4/n If these reductions are true, either HCQ or P-I would be a massive, world-changing reduction in risk for the prevention of COVID-19 (although zinc and ivermectin would be largely useless)
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14/n It seems very much like this trial was conceived, planned, AND RUN as a randomized parallel-arm trial and then halfway through switched to a cluster RCT
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15/n Ok, so that's all pretty worrying. The results may not be statistically viable, the methodology has quite a few flaws But there's actually a potentially bigger issue
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16/n The primary outcome reported in the trial was laboratory-confirmed (through either PCR or serology) COVID-19. This is the measure that the headline results is based onpic.twitter.com/R2Uj9MhpHc
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17/n But if we go to the pre-registration for the study (which, incidentally, doesn't talk about controlling for a clustered design), there's something a bit weird The primary outcome was originally "acute respiratory illness"pic.twitter.com/00efREicTD
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18/n So when the study was registered, in June 2020, the primary outcome was acute illness. A month after the final results came in, the primary outcome was changed to laboratory-confirmed COVID-19pic.twitter.com/bvnQFLBIc3
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19/n Moreover, the outcome that was registered in advance as the primary outcome has completely different results, showing a statistically significant effect for ivermectin but nothing elsepic.twitter.com/9uEHLguDRc
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20/n Now, there's nothing inherently wrong about switching outcomes, and the authors do mention a reason for changing it, but the fact that it was only changed after the study was finished is very strangepic.twitter.com/2S6fIGLb9G
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21/n The explanation in the text also doesn't quite make sense. The paper reports excluding people who had a positive serological test at baseline - how can these people have been tested if there were no serological tests when the study started?pic.twitter.com/I561MZ8JsA
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22/n So what does this all mean? Well, overall, it's quite hard to trust the trial's results
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23/n The study does not appear to follow the guidelines for implementation and analysis for cluster RCTs, which means that it's hard to know what to make of the analysishttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881078/ …
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24/n The primary outcome was also switched, with a bunch of other odd inconsistencies in the research that make it a bit hard to know if the conclusions hold water
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25/n To their credit, the authors talk about some of these things in the limitations section of the study, but not all of them and I'm not sure they really explain why these are not issuespic.twitter.com/KaUEJBj2ki
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26/n Anyway, I'm not sure I would rely on this study as evidence for much, despite the large size
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27/n Apologies, one of the above tweets is wrong. The authors did indeed take into account the clustering in their statistical analysishttps://twitter.com/jt_kerwin/status/1386920483916947464?s=20 …
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28/n The more I read this paper, the weirder it sounds. So they randomized ineligible people (how?) from two floors that were not clustered, and then assigned them to vitamin C if the other medications were contraindicated?https://twitter.com/salonium/status/1386922872317247489?s=20 …
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