The Bizarre Contortions of the PRINCIPLE trial authors

Despite finding statistically significant differences between COVID19 patients treated with Ivermectin and the usual standard of care including early sustain recovery in 21.1% of Ivermectin treated patients v. 16.2% of standard of care patients, sustained recovery in 56.9% Ivermectin treated patients vs. 51.8% of standard of care patients, time to alleviation of all symptoms (median 4 days vs. 5 days), sustained alleviation of all symptoms in 80% of patients vs. 75.4% of patients, time to initial reduction in the severity of symptoms in median 7 days vs. 9 days with initial reduction in severity of symptoms in 83.3% of Ivermectin treated patients vs. 80.1% of standard of care patients, a lower mortality rate at 28 days of 1.6% compared to 4.4% (a primary outcome btw), the authors decided that although the differences were statistically significant (HR = 1·14, 95% Interval= 1·07 – 1·23) they were not “clinically meaningful” because it did not exceed the pre-specified hazard ratio of 1.2 for the primary outcomes. However, the the PRINCIPLE trial authors designed the study to ensure a smaller benefit would be found for Ivermectin by not starting randomization into the Ivermectin arm until 14 days after symptom onset, changing the eligibility criteria in the middle of the trial to allow recruitment of all SARS-COV-2 positive adults regardless of comorbidities, and only providing doses smaller than what is typically administered once daily for three days. In all of the control trials I covered in Ivermectin as a COVID19 Prophylaxis, treatment started within at least 3 days of symptom onset and was carried out at least twice daily for 5 days if not the entire duration of the illness. These are not small changes and would make the difference between a hazard ratio above or below the pre-specified level.