Dear colleagues,
I may be wrong, but I found particularly intriguing the fact that while the World Health Organization (WHO) alleged that there is no proven or standard approach to cure or improveprognosis in Covid-19, in the recent clinical trial they released (named "Solidarity"), the control group is not placebo, but the association of hydroxychloroquine and remdesivir (an antiretroviral). (Anyone can check at ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04321616?term=SOLIDARITY&draw=2&rank=1).
If one considers that there is no current standardized therapy, the control group would've been of placebo, unless we admit that the likelihood of the benefits of hydroxychloroquine is very high.
Besides, I also missed a group of combination of hydroxyclhoroquine + azithromycin, which may disclose better outcomes compared to hydroxyclhoroquine alone.
Despite being a global emergency, shouldn't the organization adopt EITHER the position that nothing has been proven to work so far - and then consider the control group as placebo - OR that in the current context of the large amount of deaths (which does not mean high mortality), for selected groups hydroxychloroquine should be already considered, without further confirmations (as FDA did).
Am I missing any relevant information on this that may change my thoughts?
Thanks.
Flavio Cadegiani
This is more a problem of bioethics than a well planned randomised double blind study.
It is not possible to leave a patient in a respirator and progressive decrease of his/her pO2 and not giving a medication that can possibly help like chloroquine even it's benefit are not proven.
To this you have to add that WHO has very little idea of what a pandemic is.
According to all they were saying and doing my conclusion is that they are a bunch of ignorant burocrats.
I agree that ethical considerations are important in situations like Covid-19 where withholding treatment cannot be justified. One needs to appreciate that the objective of the initial trial is only to assess whether the proposed treatment is effective or not in this special group of patients. I am sure that further studies would be carried out thereafter to find answers to several other questions.
The reason is the same as for cancer. Cancer patients are in imminent danger of severe disease progression or death. It would be considered unethical to have a 'no treatment' arm of a clinical trial - 'haha you're in the placebo arm, so just die'.
So generally standard of care is the 'placebo' arm. What you're looking for is a significant discernible difference due to the application of the protocol or medicament under investigation. Therefore if standard of care shows a 5% survival rate at 5 years and treatment using the new protocol of medicament shows double, triple or greater then you have something. Often the arm with the new medicament is standard of care PLUS the new medicament or protocol.
It would be unethical to restrict use of a treatment, even if evidence for efficacy is inconclusive. It is usually possible to compare groups across treatments or using data collected from those who were ill prior to treatments being used.
There is another issue. The WHO should have read the literature on SARS-COV from 2003. If they had they would have found out that the clinical presentation, radiological findings, course of the disease and the fact that the real problem is a Cytokine storm in the case of the really sick patients. I believe they even mentioned use of steroids in those patients as having been salutary. The reference is: Clinical progression and viral load in a community outbreak of Coronavirus-associated SARS pneumonia: a prospective study. Peiris, JM et al The Lancet 2003 , 361, 1767-1772. Besides this there have been other examples of the mention of Cytokine storm in connection with viral illness. There are other examples discussing this in the context of SARS and other viruses. Now in case they were late because they were on a 10 year hiatus they still they could have read D’Elia Et al Targeting the Cytokine Storm for Therapeutic Benefit. Clinical and Vaccine Immunology 2013 , 20 (3), 319-327. Then they would have had ‘only’ 7 years to think about that. The bureaucraclies are incompetent is the problem.
It is unethical to put patients on placebo when their condition deteriorate. Local standard of care which could be any available treatment is a brilliant idea. The trial can compare not only these 4 treatment options but also any other treatment used in COVID 19 management.
RESULTS OF SOLIDARITY TRIAL STILL TO BE REPORTED - EXPECTED OUTCOME
Hydroxychloroquine alone or with Azithromycin for COVID-19: No benefit but increased risk
No significant benefit with Hydroxychloroquine and Azithromycin either alone or in combination on in-hospital mortality in COVID-19 patients in USA. However, increased risk of prolonged QT-interval with risk of ventricular arrhythmias.
References
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State
https://jamanetwork.com/journals/jama/fullarticle/2766117
Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2012410
Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing
Positive for Coronavirus Disease 2019 (COVID-19).
https://www.ncbi.nlm.nih.gov/pubmed/32356863