need to rely on the common sense of the researchers involved, as well as the journalists, opinion makers. How to filter news that are clumsy, untrue and bad faith?
Dr. André Siqueira: We are really facing a pandemic that will mark our time, it is already marking in several aspects, which ends up generating great repercussions both in health and in society, in the economy and, obviously, people are waiting for studies, about what can be done, results, prevention, vaccine, and drugs, that is, everything we hope to have. And here we have the important issue of communication, of not paying attention to the sensationalist media, both very positive and very negative, always looking for official sources to find out about the studies and avoid fake news. In this sense, skepticism is worth when receiving messages without clear sources, whether they are very positive or very negative. Looking for official sources is always the most appropriate conduct. This is also a great challenge for researchers, to find ways to explain to the lay public more clearly what the research really reveals, which has generated a lot of repercussions: some results of in vitro study, with cell culture, which are very preliminary and that are still not far from the application for the treatment of infected people. All of these stages of development and treatment evaluation need to be better known and explained to the lay public.
SBMT: The issue between scientists and journalists has been discussed for years. In your opinion, was the dissemination of the results of the CloroCovid-19 study politicized and unscientific, taking advantage of the negative results? Why?
Dr. André Siqueira: We are certainly in a climate, especially in Brazil, which is very politicized and polarized, so different sides of the political spectrum emphasize what they think is most important and this often ends up leading to misinterpretations. We do not have this political conflict, and what we want is to evaluate in a scientific and careful way, any treatment, any intervention carried out to substantiate with good evidence the practices and policies to be adopted. The highly polarized climate leads to distortions and biases that deviate from the scientific criterion. It is necessary to be able to distance oneself from these factors and to analyze the data in a transparent and objective way, even if they do not point to the “desired way”.
SBMT: At no time does the study menions overdose, only higher dose and lower dose. Both were quantified based on studies from abroad. In addition, this was the first study conducted with chloroquine proving the ideal dose. In addition, chloroquine is manufactured by Fiocruz/Farmanguinhos (Brazil), and, still, cheaper than other drugs. Do you believe that these are some of the reasons for politicizing the drug and trying to discredit the study? Why?
Dr. André Siqueira: No overdose is mentioned because there was no overdose. As stated earlier, a low dose recommended by the Ministry of Health and a high dose recommended by the Chinese government and which had been used in other contexts. So there was no overdose. Chloroquine is a well-known and used drug. We were aware of potential adverse events, not in this specific covid audience, so an early assessment of possible negative outcomes was carried out, which in fact was observed and changed immediately. In addition, it has been increasingly reported that people with covid-19 may have myocarditis and other cardiac disorders that may have predisposed to such complications. There was a tendency for changes in the electrocardiogram in patients with the highest dose, so much so that this arm of the study (with the highest dose) was suspended and this may have occurred for several factors, among them, it could be the fact that patients with covid-19 are in critical condition or could already have cardiac alterations or other co-morbidities, which are very different circumstances from those other conditions that we normally treat with chloroquine and hydroxychloroquine.
BSTM: What is the scientific basis for the high dose recommended by the Chinese and which were the grounds to use chloroquine in low doses?
Dr. André Siqueira: The matter on the doses refers to trying to find a therapy scheme with greater benefit potential against a new and unknown disease, with the lowest profile of toxicity and adverse effects as possible. From this, we have the high and the low doses, that is, to try to find a good benefit/safety ratio, what is only possible to safely answer with controlled trials.
SBMT: Is chloroquine dead for covid-19?
Dr. André Siqueira: It cannot be said yet. There are studies going on with lower doses for critically ill patients as well as the use of chloroquine in early stages of patients still without complications and prophylactic use in healthcare professionals. It cannot yet be said that chloroquine is in fact effective in any of these scenarios, for that we will have to wait for the results of these studies.
SBMT: The Federal Public Prosecutors Office at Rio Grande do Sul initiated a civil investigation to seek elements and information regarding the facts dealt with and conclusions obtained in studies carried out by Brazilian researchers. Could you elaborate on that?
Dr. André Siqueira: It is necessary to understand and defend the proper scientific procedure. Quality clinical research is carried out following international standards of methodology and ethics and with full transparency. That is what we have done and we will continue to proceed with the best existing standards.
SBMT: What is the most important message that needs to be transmitted to society about the CloroCovid-19 study?
Dr. André Siqueira: The most important message of the CloroCovid-19 study and of all clinical studies that are done by society in general is that scientists are extremely engaged in finding the best strategies for treatment, management, and control of coronavirus infection. We want fewer and fewer people to get sick and those who get sick have a better chance of surviving this infection that has such deleterious consequences. So, trust the “Good Science”, as Brazil has excellent scientists and, as the results are found, they will be disseminated in order to improve the outcome when it is still being affected by the disease or will be affected in the future.