This week, following a 30-country randomised control trial, the World Health Organisation claimed “conclusive evidence” on the effectiveness of repurposed drugs for the treatment of COVID-19, writes MedicalBrief. But already Gilead Sciences has challenged the WHO “premature” findings on remdesivir, saying that the data appeared inconsistent and that other studies had validated the drug’s benefits.
Interim results from the Solidarity Therapeutics Trial, co-ordinated by the World Health Organisation, indicated 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 hospitalised 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 hospitalised 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.
Gilead questions WHO study that cast doubts on drugs’ COVID-19 benefits
Gilead Sciences has questioned the findings of the WHO study that concluded its COVID-19 drug remdesivir does not help patients who have been admitted to hospital, reports Reuters.
The WHO trial also evaluated hydroxychloroquine, anti-HIV drug combination lopinavir/ritonavir and interferon, and concluded that they, like remdesivir, did little to help patients survive or leave the hospital more quickly.
The American company told Reuters that the data appeared inconsistent, the findings were premature and that other studies had validated the drug’s benefits, reported Daily Maverick on 16 October 2020, quoting Reuters.
In a blow to one of the few drugs being used to treat people with COVID-19, the WHO said last Thursday that its Solidarity trial had concluded that remdesivir appeared to have little or no effect on 28-day mortality or length of hospital stays among patients with the respiratory disease.
The antiviral medication was one of the drugs used to treat United States President Donald Trump’s coronavirus infection, and has been shown in previous studies to have cut time to recovery, although the European Union is investigating it for possible kidney injury.
The WHO trial was conducted among 11,266 adult patients. The evidence was conclusive, the WHO said.
Gilead said other trials of remdesivir, including with 1,062 patients that compared it with a placebo, showed that the treatment cut COVID-19 recovery time. “The emerging (WHO) data appears inconsistent, with more robust evidence from multiple randomised, controlled studies published in peer-reviewed journals validating the clinical benefit of remdesivir.”
Gilead told Reuters that it was “unclear if any conclusive findings can be drawn” given what it called differences in how the trial was conducted from site to site and between the patients who received the medicine.
Race to find a treatment
Companies such as Gilead are racing to find a treatment for COVID-19. Some 1.1 million people have died and more than 40 million have been reported infected in the pandemic, and the global economy has been thrown into chaos.
Remdesivir was developed for Ebola, Reuters reports. It was quickly repurposed and has offered some hope for patients, although the WHO’s findings may shift the science focus to new monoclonal antibodies being developed by companies including Regeneron.
* Reuters reporting by Vishwadha Chander, Deena Beasley, Stephanie Ulmer-Nebehay and John Miller in Switzerland and Ludwig Burger in Frankfurt. Editing by Shinjini Ganguli, Devika Syamnath and Timothy Heritage.
Repurposed antiviral drugs for COVID-19: Interim WHO SOLIDARITY trial results
Uploaded on the preprint server medRxiv.
This article is a preprint and has not been peer-reviewed.
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
WHO expert groups recommended mortality trials in hospitalised COVID-19 of four re-purposed antiviral drugs.
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 randomised 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 randomised, with 2,750 allocated Remdesivir, 954 Hydroxychloroquine, 1,411 Lopinavir, 651 Interferon plus Lopinavir, 1,412 only Interferon, and 4,088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover.
1,253 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 hospitalised COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomised evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials.
Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19
New England Journal of Medicine. Published on 8 October 2020
The RECOVERY Collaborative Group
Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomised trials.
In this randomised, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalised with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality.
The enrolment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P=0.15).
Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27).
There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine.
Among patients hospitalised with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care.
Remdesivir for the Treatment of Covid-19 — Final Report
New England Journal of Medicine. Published on 8 October 2020.
John H Beigel, Kay M Tomashek, Lori E Dodd, Aneesh K Mehta, Barry S Zingman, Andre C Kalil, Elizabeth Hohmann, Helen Y Chu, Annie Luetkemeyer, Susan Kline, Diego Lopez de Castilla, Robert W Finberg, Kerry Dierberg, Victor Tapson, Lanny Hsieh, Thomas F Patterson, Roger Paredes, Daniel A Sweeney, William R Short, Giota Touloumi, David Chien Lye, Norio Ohmagari, Myoung-don Oh, Guillermo M Ruiz-Palacios, Thomas Benfield, Gerd Fätkenheuer, Mark G Kortepeter, Robert L Atmar, C Buddy Creech, Jens Lundgren, Abdel G Babiker, Sarah Pett, James D. Neaton, Timothy H Burgess, Tyler Bonnett, Michelle Green, Mat Makowski, Anu Osinusi, Seema Nayak, H Clifford Lane for the ACTT-1 Study Group Members
Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.
We conducted a double-blind, randomised, placebo-controlled trial of intravenous remdesivir in adults who were hospitalised with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalisation for infection-control purposes only.
A total of 1062 patients underwent randomisation (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test).
In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity).
he Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).
Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalised with Covid-19 and had evidence of lower respiratory tract infection.
Gilead questions WHO study that cast doubts on drug’s COVID-19 benefits – Reuters
Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results
Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. NNEJM full study
Remdesivir for the Treatment of Covid-19 — Final Report. NEJM full study