IHU- Méditerranée Infection, Marseille, is a significant French research institute that has continued its work on CV 19. For the record, here are excerpts from some recent work, headlined from threads where such would be buried:
EXH 1: >>COVID-IHU #15
Version 1 du 27 Mai 2020
Early diagnosis and management of COVID-19 patients: a real-life cohort study of 3,737 patients, Marseille, France
In our institute in Marseille, France, we proposed early and massive screening for coronavirus disease 2019 (COVID-19). Hospitalization and early treatment with hydroxychloroquine and azithromycin (HCQ-AZ) was proposed for the positive cases.
We retrospectively report the clinical management of 3,737 patients, including 3,054 (81.7%) treated with HCQ-AZ for at least three days and 683 (18.3%) patients treated with other methods (“others”). Outcomes were death, transfer to the intensive care unit (ICU), ? 10 days of hospitalization and viral shedding.
By testing 101,522 samples by polymerase chain reaction (PCR) from 65,993 individuals, we diagnosed 6,836 patients (10.4%), including 3,737 included in our cohort. The mean age was 45 (sd 17) years, 45% were male, and the fatality rate was 0.9%. We performed 2,065 low-dose computed tomography (CT) scans highlighting lung lesions in 581 of the 933 (62%) patients with minimal clinical symptoms (NEWS score = 0). A discrepancy between spontaneous dyspnoea, hypoxemia and lung lesions was observed. Clinical factors (age, comorbidities, NEWS-2 score), biological factors (lymphopenia; eosinopenia; decrease in blood zinc; and increase in D-dimers, lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), and c-reactive protein (CRP)) and moderate and severe lesions detected in low-dose CT scans were associated with poor clinical outcome. Treatment with HCQ-AZ was associated with a decreased risk of transfer to the ICU or death (HR 0.19 0.12-0.29), decreased risk of hospitalization ?10 days (odds ratios 95% CI 0.37 0.26-0.51) and shorter duration of viral shedding (time to negative PCR: HR 1.27 1.16-1.39). QTc prolongation (>60 ms) was observed in 25 patients (0.67%) leading to the cessation of treatment in 3 cases. No cases of torsade de pointe or sudden death were observed.
Early diagnosis, early isolation and early treatment with at least 3 days of HCQ-AZ result in a significantly better clinical outcome and contagiosity in patients with COVID-19 than other treatments. Long-term follow-up to screen for fibrosis will be the next challenge in the management of COVID-19.>>
EXH 2: >>Adjusting series of patients for trial comparisons for COVID –
Author list :
3Audrey GIRAUD -GATINEAU1,2,3,4 (PhD student); Jean Christophe LAGIER 1,4,5 (MD); 4 Yolande OBADIA 1
(MD); Hervé CHAUDET 1,2,3 (MD); Didier RAOULT 1,5* (MD)
: SARS – COV-2 has emerged and spread around the world since December 2019. Studies initiated in Marseille by our hospital centre have suggested significant clinical effectiveness of treatment by combining hydroxychloroquine and azithromycin (HCQ+AZ). However, due to the
urgency of responding to the pandemic, they were not obtained through randomized controlled trials. Alternative assessment methods are therefore needed.
We compared our data in silico with those published by two studies comparing 32 other antiviral drugs. For this purpose, random sampling was performed in our cohort to 33 obtain similar groups for disease severity, gender, age and comorbidities associated with 34 chronic diseases with patients included in the remdesivir and lopinavir-ritonavir trials.
Dual HCQ+AZ therapy was associated with 3 times fewer deaths than
similar 37groups treated either with lopinavir-ritonavir(9% vs 20%, p-value = 0·03) or standard care 38 (8% vs 25·2%, p-value = 0·001). Compared with patients included in the remdesivir
study by 39 Wang et al., we also showed a significant difference in the clinical outcome (proportion of 40cured patients with negative viral load) in favour of HCQ+AZ (77.8% versus 58·2% p = 0·0001). 42 43
Although comparison of HCQ+AZ with other antiviral drugs has limitations 44due to aggregated data, this study provides additional evidence showing that HCQ+AZ should 45 be the systematic treatment of choice after diagnosis of COVID -19 -positive cases. 46 47
This work was supported by the French Government under the “Investments for theFuture” programme managed by the National Agency for Research (ANR), Méditerranée- Infection 10-
IAHU – 03 , and was also supported by Région Provence Alpes Côte d’Azur and European funding FEDER PRIMMI (Fonds Européen de Développement Régional -51 Plateformes de Recherche et d’Innovation Mutualisées Méditerranée Infection)>>
EXH 3: >>Assay
Randomised Controlled Trials during epidemic
Philippe Brouqui, Pierre Verger, Didier Raoult
Aix Marseille Université, IRD, MEPHI, VITROME,
ORS Paca, IHU-Méditerranée Infection, Marseille,
In epidemics there is an urgent need for new knowledge on drug efficacy to help policymakers fight the crisis. Yet the best research methodology to do this is a matter of de bate, write Philippe Brouqui, Pierre Verger and Didier Raoult .
The outbreak of an emerging infectious agent needs the rapid involvement of research to bring new knowledge. Past experience with Ebola virus outbreaks and, more recently SARS-CoV 2, have raised a question over the place of randomised controlled trials (RCTs) as the methodology of choice to
answer clinical questions in an novel epidemic situation. Drug safety and effectiveness is a long process which can take years. For antimicrobials, just 25% of drugs submitted to phase 1 succeed to Phase 3 and further licensing (1). This is why, in an epidemic, drug repurposing is often looked at, because drug toxicity has already been evaluated (2).
An RCT isdesigned to attempt to reduce bias, particularly in trials evaluating new drugs. The principle is to random assign volunteers into two or more treatment options and then compare them against a measured outcome. As RCTs reduce causality and spurious bias, they are considered to be the most reliable form of scientific evidence. For these reasons, they are required for market authorisation of a new pharmaceutical drug and cited by healthcare policies as a mandatory means for decision -making about treatments.
When gold standard becomes unethical
In emerging disease outbreaks, there is an urgent lack of treatments for the new pathogen. When a particular therapeutic option is supported by scientifically demonstrated efficacy in vitro and or in animal model, and supported further by clinical case reports and/or pilot series in humans, it is ethically difficult to argue that the data still needs to be confirmed in an RCT before it can be made available to patients. Especially if it seems “obvious” that control (untreated) subjects will have poorer outcomes than those receiving treatment. As one study mocked, there would be few volunteers for the placebo group in an RCT on the parachute’s effectiveness in avoiding death by jumping out of an airplane, unless the jump had an average height of 0.6 m (3).
When even imperfect scientific data show a particularly obvious effect, it is no longer ethical to perform an RCT since it forces patients to accept either not to be treated (in the control arm), or to be treated with a molecule known to be effective. Consider the advent of penicillin. It took five
patients before Sir Edward Abraham could definitively demonstrate that penicillin saved 100% of patients with staphylococcus or streptococcus infections. Nobody today would dare to test the efficacy of penicillin on pneumococcal pneumonia compared to placebo . . . >>
Food for thought, especially given the fiasco of the seemingly decisive Lancet paper which then had to be withdrawn. The remarks on the gold standard fallacies are particularly significant.
The underlying issue is that selective hyperskepticism is leading to ignoring of cumulatively adequate but somehow unwelcome findings, tracing to ethical weaknesses including the error of imagining skepticism an intellectual virtue and using it to substitute for prudence. We need to restore that due balance to our reasoning and decision-making.
A useful brief summary on prudence is:
Prudence is the virtue that disposes practical reason to discern our true good in every circumstance and to choose the right means of achieving it; “the prudent man looks where he is going.”65 “Keep sane and sober for your prayers.”66 Prudence is “right reason in action,” writes St. Thomas Aquinas, following Aristotle.67 It is not to be confused with timidity or fear, nor with duplicity or dissimulation. It is called auriga virtutum (the charioteer of the virtues); it guides the other virtues by setting rule and measure. It is prudence that immediately guides the judgment of conscience. The prudent man determines and directs his conduct in accordance with this judgment. With the help of this virtue we apply moral principles to particular cases without error and overcome doubts about the good to achieve and the evil to avoid.
Further food for thought, on seven indicative, inescapable first duties of responsible reason: to truth, to right reason, to prudence, to sound conscience, to neighbour, so to fairness and justice, etc. . END