How about if I show my thought process in analyzing this paper so that you can determine how solid my analysis is?
This paper is about treating ambulatory covid patients with various treatments and comparing results. Researchers are separated from patient selection, so they can't bias the patient selection. The statisticians are involve…
How about if I show my thought process in analyzing this paper so that you can determine how solid my analysis is?
This paper is about treating ambulatory covid patients with various treatments and comparing results. Researchers are separated from patient selection, so they can't bias the patient selection. The statisticians are involved in randomization of patients, but patient characteristics are hidden from them.
Now let's consider what covid is. Covid is caused by a viral infection of the nasopharynx which goes viremic before symptom onset. Covid pathology is multimodal, but the primary damage is to the microvascular endothelium, with clotting and inflammation resulting from the damage to the endothelium. In some patients, there is failure to reduce inflammation after the immune system has cleared the virus, resulting in immune attack of the infected tissues. Covid is a progressive disease where progression occurs due to inflammation and hypoxia. Death can occur from covid due to ARDS, systemic organ failure, clotting in coronary arteries--either embolii or thrombii, pulmonary embolism, or stroke. Max viral load occurs at three days in mild covid cases and virus is cleared by eight days, per Didier Raoult, who performed cell culturing as confirmation. Raoult's result is confirmed by two other lines of evidence--a Hopkins study showed a floor in false negative PCR test results at three days post symptom onset, with negative results increasing in either direction along a time curve. And Accinelli found that covid mortality was associated with treatment of an antiviral (HCQ in his study) when treatment was initiated after 72 hours from symptom onset, but no mortality occurred within the 72 hour window.
Now to the paper. Treatment with IVM is controversial, so we shall have to look at the data.
The dosing with IVM looks adequate, tho a bit on the low side. The primary endpoint is fairly squishy and this is likely due to the trial being underpowered to consider hospitalization or mortality as primary endpoints. ER visits had to be added in order to test significance. There was one death in the IVM arm and none in placebo, but this isn't significant for trial results.
Couriers delivered treatment to patients. The mean time of treatment initiation from symptom onset was 4.7 days. Almost assuredly, no patients received treatment within the 72 hour window post symptom onset. In terms of significance affecting trial results, this is a mountain. Giving antivirals for covid after the treatment window looks to be consistently ineffective. In the best case, for mild covid patients, the immune response is winning starting at 72 hours, so antivirals will have minimal impact. In the worst case, max viral load isn't reached until later, with exponential increase in damage occurring each day, resulting in progression, hospitalization, and possibly death. Delaying antiviral treatment does these weaker patients no good, which is what Accinelli found.
So the glaring weakness of the Boulware paper that you referenced is delayed time to treatment from symptom onset. Imo, it should be retracted.
This paper shows that researcher bias can be inserted thru improper trial design in RCTs. Isn't Boulware paid by Gilead?
How about if I show my thought process in analyzing this paper so that you can determine how solid my analysis is?
This paper is about treating ambulatory covid patients with various treatments and comparing results. Researchers are separated from patient selection, so they can't bias the patient selection. The statisticians are involved in randomization of patients, but patient characteristics are hidden from them.
Now let's consider what covid is. Covid is caused by a viral infection of the nasopharynx which goes viremic before symptom onset. Covid pathology is multimodal, but the primary damage is to the microvascular endothelium, with clotting and inflammation resulting from the damage to the endothelium. In some patients, there is failure to reduce inflammation after the immune system has cleared the virus, resulting in immune attack of the infected tissues. Covid is a progressive disease where progression occurs due to inflammation and hypoxia. Death can occur from covid due to ARDS, systemic organ failure, clotting in coronary arteries--either embolii or thrombii, pulmonary embolism, or stroke. Max viral load occurs at three days in mild covid cases and virus is cleared by eight days, per Didier Raoult, who performed cell culturing as confirmation. Raoult's result is confirmed by two other lines of evidence--a Hopkins study showed a floor in false negative PCR test results at three days post symptom onset, with negative results increasing in either direction along a time curve. And Accinelli found that covid mortality was associated with treatment of an antiviral (HCQ in his study) when treatment was initiated after 72 hours from symptom onset, but no mortality occurred within the 72 hour window.
Now to the paper. Treatment with IVM is controversial, so we shall have to look at the data.
The dosing with IVM looks adequate, tho a bit on the low side. The primary endpoint is fairly squishy and this is likely due to the trial being underpowered to consider hospitalization or mortality as primary endpoints. ER visits had to be added in order to test significance. There was one death in the IVM arm and none in placebo, but this isn't significant for trial results.
Couriers delivered treatment to patients. The mean time of treatment initiation from symptom onset was 4.7 days. Almost assuredly, no patients received treatment within the 72 hour window post symptom onset. In terms of significance affecting trial results, this is a mountain. Giving antivirals for covid after the treatment window looks to be consistently ineffective. In the best case, for mild covid patients, the immune response is winning starting at 72 hours, so antivirals will have minimal impact. In the worst case, max viral load isn't reached until later, with exponential increase in damage occurring each day, resulting in progression, hospitalization, and possibly death. Delaying antiviral treatment does these weaker patients no good, which is what Accinelli found.
So the glaring weakness of the Boulware paper that you referenced is delayed time to treatment from symptom onset. Imo, it should be retracted.
This paper shows that researcher bias can be inserted thru improper trial design in RCTs. Isn't Boulware paid by Gilead?
Raoult: https://link.springer.com/article/10.1007/s10096-020-03913-9
Hopkins: https://www.acpjournals.org/doi/10.7326/M20-1495
Accinelli: https://www.sciencedirect.com/science/article/pii/S1477893921002040