#15,505One of the reasons why I devote so little AFD blog space to `forward looking' and `aspirational' pharmaceutical press releases - unless it is to warn against them - is that many that look promising at the start, end up falling flat in the end.
Overnight the World Health Organization published a press release (below) and a pre-print study, on the disheartening results from six-months worth of clinical trials on several heavily touted treatment options for COVID-19 - remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon regimens - finding all of them had little or no effect on 28-day mortality or in-hospital course of illness.
Some of these findings have been hinted at by other studies released over the summer, making the following dismal results less shocking, but still disappointing.
Solidarity Therapeutics Trial produces conclusive evidence on the effectiveness of repurposed drugs for COVID-19 in record time15 October 2020
Reading time: Less than a minute (223 words)
In just six months, the world’s largest randomized control trial on COVID-19 therapeutics has generated conclusive evidence on the effectiveness of repurposed drugs for the treatment of COVID-19.
Interim results from the Solidarity Therapeutics Trial, coordinated by the World Health Organization, indicate that remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon regimens appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients.
The study, which spans more than 30 countries, looked at the effects of these treatments on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized patients. Other uses of the drugs, for example in treatment of patients in the community or for prevention, would have to be examined using different trials.
The progress achieved by the Solidarity Therapeutics Trial shows that large international trials are possible, even during a pandemic, and offer the promise of quickly and reliably answering critical public health questions concerning therapeutics.
The results of the trial are under review for publication in a medical journal and have been uploaded as preprint at medRxiv available at this link:https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1
The global platform of the Solidarity Trial is ready to rapidly evaluate promising new treatment options, with nearly 500 hospitals open as trial sites.
Newer antiviral drugs, immunomodulators and anti-SARS COV-2 monoclonal antibodies are now being considered for evaluation.
WHO Solidarity Trial Consortium, Hongchao Pan, Richard Peto, Quarraisha Abdool Karim, Marissa Alejandria, Ana Maria Henao Restrepo, Cesar Hernandez Garcia, Marie Paule Kieny, Reza Malekzadeh, Srinivas Murthy, Marie-Pierre Preziosi, Srinath Reddy, Mirta Roses, Vasee Sathiyamoorthy, John-Arne Rottingen, Soumya Swaminathan
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
AbstractInfo/HistoryMetrics Preview PDF
WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs. METHODS Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-β1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry.
In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise).
Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050).
No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration.
These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151, NCT04315948)
Competing Interest Statement
Of note, this report comes just over a week after another report - published in the NEJM - found:
. . . . a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with Covid-19. Patients who received remdesivir had a shorter time to recovery (the primary end point) than those who received placebo (median, 10 days vs. 15 days; rate ratio for recovery, 1.29 [95% CI, 1.12 to 1.49]) and were more likely to have improvement in the ordinal scale score at day 15 (key secondary end point; odds ratio, 1.5; 95% CI, 1.2 to 1.9).
While not a resounding result, this more positive NEJM study was based on a much smaller cohort of patients (541 assigned to remdesivir and 521 to placebo), compared to to the WHO study (2750 receiving remdesivir and 4088 receiving no study drug), which may help explain the divergence in results.
Although there are other therapeutics still being evaluated, their effectiveness has yet to be established, and we are moving into what appears to be a heightened period of COVID activity.
Convalescent plasma remains on the table, although we saw a high profile Dutch Convalescent Plasma Study For COVID-19 Halted For Redesign over the summer, and a recent Cochrane analysis found insufficient evidence to say - one way or the other - whether convalescent plasma is beneficial for people admitted to hospital with COVID-19.
Other therapies awaiting evaluation include antiviral drugs, immunomodulators and anti-SARS COV-2 monoclonal antibodies. Hopefully somewhere along the way, something will prove beneficial to COVID-19 patients.
But until then, Caveat Lector.