Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 , Skipper et al., Annals of Internal Medicine, July 16, is fraud.
This a second paper based on the same clinical trial NCT04308668, Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2 (COVID-19 PEP). David Boulware, MD, was the Chief Investigator. The trial split into two parts: post-exposure prophylaxis (misreported in Boulware et al., NEJM, June 3), and early treatment (misreported in the currently discussed Skipper et al). Boulware and Skipper are among the authors in both papers, so they are referred here as BS-1 and BS-2, respectively. Dr. David Boulware is one of the leading authorities on hydroxychloroquine in COVID-19; the White House medical team asked his advice on COVID-19 prophylaxis. Caleb P Skipper (the guy with no photo) seems to be the designated scapegoat. His name did not appear on scientific papers before 2019.
Publication of BS-2 repeated the same pattern as BS-1 – puff media pieces, exaggerating the paper claims, are published before the actual study. The MSM bizarrely celebrates the news that a promising drug is useless for treatment or prophylaxis of the pandemic disease (as it erroneously believes it). The scientific community needs some time to evaluate the paper. When they do that, it is too late. When criticism comes ins, the media moves on to another hoax.
The timeline shows the same thing that other source: hydroxychloroquine was not controversial before “touted” by Trump, but rather universally accepted as one of the most useful tools in COVID-19 treatment and prophylaxis. The study was privately funded, apparently with a bona fide intent to investigate its use for early treatment / post exposure prophylaxis. The following is the table of changes in the records on ClinicalTrials.gov
|1||March 11, 2020||None (earliest Version on record)|
|2||March 17, 2020||, Study Status, Contacts/Locations, Oversight and Study Identification|
|3||March 19, 2020||Contacts/Locations, Arms and Interventions and Study Status|
|4||March 24, 2020||Study Status, Contacts/Locations, Study Identification, Outcome Measures, Study Design, Conditions, Study Description, Eligibility and Arms and Interventions|
|5||March 25, 2020||Outcome Measures and Study Status|
|6||April 1, 2020||Contacts/Locations, Study Description, Study Status, Eligibility, Study Design and Sponsor/Collaborators|
|7||April 6, 2020||Study Description, Study Status and Study Identification|
|8||April 28, 2020||IPDSharing, Outcome Measures, Study Status, Contacts/Locations, Eligibility and Study Description|
|9||June 24, 2020||, Study Status, Contacts/Locations, IPDSharing, Study Design, Documents, References and Eligibility|
|10||July 15, 2020||Study Status and Study Identification|
March 11, 2020. The study is registered.
March 17, 2020. Some initial information, including a 274-word Description, is posted.
March 19, 2020. The number of treatment days is changed from 1+6 to 1+4. This is the date when Trump “touted” chloroquines. Dr. Boulware still maintains a positive attitude toward HCQ.
March 24, 2020. The title is changed from “Post-exposure Prophylaxis” to “Post-exposure Prophylaxis / Preemptive Therapy”. Methodology is slightly tweaked. Let us not nitpick – the trial has just started. The anticipated study completion date changed from May 2021 to May 12, 2020 – possibly a mistake correction.
On the same day, Dr. David Boulware is hired by Revive Therapeutics Ltd. (PNK: RVVTF; Toronto, Canada) as Scientific Advisor for Infectious Diseases including COVID-19. RVVTF has just entered the business of psychedelic mushrooms. It also has rights for an “orphan drug” Bucillamine, which it positioned as a competitor to HCQ in early COVID-19 treatment.
Despite that, Dr. Boulware answered NO to the question about relevant financial conflicts of interest.
April 1, 2020. The trial methodology is significantly changed. This is wrong. Pre-registration of clinical trials exists to assure that the methodology was decided before the trial and was not changed, compromising statistical integrity of the results.
April 6, 2020. The methodology is changed again, apparently to make results less favorable to HCQ. The endpoint in the sub-trial corresponding to BS-2 was changed from “decreas[ing] hospitalizations” to “decreasing hospitalizations and symptom severity”. The composite endpoints like the latter one are usually avoided. Of note, the hospitalization rate in the HCQ group was 50% of the hospitalization rate in the untreated group. This was disclosed in the paper: “We do note that 8 COVID-19–related hospitalizations (including 1 death) occurred with placebo versus 4 COVID-19 hospitalizations (and 1 additional death; 5 events in total) with hydroxychloroquine.”
Despite all these changes and additions, the study description remains too short, and provides a lot of wiggle room for study conduct and interpretation.
April 23, 2020. “Revive Therapeutics Announces U.S. FDA Recommendation to Proceed Directly Into A Phase 3 Confirmatory Clinical Trial” with Bucillamine, according to RVVTF press-release
April 24, 2020. U.S. FDA issues a strong worded Drug Safety Communication about the use of HCQ for COVID-19 treatment, with an odd caveat that it “Does not affect FDA-approved uses for malaria, lupus, and rheumatoid arthritis”.
April 28, 2020. The trials methodology is changed again. A proper document describing the study on 20+ pages, excluding introduction and references, was uploaded only on April 24, eight days before the enrollment ended.
May 6, 2020. Enrollment into the trial ends.
May 30-31, 2020. An Indian study of using HCQ for COVID-19 prophylaxis in healthcare workers is published in the Indian Journal of Medical Research. It reports success of hydroxychloroquine prophylaxis against COVID-19 in 80% of cases. Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19
June 3, 2020. BS-1 is published. Despite all the efforts of the researchers, it shows effectiveness of HCQ against COVID-19. But the interviews of Dr. Boulware and the big tech media claim otherwise.
July 16, 2020. BS-2 is published. It is not clear why it took so long to publish it.
In total, the trial methodology was substantially changed at least six times over the two months of the study.
The paper reported two-fold decrease in hospitalizations in the HCQ group. HCQ was administered with neither azithromycin nor zinc, but at higher than usual dose. Considering the high noise / low resolution of the trial design, this confirms effectiveness of HCQ in prophylaxis and early treatment of COVID-19.
The study reported adverse effects in some of the HCQ recipients. HCQ might cause minor side effects. In this case, it was exacerbated by the fact that the participants the larger than usual doses 1,400 mg on the first day, 600 mg daily after that (instead of 400 mg/day, sometimes with an extra 400 mg on the first day).
On a positive side, Dr. Boulware co-signed the open letter to The Lancet calling out Mehra et al. fraud.
Work in Progress