Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 infection

[-] stereomatch | 6 points | Mar 10 2021 14:44:42

Summary: it seems this study suffers from a very serious confounder - the lack of steroids treatment at day 8 (see Confounders section below). The patients are all post-day-8 ie squarely in hyperinflammatory stage territory, and they were NOT given steroids for part of the trial. This may explain the extremely high death rates of 22-23 percent across the board. Because if you deny a patient steroids at day 8 you are essentially giving them a death sentence. That type of hurdle is impossible to overcome with puny ivermectin or HCQ or anything else. The patients needed steroids and were denied them because they were listening to the WHO/NIH flawed guidance at that time - to NOT give steroids - a guidance they later reversed (no apologies were offered to the MATH+ folks for being right all along - this is a point the MATH+ folks have not belabored enough).

Inclusion criteria were as follows: (1) laboratory test confirming infection by SARS-CoV-2 (positive serologic test IgM or rt-PCR); (2) hospitalized with a clinical, epidemiological, and radiological picture compatible with COVID-19; (3) over 18 years old; (4) present a severe form of the disease characterized by one of the following clinical signs: dyspnea, tachypnea (30 bpm), peripheral oxygen saturation <93% (pulse oximeter evaluation), PaO2/FiO2 ratio <300, or infiltrate pulmonary50% of the parenchyma seen on chest tomography or chest radiography. The exclusion criteria were as follows: (1) under 18 years old; (2) indigenous people; (3) patients not fluent in Portuguese; (4) unable to understand the objectives and methods of the study; (5) critically ill patients who are not accompanied by legal representatives; (6) those who reject participation in the study; (7) patients with cardiac arrhythmia that include prolongation of the QT interval; (8) previous use of any of the medications surveyed for more than 24 h.

These were clearly patients at day 8-10 or more in terms of their stage - oxygen less than 93 etc. These are patients in dire need of immediate steroids therapy (as is the recommendation at day 8 according to the MATH+ protocol). In my experience also the decline from this point onwards is fast, and needs to be arrested immediately.

At this point I don't think Ivermectin or HCQ is the primary treatment, although they can be given and may have benefit in some patients (for example those with viral persistence etc - that type of an effect will not be seen in all the patients).

While they only screened for prior use of the drugs to 24 hours (which is insufficient as ivermectin has prophylaxis effect even when used every 14 days according to I-MASK+ protocol). However the death rates of 22 percent etc. they quote are very high suggesting perhaps these were all drug-naive patients (?) - (EDIT: see the Confounders section below for an interesting insight - lack of steroids treatment at day 8):

Mortality was similar in the three groups, 22.2% for the HCQ group, 21.3% for the CQ group, and 23.0% for the ivermectin group, with no statistically significant difference. Table 2 and Figure 2 describe in detail the comparison of hospital outcomes between treatment groups.

Eligible participants were allocated at a 1:1:1 ratio to receive orally (or via a nasogastric tube in case of orotracheal intubation) either: (A) CQ difosfate (450 mg, twice on day 0, and once daily from day 1 to day 4, total dose 2.7 g); or (B) HCQ sulfate (400 mg twice on day 0, and once daily from day 1 to day 4, total dose 2.4 g); or C) ivermectin (14 mg once at day 0 + 1 placebo tablet at day 0, and once daily from day 1 to day 2, + 1 placebo tablet daily from day 3 to 4, total dose 42 mg). For participants with body weight under 55 kg, the ivermectin dose was adjusted to 10 mg each dose. Investigational product

So the ivermectin dose was 42mg total (14mg per day on 3 separate days). This is a reasonable dose to give for the inflammatory stage ie post-day-8 which these patients were (given their severity).

However at this stage the hyperinflammatory storm is raging, and it is steroids which are the primary treatment - their dosage and swiftness of delivery dictate outcomes. Start steroids at day 7 and you need only 20mg prednisolone, but if you delay until day 10, then you need 40mg to 80mg per day to show sequential daily improvement (which is what you are going for at this point).

Confounders - steroids (or lack thereof)

As per hospital protocol, every patient without contraindication received prophylactic doses of enoxaparin (1 mg/kg once a day). All patients meeting the criteria of acute respiratory distress syndrome used azithromycin (500 mg 1× for 5 days) and ceftriaxone (1 g 2× for 7 days). Oseltamivir (75 mg 2× for 5 days) was also prescribed when influenza infection was suspected. The use of corticosteroids was a decision of the assistant physician, as new scientific evidence on its effectiveness emerged during the course of the study.

enoxaparin - good - this is an anti-coagulant
azithromycin/ceftriaxone - antibiotics
Oseltamivir (Tamiflu) - if influenza suspected
Steroids - this is the zinger! - they were evidently not using steroids at the start of this trial (ie they went against MATH+ protocol - and the preexisting wisdow of doctors - and started following WHO/NIH guidelines to NOT use steroids! - and this may have led to the excess mortality of 22-23 percent seen in this study across the board). Later after UK RECOVERY trial results showed steroids helped, MATH+ was vindicated (but people still only remembered they were controversial!) - at which time this trial probably started steroids! This could explain the very high death rate of 22-23 percent across the board. Essentially steroids is the confounders here - or specifically lack of steroids - because if you are not giving steroids at day 8, you are essentially relegating patients to the grave which no other drugs can dig patients out of. No drugs can do what steroids can do at this point. This is an instructive point because in other trials too, it is not just that steroids were given, but how much, and at what time is was it prompt - any delay in starting steroids, or any stinginess ie not giving large doses are MUCH bigger confounders than any impact ivermectin etc can do. Essentially by choosing to not give steroids to a patient you are killing the patient.

I find it interesting that while studies talk of needing data to come to a conclusion, they are quick to extend results of these drugs in very specific situations as indications of wider value ie even in prophylaxis or early disease. This extrapolation of negative results is quite common in these types of studies, even though it is clear their data provides NO visibility into the other modes of use.

However, in this case they ARE careful to qualify the setting in which they saw no benefit:

Conclusion: Although CQ, HCQ or ivermectin revealed a favorable safety profile, the tested drugs do not reduce the need for supplemental oxygen, ICU admission, invasive ventilation or death, in patients hospitalized with a severe form of COVID-19.