This manuscript has been published on the 29th of May
2020 by the honorable BMJ as a rapid response to a related article.
However since a DOI has not been assigned and two subsequent manuscripts
have cited it1,2, I’m preprinting a copy wishing it
might reach all the interested colleagues and researchers in an easier
way.
Dear Editor,
I’ve read with much interest a recent article published at your
honorable journal discussing the decision made by NIH to select some
hospitalized COVID-19 patients to test the potential of the
investigational drug remdesivir and the author was very concerned that a
previous trial has never been finished and it’s becoming hard to recruit
patients to be tested for this drug3 and I’d like to
try to answer his concern from a pharmacovigilant point of view.
The results published in the Lancet by Wang and colleagues, have showed
no statistically significant COVID-19 benefits for remdesivir treatment
beyond those of standard of care treatment but unfortunately, the
authors have recommended “future studies of remdesivir, including
earlier treatment in patients with COVID-19 and higher-dose regimens or
in combination with other antivirals or SARS-CoV-2 neutralising
antibodies in those with severe COVID-19 are needed to better understand
its potential effectiveness”4. Wang and colleagues
have clearly stated that the primary endpoint of time to clinical
improvement was not significantly different between groups and that
all-cause mortality at day 28 was 14% in the remdesivir arm as compared
to 13% in the placebo for patients with late use of remdesivir.
However, they reported a numerically higher mortality, but also
non-significant, in the placebo group if remdesivir used early during
COVID-19 and perhaps this might have been one of the reasons for their
positive recommendation that led NIH to unfortunately continue trying to
recruit more selected patients to continue the failing trials.
Similarly, I also disagree with any suggested clinical significance of
their observation that those receiving remdesivir had a numerically
faster time to clinical improvement than those receiving placebo. This
non-significant numerical interpretation of clinical results related to
this investigational, experimental and potentially hazardous remdesivir
should be considered irrelevant from my pharmacovigilant point of view.
Noteworthy, it’s crucial to notice that they’ve also reported that
remdesivir produced adverse events leading to its stoppage in 18 (12%)
patients versus four (5%) patients who stopped placebo early, and I
suggest that these results are the most important reported numerical, as
well as significant findings and I recommend them to be considered very
carefully looking for a deeper analysis of these adverse effects that
might have helped to encourage the investigators to prematurely stop
remdesivir clinical trial. The adverse events have not only included
minor gastrointestinal symptoms (anorexia, nausea, and vomiting), but
also aminotransferase or bilirubin increases, and most importantly
worsened cardiopulmonary status as stated in Wang and colleagues
published manuscript. From a pharmacovigilant point of view, I recommend
all colleagues working on each undergoing remdesivir clinical trial to
fully investigate the cardiopulmonary adverse effects as it might
eventually resemble that of hydroxychloroquine that is being revealed
both ineffective and potentially hazardous 5 and
started to be banned by some countries for further use for COVID-196.
Unfortunately, on the same day Wang and colleagues published their
results, another numerical misinterpretation, as I suggest, of data has
been made by the National Institute of Allergy and Infectious Diseases
(NIAID), an NIH affiliated entity which has reported the median time to
recovery was 11 days for COVID-19 patients treated with remdesivir
compared with 15 days for those who received placebo and it was
surprisingly officially declared as a 31% faster time to recovery7. I consider this and similar claims as totally
misleading and I believe that it should be only interpreted as 4 days
difference compared to placebo, this doesn’t by any means deserve to be
focused on through a press release, nor justified as reason for early
termination of the study, taking also into consideration that even in
this study, no significant difference in remdesivir mortality rate
compared to placebo was observed and I’m waiting for the full results to
be published looking for other confounding factors that might be also
present.
Interestingly, I would like to refer all my colleagues to read the full
press release statement wisely made by remdesivir manufacturer’s Gilead
on the same day these results have been misinterpreted by the media as
well as by stock markets that soared its shares, I’m only quoting short
excerpts:
“Remdesivir is not yet licensed or approved anywhere globally and has
not yet been demonstrated to be safe or effective for the treatment of
COVID-19. Further, it is possible that Gilead may make a strategic
decision to discontinue development of remdesivir or that FDA and other
regulatory authorities may not approve remdesivir, and any marketing
approvals, if granted, may have significant limitations on its use. As a
result, remdesivir may never be successfully commercialized”8 to be noted that Gilead is sponsoring multiple
clinical trials all over the world for its remdesivir potential for
COVID-199 and I suggest it knows better than NIAID
about its efficacy and safety.
Finally, the main bulk of this manuscript was submitted on the first of
May to The Lancet and on the 11th of May, NIH has declared that it has
stopped its big remdesivir trial and so I wish to thank all the
honorable scientists who fought with honor to make this decision
appear10, to be noted that I’ve received the formal
”The Lancet” rejection without peer-review comments on the 21st of May.
Conflict of interests
None
Funding
None
References:
1. Kelleni MT. Remdesivir-Gate for COVID-19. Acta Scientific
Gastrointestinal Disorders. 2020, July 01;3(8):01.
2. Mina Kelleni. Tocilizumab, Remdesivir and Favipiravir repurposed for
COVID-19: The Good, The Bad and The Ugly.
Authorea. November 30, 2020. DOI:
10.22541/au.160677059.91320681/v1 3. Kmietowicz Z. Covid-19: Selected NHS patients will be treated with
remdesivir. BMJ. 2020;369:m2097.
4. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe
COVID-19: a randomised, double-blind, placebo-controlled, multicentre
trial. Lancet. 2020;395(10236):1569-1578.
5. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or
chloroquine with or without a macrolide for treatment of COVID-19: a
multinational registry analysis. The Lancet.
6. Reuters (Matthias Blamont). France, Italy, Belgium act to stop use of
hydroxychloroquine for COVID-19 on safety fears. 2020, May 27;
https://www.reuters.com/article/us-health-coronavirus-hydroxychloroquine/france-italy-belgium-act-to-stop-use-of-hydroxychloroquine-for-covid-19-on-safety-fears-idUSKBN233197.
7. National Institute of Allergy and Infectious Diseases. NIH Clinical
Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19.
2020, April 29;
https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19.
8. Gilead Sciences. Inc. Gilead Sciences Statement on Positive Data
Emerging From National Institute of Allergy and Infectious Diseases’
Study of Investigational Antiviral Remdesivir for COVID-19. 2020, April
29;
https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-sciences-statement-on-positive-data-emerging-from-national-institute-of-allergy-and-infectious-diseases-study-of-investigational-antiviral-rem.
9. Gilead Sciences. Inc. Remdesivir Clinical Trials,. 2020, May 29;
https://www.gilead.com/purpose/advancing-global-health/covid-19/remdesivir-clinical-trials.
10. MATTHEW HERPER. Inside the NIH’s controversial decision to stop its
big remdesivir study. 2020, May 11;
https://www.statnews.com/2020/05/11/inside-the-nihs-controversial-decision-to-stop-its-big-remdesivir-study/?fbclid=IwAR1mYotmch21UM-NuchLqHYTbuy-NSs0B5Pt3oM_94Yjb4w6J0wU94_1cek.