HYCOVID - is the termination of the French trial on hydroxychloroquine a serious fault?
Author (s): Le Collectif Citoyen pour France
The pre-publication recounting the results of the HYCOVID trial was posted online on October 19 under the title: "A double-blind, placebo-controlled trial of hydroxychloroquine in mild to moderate COVID-19"
Like the other French Discovery trial, the results were overdue, especially since on June 18, the CHU told Ouest France “We included the last patient. We now expect a publication of the study results in late June or early July. "
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Despite an almost 50% reduction in mortality at 28 days for patients on HCQ versus placebo, with a result deemed statistically insignificant due to too small the size of the patient cohort, the HYCOVID trial was abandoned.
Real non-interest of the molecule or "political" stop of the treatment? Let's try to see more clearly in this nth twist in the history of hydroxychloroquine
What is the Hycovid trial?
The Hycovid trial, coordinated by Dr Dr. Vincent Dubée d'Angers, is " a prospective, multicenter, randomized, double-blind, parallel-group study to evaluate, in non-severe COVID-19 patients at high risk As a complication , the efficacy of hydroxychloroquine versus placebo in avoiding intubation with mechanical ventilation or death.
“This work was supported by a grant from the French Ministry of Health through a national call for projects for therapeutic trials on COVID-19. The trial also benefited from an exceptional donation from the Pays de la Loire region and the Angers Loire Métropole agglomeration ”
The patients included in this study had to meet the following criteria: patients with COVID-19 with worsening risk factors, i.e. age ≥ 75 years or age between 60-74 years with the presence of at least one comorbidity (obesity, hypertension, diabetes mellitus) or need for additional oxygen (≤3 L / min)
Importantly, it is specified in the protocol :
- "A number of 615 patients per group must be studied to demonstrate, in a bilateral hypothesis, an absolute difference of 6% between the two groups (relative difference of 30%) with an alpha risk of 5% and a power of 80 %. Taking into account the patients lost to follow-up and those who cannot be assessed (estimated at 5%), it is necessary to include a total of 1300 patients . "
- “The expected benefit of hydroxychloroquine is significant. The expected effect is an absolute reduction in the need for invasive ventilation and / or death estimated at 6% ”
Finally, the objectives of the HYCOVID trial
- "The main objective is to assess the efficacy of hydroxychloroquine compared to placebo on the mortality rate and the use of invasive ventilation within 14 days of starting treatment in non-severe COVID-19 patients at high risk of complicated course.
- The secondary objectives are: 1) To assess the efficacy of hydroxychloroquine versus placebo in COVID-19 patients with regard to: a- the mortality rate or the use of invasive ventilation during the 28 days following inclusion and the start of treatment, b- clinical improvement using the WHO ordinal scale for clinical improvement of COVID19 c- all-cause mortality d- duration of viral shedding e- incidence of cases of venous thromboembolism 2) To assess the efficacy of hydroxychloroquine versus placebo in the subgroup of patients aged 75 years or over with regard to: a- clinical improvement using the WHO ordinal scale forclinical improvement of COVID19 b- all-cause mortality 3) To assess the safety of hydroxychloroquine compared to placebo on the occurrence of serious adverse events
- Auxiliary objectives: To evaluate in a subgroup of COVID-19 patients the impact of hydroxychloroquine compared to placebo on cytokines and biological markers of immunity, inflammation and hemostasis. "
This trial was therefore to include 1300 patients divided into 2 groups (patients treated with hydroxychloroquine and patients on placebo) with a double-blind randomization (i.e. a random allocation of patients between HCQ and placebo, nor doctors or patients not knowing who is taking a placebo or HCQ) so that if an effect is visible on one of the objectives of the trial, it can in no way be the result of a choice of doctors to favor treatment (for example by giving the treatment to the least risky patients)
The patients received the following protocol: 800mg on the first day (in 2 doses of 400mg) then 400mg per day for 8 days for a total of 9 days of treatment, ie 4000mg for the entire treatment (by the way, these doses are " normal ”unlike the Recovery trial which gave patients a total dose twice as large and potentially lethal )
Began on 1 st April to 21 May, the test was officially halted on 26 May with the recruitment of 250 patients only after the matter of LancetGate *, arrested "by the French regulatory authority due to reports of hydroxychloroquine toxicity in other tests. It was definitively stopped by the sponsor on June 9, 2020 due to a low inclusion rate in the context of the slowdown of the pandemic in France and the decision of the WHO to suspend its trials on hydroxychloroquine . "
However, the Mehra et al . was withdrawn * in early June and WHO resumed its hydroxychloroquine trial on June 3 . But the authors of the HYCOVID trial, write that the trial was finally abandoned on June 9 following the slowing of the epidemic and the WHO decision to suspend its trials while the WHO trials have been to them continued until July 4, which is very surprising in view of the promising results below. We also note that in the study, patients were only included until May 21 (not until May 26 or June 9 ...), which is surprising because the study by Mehra and al. - affirming the dangerousness of the molecule and at the origin of the discontinuation of the use of hydroxychloroquine in a large part of the world - was only published on May 22.
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Among the results, several are remarkable, at 28 days, and it can be noted that hydroxychloroquine gives encouraging results:
- there were almost half the deaths in the HCQ group versus control group with relative risk (RR 0.54; 95% CI: 0.21–1.42),
- A decrease in the number of intubated or mechanically ventilated patients (HCQ: 3/124 versus placebo 4/123) with a (RR 0.74; 95% CI: 0.17–3.26),
- 9.8% (12/123) of patients in the placebo group had died or had been intubated compared to 7.3% (9/124) in the hydroxychloroquine group with (RR 0.74; 95% CI: 0.33–1.70).
Curiously, at 28 days, 12 patients died or intubated while 11 patients had died and 4 were intubated in the placebo group, which should have given a total of 15, further increasing the difference from the 9 patients in the HCQ group. No explanation on this point in the article.
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The subgroup treated with azithromycin in addition to hydroxychloroquine between days 0 and 14 shows a relative risk of death or mechanical ventilation of (RR 0.42; 95% CI: 0.05-3, 54) or a reduction of almost 60% of the risk. Once again this result is not statistically significant due to the size of the patient group,
Also, none of the 10 patients who obtained azithromycin in addition to hydroxychloroquine at randomization achieved the composite outcome of death or intubation, compared to 3 of 11 in the placebo group. This means that there was no “death or intubation” in the HCQ + AZI subgroup while 3/11 patients in the placebo group either died or had to undergo intubation.
All of these results, although statistically insignificant, because once again the size of the cohort is too small, were a strong signal of the potential efficacy of hydroxychloroquine and of the “Raoult” HCQ + AZI dual therapy. It is inexplicable and very serious to have decided to abandon this HYCOVID trial.
In any case, none of the results being statistically significant, this study can absolutely not affirm that HCQ is not effective, nor that there is no effect of this treatment.
This trial was funded by the French Ministry of Health and the French have the right to know that the HYCOVID trial, which showed very encouraging signs of efficacy in a target population, was abandoned without scientific reason and is depriving the population a potential treatment reducing COVID19 mortality by more than 50%. A potentially very serious fact, and which will undoubtedly make victims' associations react which should take legal action on this crucial point.
* As a reminder, the LANCETGATE case concerns a publication by Mehra et al. of May 22 affirming the dangerousness of hydroxychloroquine for Covid19 patients which was retracted on June 5 because the Surgisphere company that provided the data for this study was not able to justify them ... This company turned out to be a empty shell and the data had certainly been invented.
Author (s): Le Collectif Citoyen pour France