Note of repudiation of the attack on SBMT members seeking treatment for COVID-19
Chloroquine is a drug that treats malaria, one of the tropical diseases that historically has had the greatest impact on our public health, in addition to other known therapeutic applications. The CloroCovid-19 research attempts to discover one of the solutions to one of the greatest challenges facing humanity today which is the infection by the […]28/04/2020
Chloroquine is a drug that treats malaria, one of the tropical diseases that historically has had the greatest impact on our public health, in addition to other known therapeutic applications. The CloroCovid-19 research attempts to discover one of the solutions to one of the greatest challenges facing humanity today which is the infection by the new coronavirus (SARS-COV2).
The Brazilian Society of Tropical Medicine strongly condemns the attacks suffered by more than 70 Brazilian researchers, who belong to the staff of important institutions in research such as Fiocruz, USP, UnB, Dr. Heitor Vieira Dourado Tropical Medicine Foundation, State University of Amazonas and University of São Paulo that carry out the research CloroCovid-19, whose objective is to test the efficacy and safety of chloroquine in the treatment of patients affected by COVID-19. It is regrettable that Brazilian scientists, members of the BSTM, have been deplorably attacked by vile ideological propaganda, in an attempt to create discredit to Brazilian science. The commitment to public health, ethics, honesty and science to mitigate the effects suffered by the population are fundamental principles of the BSTM. At a time when millions of people infected with SARS-COV2 are suffering across the globe, it is paramount that Brazilian researchers are respected, so that, together with worldwide efforts, they can seek a cure for COVID-19.
The SARS-CoV2 pandemic can only be overcome by encouraging the development of technologies, research that seeks, through science, to find solutions to the greatest challenge experienced in the health world for tens of years. To this end, humanitys need for collaboration is strict, and it can only be overcome with strong support for science and the collaboration of everyone in Brazil and the rest of the world.
The CloroCovid study was submitted to evaluation and correctly approved by the National Health Council, through the evaluation of the Research Ethics Committee (CONEP). The data, as soon as available, were made public through the submission of a report to CONEP, as well as in a scientific journal recognized worldwide so that the scientific community in the globe could access the carefully analyzed information on the clinical findings of the treatment of COVID-19 with chloroquine.
In this sense, it is unacceptable that Brazilian researchers are putting their lives at stake to solve this pandemic under attacks full of sophisms, shallow and ideological derivatives, without any support in reality or under scientific evidence. The BSTM ratifies its commitment to ethics, honesty, respect and does not accept attacks like these suffered by its members who are seeking to remove the pain of others.
Board of the Brazilian Society of Tropical Medicine
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Full reproduction of the letter Right of reply and clarifications published by researcher Marcus Vinícius Guimarães de Lacerda on April 16, 2020
The CloroCovid-19 study brings together a group of more than 70 professionals, including researchers, graduate students and collaborators from institutions with a tradition in research, such as Fiocruz, Dr. Heitor Vieira Dourado Tropical Medicine Foundation, State University of Amazonas and University of São Paulo. For over 20 years, the team has been conducting research studies on malaria, HIV/AIDS, tuberculosis, snake bite accidents, and other emerging diseases, with international recognition and participation in international councils, including the WHO.
Clorocovid-19 was structured as a phase II study, meaning that it is more interested in patient safety, therefore, it included only severe patients with severe acute respiratory syndrome (SARS), with suspected (and later laboratory confirmation) of COVID-19.
The study also intends to verify if there is a beneficial effect of chloroquine, in comparison with data from other international studies, in which patients in similar clinical conditions did not use chloroquine.
In ethical terms, since the Ministry of Health had recommended the use of chloroquine for severe cases of COVID-19, we do not find it opportune at this time to use a placebo group, that is, without using chloroquine. Thus, two distinct doses of chloroquine were used:
(1) low dose, 450mg 2x/day on the first day and 450mg 1x/day for another 4 days (total of 5 days of treatment);
(2) high dose, 600mg 2x/day for 10 days.
The Brazilian Ministry of Health, together with the Secretariat of Science and Technology and Strategic Inputs (SCETIE), indicated the low dose for the treatment of patients with severe clinical conditions, under the advice of the studys main investigator, Dr. Marcus Lacerda. The dose was initially used by the General Hospital of Massachusetts, in the United States (USA).
The choice of a high dose had the following scientific rationale:
(1) higher doses have greater antiviral activity in vitro, that is, in the laboratory, being even higher than the dose used for malaria, for example;
(2) it is the same dose, by weight of the patients, used in China, and which currently appears in the Chinese Consensus on the treatment of COVID-19;
(3) use in patients with shock, that is, with low intestinal perfusion, and, therefore, absorbs the medication less, which is only available in pills;
(4) in a disease that proved to be, in the western world, very lethal, the risk of benefit from efficacy x side effects, of different doses, needed to be evaluated and known within scientific parameters;
(5) good safety of this same high dose in cancer patients, in several published studies, which they used for even longer periods, of 28 days.
In the short term, there is no difference in toxicity between the two presentations of the medication (hydroxychloroquine and chloroquine diphosphate). The toxicity of the chloroquine diphosphate form is only greater for prolonged periods of use, as in lupus and rheumatoid arthritis.
Initially, the study predicted the inclusion of 440 hospitalized patients already in serious condition, at Hospital Delphina Aziz, a reference for COVID-19 in the State of Amazonas. The Amazonas State Government, CAPES and FAPEAM are the official sponsors of the study. Other promised federal public resources have not yet been effectively made available.
The study was submitted to the National Commission for Ethics in Research (CONEP), with CAAE 30152620.1.0000.0005, on March 20, being quickly approved on March 23 and the inclusion of patients started on the same day, due to the urgency the situation. Such data can be easily accessed in the Research Ethics Bulletin (Weekly Report 01), published online by CONEP.
All patients and/or family members were instructed on the purpose of the research and signed Terms of Free and Informed Consent, one copy was filed at the center and the other delivered to the patient, with original signatures.
An independent monitoring and safety committee was set up promptly. The committee is comprised of national and foreign medical specialists in the field, who started to remotely monitor the results on a daily basis.
As soon as the first deaths were observed, of patients using any of the doses of chloroquine, which is close to the world average, the committee promptly requested the analysis of the data. As of the date of the analysis, 11 people (from both groups) had died from COVID-19, most of whom were elderly, as is the profile of critically ill patients, worldwide. At that time, there was a tendency for more side effects in patients using the highest dose.
The high dose was immediately suspended and all participants started using the lowest dose on April 6. CONEP was officially communicated of what happened on April 11 in the Brazil Platform, and the data, for greater transparency and international visibility, were released on the MedRxiv website (https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v1), to ensure the timely transparency and international visibility of the results until the due review by scientific peers. The intention was to warn other researchers around the world about the toxicity of a high dose, which, although theoretically it seems more effective, was causing more harm than good.
The first conclusion of the study, therefore, was that critically ill patients with COVID-19 should no longer use the dose recommended in the Chinese consensus, a fact that until now was not supported by evidence, since no study has adequately performed the safety assessment, as daily electrocardiograms, as it happened in Manaus/AM, under the advice of experienced and renowned cardiologists. High doses appear to be safe for cancer patients, but not in severe patients with COVID-19, especially the elderly. A possible explanation raised in the article is the occurrence of myocarditis, that is, the inflammation of the heart muscle.
The study does not allow us to conclude that a low dose chloroquine works or not for COVID-19, because it does not have the control comparator group, that is, without using the medication. Further studies to answer this question are being carried out at this time, in other parts of the planet.
The pre-publication had important repercussions in the USA, and the study was used as a way to draw the attention of the American population about the potential risks of the use of chloroquine in COVID-19. The New York Times and CNN gave the preliminary results broad coverage and visibility on April 12.
A cascade of counter-attacks then began, with Yuko Social activist, investor and CEO Michael Coudrey, responsible for media control for politicians and organizations, posting on Twitter on April 14 that the Brazilian study was irresponsible and that we had used patients as human guinea pigs, something absolutely incorrect, since, as noted, all ethical and legal requirements were strictly followed. With 239.8 followers on Twitter, the message went viral, and arrived in Brazil on April 15 when it was immediately replicated and widely disseminated on websites, social media and other media.
The misinterpretation of the activist and his followers was that all deaths in the study were due to the use of high doses, and not all patients used the high dose and all of them had very serious COVID-19, dying due to the disease, which occurred within the world average. All records are available at the center, according to good clinical practices, followed by the entire team of professionals involved in the study.
A wave of reactions of ideological nature, from people who never read the study in its entirety, without any scientific training, motivated violent manifestations of a personal nature to the main researcher, his family and his team, which has diverted the attention and focus of the work carried out here during the pandemic. The military police of the State of Amazonas are vigilant and guaranteeing immediate security for all. Patients and their families are afraid of what may have happened in the research, despite the team being in constant contact with all participants and their families, with the aim of guiding and comforting people who have already undergone immense trauma.
The debate is not only having a strong ideological bias, but also damaging the reputation of researchers with a strong research tradition in Brazil and in the world, which can be a serious deleterious effect at times as we are experiencing.
Researchers have no ideological or partisan ties and their commitment is only to good science. We do not issue an opinion that is not based on scientific data. The preliminary data published in MedRxiv, with patients from Manaus, have already been updated, the same conclusions persist, and are currently being evaluated by reviewers of a highly regarded international scientific journal in the medical scientific environment.
The institutions involved will take appropriate legal steps to ensure that all facts are clarified, and those responsible for the mass disclosure of untruths are punished.
Articles from other groups that are yet to be published will certainly legitimize our results. We just had the privilege of being the first to show what no one wanted to see.
Do not destroy our dreams, nor the dreams of children who want to one day research and produce good science.
Marcus Vinícius Guimarães de Lacerda MD, PhD
Leônidas & Maria Deane Institute (Fiocruz-Amazon)
Dr. Heitor Vieira Dourado Tropical Medicine Foundation…