Conflicting Remdesivir Trial Results Released; Experts Urge More Research
SARS-CoV-2 (red), the virus that causes COVID-19, attacking a dying cell (blue).

Preliminary results of a clinical trial released by the US National Institutes of Health (NIH) found that in patients who received remdesivir recovered faster than those who did not receive the treatment.

The largest trial to date, which followed 1063 patients, found that patients who received the drug recovered on average 4 days earlier than those who did not. Additionally, the death rate was 8% in the group that received remdesivir compared to 11.6% in the control group, although this result was not statistically significant.

“What [this trial] has proven is that a drug can block the virus,” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases (NIAID), told reporters in a rare show of optimism on Wednesday. Fauci has emerged as the most reliable expert voice on the US national coronavirus taskforce.

He reflected that the moment he saw the results were reminiscent of the moment the NIAID reviewed preliminary results from the first large-scale study on the use of antiviral combination therapy for HIV/AIDS – the first in a series of technological breakthroughs against that virus.

“We think it’s really opening the door to the fact that we now have the capability of treating [COVID-19],” he said.

In seemingly contradictory news, a new study published Wednesday in The Lancet found that remdesivir did not significantly speed recovery or reduce deaths in patients suffering from severe COVID-19 in Wuhan, China. 

Some 14% of patients in the remdesivir treatment group died after 28 days, compared to 13% in the group that did not receive the treatment. The Lancet study followed 237 adult patients with severe COVID-19 in Wuhan, China, the original epicentre of the pandemic.

“Unfortunately, our trial found that while safe and adequately tolerated, remdesivir did not provide significant benefits over placebo”, says lead researcher Bin Cao from China-Japan Friendship Hospital and Capital Medical University in China, in a press release. The formal publication in the Lancet confirmed initial reported findings that were accidentally leaked on the World Health Organization’s clinical trials registry last week.

Independent experts have urged for continued research in order to create a larger pool of conclusive evidence to judge remdesivir’s effectiveness on COVID-19. The Wuhan study had been terminated early due to lack to new patient enrollment, resulting in a much smaller sample size.

“Each individual study is at heightened risk of being incomplete [in a pandemic situation],” wrote John Norrie, professor of Medical Statistics from the University of Edinburgh, in a separate Lancet comment. “Pooling data across several such ‘underpowered’ but high-quality studies looks like it will be our best way to obtain robust insights into what works, safely, and on whom.”

Remdesivir, a failed Ebola antiviral developed by Gilead Sciences, was tapped as one of a handful of promising COVID-19 treatments for a global Solidarity trial coordinated by WHO. It has only been available to patients under emergency or compassionate use protocols, which allow patients to access experimental medications in the absence of any known treatments for COVID-19.

WHO experts declined to pass judgement on remdesivir in a press briefing Wednesday. Maria Van Kerkhove, WHO’s Technical Lead on the COVID-19 crisis, remarked, “Typically you don’t have one study that will come out that will be a game changer. Once we look at all of the studies, and we judge them collectively we can come away with some kind of a conclusion of ‘yes we see an effect’ or ‘no we don’t.’”

WHO Executive Director of Health Emergencies, Mike Ryan, said that he had not yet read the full study, but “fervently hoped” that one of the many drugs under investigation around the world would help improve clinical outcomes. 

In a parallel move, Gilead unveiled early results from a trial exploring the efficacy of different durations of remdesivir treatment on Monday. The so-called SIMPLE trial found that treatment outcomes were similar in patients with severe COVID-19 receiving a 10 day course and those receiving a 5 day course. However, the Gilead trial results fail to assess remdesivir efficacy against a control group, making The Lancet study the first published RCT to explore whether remdesivir has any overall benefit to COVID-19 patients.

Findings from the Lancet Study – Small Sample Size a Major Limitation
3D molecular structure of remdesivir, an antiviral drug

The Lancet study found no significant differences in the death rate or amount of virus in the body between patients who received remdesivir and those who did not. 

Overall, 22 of 158 patients died in the remdesivir group compared with 10 of the 78 in the placebo group after 28 days. Treatment with remdesivir did not reduce the amount of SARS-CoV-2, the virus that causes COVID-19, in the body or respiratory tract compared to the control group.

However, patients who were treated within 10 days of illness onset had a slightly lower mortality rate at 11% compared to 15% in those who did not receive remdesivir. Similarly, patients who were on invasive mechanical ventilation were weaned off an average of 8.5 days earlier compared to those who did not receive the drug. No significant differences were noted between the groups in overall length of oxygen support, length of hospital stay, or time to discharge or death.

Still, the authors say that the results must be interpreted with caution due to the small sample size in the study.

“This is not the outcome we hoped for, but we are mindful that we were only able to enroll 237 of the target 453 patients because the COVID-19 outbreak was brought under control in Wuhan,” said Cao. “What’s more, restrictions on bed availability resulted in most patients being enrolled later in the disease course, so we were unable to adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.”

Despite the limitations, independent experts praised the study’s protocol, including the use of a well-designed control group. All patients enrolled in the study received standard care including treatment with lopinavir–ritonavir, interferons, and corticosteroids.

“Most other released data did not have a proper comparison group, while this trial has a group given standard treatment but no remdesivir, allocated at random. The description of the methods makes it clear that this was a well-conducted trial,” said Stephen Evans, a professor in the Department of Medical Statistics at the London School of Hygiene & Tropical Medicine, in a separate comment.

WHO Director-General to Reconvene Emergency Committee for COVID-19

WHO Director-General Dr Tedros Adhanom Ghebreyesus will reconvene the emergency committee under the international health regulations on Thursday to reassess the status of the COVID-19 pandemic.

The meeting will take place three months after Dr Tedros declared COVID-19 a ‘public health emergency of international concern’ (PHEIC) on 30 January. The group of experts was deadlocked over whether COVID-19 constituted a PHEIC, the highest level of alarm the WHO can raise, in late January, meeting several times to debate the issue. 

WHO is committed to transparency and accountability in accordance with the International Health Regulations. I will reconvene the emergency committee tomorrow,” said the Director-General on Wednesday.

However, Dr Tedros refrained from making public comment on the plans for the 74th World Health Assembly, WHO’s largest and most important annual meeting of Member States, usually planned for mid-May. Sources told Health Policy Watch on Tuesday that the Organization was considering for the first time a one-day virtual World Health Assembly on 18 May – focusing only on COVID-19. 

European Countries and US States Slowly Unwind Lockdown Restrictions – Even as the US Surpasses 1 Million Infections

The US crossed the threshold of 1 million coronavirus cases on Tuesday, confirming 1,013,168 cases and 58,368 deaths as of Wednesday morning.

Even so, many states are gearing to reopen – Alabama will replace its stay-at-home order with a safer-at-home mandate beginning Thursday, allowing employers and beaches to reopen “subject to good sanitation and social distancing rules,” Governor Kay Ivey said. Florida Governor Ron DeSantis stated on Wednesday that he will outline reopening plans during an Oval Office meeting with President Donald Trump.

Still, public health experts fear a second, deadlier wave of coronavirus in the fall. Anthony Fauci said, “I’m almost certain it will come back, because the virus is so transmissible and it’s globally spread,” during an Economic Club of Washington webinar.

Meanwhile, several European nations are eyeing a gradual end to their coronavirus lockdowns as infection rates slow and death rates decline. Swiss councillor Alain Berset announced in a Federal Council press conference on Wednesday that the country’s three-step re-opening will be sped up due to a dramatic decrease in the infection curve. The council has now authorized the reopening of more businesses than was previously allowed for 11 May, also authorizing restaurants and gyms to reopen, with appropriate sanitation and social distancing methods. Switzerland has recorded 29,407 coronavirus cases with 1408 deaths.

Spain is hoping for a return to relative normality by the end of June, said officials in Madrid, announcing a four-phase plan on Tuesday to lift the toughest set of restrictions as the daily death toll fell to 301, less than a third of a record high of 950 in early April. Meanwhile in France, widespread coronavirus testing will be launched on 11 May so that the country can slowly unwind its lockdown to avoid an economic meltdown.

Still, Europe remains the worst-affected continent, with over 1.2 million confirmed cases and more than 125,000 deaths. Spain, Italy, France and the United Kingdom are the most affected countries with 236,899, 201,505, 169,053 and 162,350 cases respectively; each has recorded over 20,000 deaths.

Total cases of COVID-19 as of 8:30PM CET 29 April 2020, with cumulative case distribution globally.

Gauri Saxena contributed to this story

This story was updated 4 May.

Image Credits: NIAID, ChiralJon – Remdesivir 3D, Johns Hopkins CSSE.

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