If the doses used in the British trial exceed those currently foreseen in a healthcare context in France, they may be authorized in a research context.
Question asked by Michel on 06/07/2020
We have received several questions relating to a specific aspect of the results of the UK Recovery trial, which recently delivered disappointing results on hydroxychloroquine (HCQ) against Covid-19. Michel writes to us as follows: “[…] I was very surprised to read that the dose in recovery is 2,400 mg per day, ie more than three times the maximum dose authorized by the Marketing Authorization [Marketing authorization , editor’s note]. I understood that at this dose, it was guaranteed suicide. Can you tell me if this info is true? […] In other protocols, we never exceed 600 mg per day. “
On social networks, several Internet users even accuse Recovery researchers of having used abnormal doses of hydroxychloroquine, with the intention of producing results discrediting the molecule. What is it really?
Let us first recall the nature and objective of Recovery. Initiated at the end of March in the United Kingdom, this trial evaluates the effectiveness of different therapies in 11,000 patients with Covid-19, enrolled in 175 hospitals in the country. Each participant is randomly assigned a treatment from among several “candidate treatments”, including tocilizumab, plasma from convalescent patients, or the famous hydroxychloroquine (HCQ).
Recovery results are continuously analyzed, every two weeks, by an independent committee. On June 5, project managers presented the HCQ assessment data , and explained that “there was no significant difference in the primary endpoint of 28-day mortality” for the population studied. There was also “no evidence of beneficial effects on length of hospital stay or other variables.”
A “loading dose” of 2400 mg
Regarding the subject of the dosage, when a participant in the Recovery study is assigned the “hydroxychloroquine” treatment, he immediately receives 800 milligrams of hydroxychloroquine sulfate (the equivalent of 4 tablets of Plaquenil), a dosage which will be repeated six times. hours later , followed by a dose of 400 mg six and twelve hours later. Either a “loading dose” of 2 400 mg achieved after the fourth taking medication (the 24 th hour, early in the 2 th day of treatment). During the next nine days, hydroxychloroquine sulfate is administered at a level of 400 mg every twelve hours (equivalent to 800 mg of Plaquenil daily).
In France, the maximum dose set for therapy may be exceeded in clinical trials
Are these doses too large, as several Internet users denounce?
In the UK, neither chloroquine nor hydroxychloroquine has been granted marketing authorization for the treatment of Covid-19, as confirmed to CheckNews by the Medicines and Healthcare Products Regulatory Agency (MHRA).
For the treatment of pathologies for which HCQ sulfate is authorized, the recommendations relate to a maximum dose evaluated from the patient’s weight (dose less than 500 mg for an adult man of average height).
The MHRA, on the other hand, explains to CheckNews that, concerning Covid-19, the prescription of CQ and HCQ is authorized in the context of clinical trials . The agency tells us that it has not set recommendations on the maximum dosages mobilized in a research framework, the evaluation of the trials being made on a case-by-case basis (depending on the duration of treatment, the patient population, risk monitoring, etc.)
On the French side, the use of Plaquenil for the treatment of Covid-19 was authorized at the end of March in a derogatory manner (excluding AMM). The National Medicines Safety Agency (ANSM) recalls that, for pathologies associated with the MA, the maximum dosage “is 600 mg per day for an adult” .
However, this threshold does not apply to clinical trials either and, as soon as the ethics committees validate the protocols, other dosages can be used. At the end of March, the agency thus stressed that a “dosage comprising a loading dose [of 800 mg on the first day was] tested in the European Discovery trial in hospitalized patients with monitoring of the ECG and plasma concentrations” (the agency specifying that the use of this dosage should be considered “only in the secure environment of a clinical trial” ).
Among the other studies on HCQ already published which involve a higher “loading dose”, one can in particular quote work presented in early May in the British Medical Journal , where the protocol begins with the administration of 1200 mg. daily for the first three days, followed by a daily dose of 800 mg for two to three weeks.
To assess the effect of HCQ on Sars-CoV-2 at high concentrations
Is the “loading dose” of 2400 mg of hydroxychloroquine sulfate used in Recovery, significantly higher than in previous research, dangerous?
In a document presenting the protocol of the Recovery study, its managers explain knowingly using a high “loading dose” in order to “reach as soon as possible inhibitory plasma concentrations of the virus”. According to the authors, “the concentrations of HCQ in the blood plasma” which result from this massive and early administration “are in the upper range of those encountered, at steady state, during the treatment of rheumatoid arthritis. “.
Contacted by CheckNews , Professor Peter Horby, co-author of the work, justifies the approach: “The proposed mechanism of action for hydroxychloroquine against Covid-19 is antiviral and, therefore, to be effective, it is necessary to reach concentrations capable of inhibit the virus. It requires high doses. The dose we used was based on pharmacokinetic modeling of the distribution and metabolism of hydroxychloroquine, as well as [ in vitro ] data on the inhibitory concentration of HCQ against Sars-CoV-2 virus ” .
This idea that high plasma concentrations of HCQ are a prerequisite for any effect on this coronavirus has already been defended by other pharmacologists , and had not been evaluated until now. According to Mathieu Molimard, head of the department of medical pharmacology in Bordeaux, “the dose administered in Recovery is the maximum that could be given, under strict surveillance conditions, without increasing the risks too much. They gave themselves the chance to see something. But the truth is, the latest data available (and in particular a study carried out by the Food and Drug Administration ) shows that it would take even higher doses – and therefore much more dangerous – to have an effect.
What about the doses administered over ten days?
For Professor Horby, the risks associated with a large loading dose in the context of a clinical trial, as well as those associated with taking 9600 mg of Plaquenil spread over ten days, “are very low”. “Experts in the pharmacokinetics of CQ and HCQ worked on the models that led us to make these dosage decisions , ” he explains.
Regarding the “loading dose”, it should be noted that this is administered gradually, over the course of a day, and not all at once. The objective here is to give the active molecule time to diffuse into the cells. This avoids a peak concentration, and thus reduces the toxic risk. A faster administration would, on the other hand, have extremely deleterious effects .
“We have taken great care to select a dose of HCQ that balances potential efficacy and safety,” insists the researcher. Surprisingly at the reviews, he observes that “the maximum doses people cite are related to long-term use of hydroxychloroquine. Short term use (ten days) will not have long term complications such as retinal damage, and the doses we use are much lower than those associated with acute toxicity or poisoning ”.
Did the researchers confuse the authorized dosages of two molecules?
The controversy over the high dosages of HCQ used in Recovery has also been fueled by a heavy accusation against the researchers. According to a thesis shared for several days on social networks, the researchers would have, by mistake, based their calculations on the authorized dosage for another molecule.
This allegation originates in an interview given to the France Soir platform by Martin Landray, one of the coordinators of the trial. Asked about the dosage question, he reportedly replied, “The doses were chosen based on pharmacokinetic modeling and these are in line with the dosages used for other diseases such as amoebic dysentery.” In a second article published by France Soir , this declaration is submitted to the opinion of a French doctor (Professor Perronne). This one declares:“This is the first time that I have learned that hydroxychloroquine is used in amoebic dysentery, in addition to super-toxic doses for humans. […] I think he confused hydroxychloroquine with hydroxyquinoline. This man, who calls himself a doctor, is incompetent and dangerous. “
Peter Horby formally denies this interpretation and affirms that France Soir misreported the words of his colleague: “There is absolutely no confusion among us between hydroxychloroquine and hydroxyquinoline, contrary to what France Soir reports. The confusion comes from the interview with France Soir which reports the term “amoebic dysentery” instead of “amoebic hepatic abscess” (AHA), pathology for which chloroquine has been used as a treatment in the past, at comparable doses. to the ones we used in Recovery with the HCQ. ”
The researcher refers us to a document from 1995, in which the World Health Organization considers that chloroquine can be used safely against AHA, with a total of 7.2 grams over three weeks (in addition to other treatments). Reminding us that HCQ is less toxic than CQ, Peter Horby notes that an equivalent weight of HCQ is used, over ten days, in Recovery. But he insists: “This dose used by WHO for AHA was not mentioned to ‘justify’ the doses used in the Recovery trial. It was just an example of another disease where high doses have been used in the past. ”
[update of June 16] Following the publication of Peter Horby’s denials in our columns, France Soir broadcast the extract of the interview with Mr. Landray, as well as correspondence with this researcher. These elements confirm that Landray has kept the words attributed to him.
Contacted on June 12 for their explanations, the two managers of the Recovery trial finally responded to our requests on June 16, shortly before 11 a.m. Here is the response from Peter Horby: “It was a simple mistake interviewing Martin [Landray]. RECOVERY’s documents, all available online since the start of the trial (linked documents dated April 19), clearly refer to amoebic liver abscess, not dysentery. However, this is irrelevant because the information on the amoebic liver abscess played absolutely no role in the choice of the dose. “
New Jersey Study of 1,274: Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19; A multi-center observational study where hydroxychloroquine exposure was associated with a decreased rate of subsequent hospitalization
Ghana: “HCQ and AZ associated with viral clearance in COVID-19 patients.” Clinical characteristics, treatment regimen and duration of hospitalization among COVID-19 patients in Ghana: a retrospective cohort study