Remdesivir accelerates COVID-19 recovery in US randomised trial, results from another remdesivir trial from China

By Denise Baez

NEW YORK -- April 30, 2020 -- In this DG Alert, we look at results from the first 2 randomised controlled trials (RCTs) of remdesivir for coronavirus disease 2019 (COVID-19).

Preliminary data from the first RCT evaluating remdesivir for hospitalised patients with severe COVID-19 and lung involvement in the United States showed that those who received remdesivir recovered faster than placebo-treated patients. 

The Adaptive COVID-19 Treatment Trial (ACTT) began on February 21, 2020, and is sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

An independent data and safety monitoring board (DSMB) overseeing the trial met on April 27, 2020, to review data from 1,063 patients and share their interim analysis with the study team. Based upon their review of the data, they noted that remdesivir was better than placebo from the perspective of the primary endpoint, which is time to recovery -- defined as being well enough for hospital discharge or returning to normal activity level.

Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo.

Results also suggested a survival benefit, with a mortality rate of 8.0% in the remdesivir group compared with 11.6% in the placebo group (P = 0.059).

More detailed information about the trial results, including more comprehensive data, will be available in a forthcoming report.

Findings from another, but smaller RCT of remdesivir, published in The Lancet, arrived at different conclusions. 

The study, which involved 237 critically ill adults with COVID-19 from 10 hospitals in Wuhan, China, showed that treatment with remdesivir did not speed-up recovery compared with placebo. 

However, the authors cautioned that interpretation of their findings is limited because the study was stopped early by the DSMB because of difficulty recruiting patients after the outbreak in Wuhan was brought under control.

“Unfortunately, our trial found that while safe and adequately tolerated, remdesivir did not provide significant benefits over placebo”, said Bin Cao, MD, China-Japan Friendship Hospital, Beijing, China. “This is not the outcome we hoped for, but we are mindful that we were only able to enrol 237 of the target 453 patients because the COVID-19 outbreak was brought under control in Wuhan. 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.”

Between February 6, 2020, and March 12, 2020, the researchers enrolled 237 adults hospitalised with severe laboratory-confirmed severe COVID-19. To be eligible, patients had to enter the study within 12 days of symptom onset, have pneumonia confirmed by chest imaging, and oxygen saturation of ≤94%. Participants were randomised to daily infusions of remdesivir (n = 158; 200 mg on day 1 followed by 100 mg on days 2 to 10) or placebo infusions (n = 79) for 10 days. One patient in the placebo group withdrew before receiving treatment. Patients were permitted concomitant use of lopinavir/ritonavir, interferons, and corticosteroids.

The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of 2 levels on a 6-point ordinal scale of clinical status (from 1 = discharged to 6 = death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment.

Use of remdesivir was not associated with a difference in time to clinical improvement. Average time to clinical improvement was 21 days for the remdesivir group versus 23 days for the placebo group (hazard ratio [HR] = 1.23; 95% confidence interval [CI], 0.87-1.75). 

Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of ≤10 days (mean 18 days vs 23 days; HR = 1.52; 95% CI, 0.95-2.43). 

Death within 28 days of randomisation was similar between the remdesivir and placebo groups (14% vs 13). However, patients treated with remdesivir within 10 days of illness onset had a lower mortality rate (11% vs 15%), although the difference was not statistically significant. 

Duration of invasive mechanical ventilation was a mean 7 days in the remdesivir group compared with a mean 15.5 days in the placebo group, but the difference was not statistically significant.

Treatment with remdesivir did not result in significant reductions in viral load or detection of the virus in the upper or lower respiratory tract compared with placebo.

“Participants in our trial were less ill, and treated earlier in their disease course, compared with a recent observational study of patients with COVID-19, who received remdesivir on compassionate grounds,” said Ronghui Du, MD, Wuhan Lung Hospital. “Yet, remdesivir did not provide greater benefits in our study population as expected. Ongoing clinical trials of remdesivir will provide important additional information about whether and under what circumstances it may provide benefit.”

The authors noted several limitations to their study, including that stopping early gives insufficient power to detect differences in clinical outcomes, and it did not account for the possible emergence of reduced susceptibility to remdesivir because of a lack of data at the time. They pointed out that the frequent use of corticosteroids in patients in the study might have aided viral production. 

Reference: https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

SOURCE: National Institutes of Health, The Lancet

COVID-19

APRIL 29, 2020

Pregnant women with COVID-19 have comparable clinical outcomes with reproductive-aged non-pregnant women

Pregnant women have comparable clinical course and outcomes compared with reproductive-aged non-pregnant women when infected with SARS-CoV-2, according to a study published in the International Journal of Infectious Diseases. 

The study also concluded that no evidence supported vertical transmission of COVID-19 in the late stage of pregnancy including vaginal delivery.

Xu Qiancheng, The Central Hospital of Wuhan, Wuhan, China, and colleagues retrospectively reviewed medical records of pregnant and reproductive-aged non-pregnant women hospitalized with COVID-19 from January 15 to March 15, 2020. The severity of disease, virus clearance time, and length of hospital stay were measured as the primary interest and the vertical transmission potential of COVID-19 was also assessed.

The study enrolled 82 patients (28 pregnant women, 54 reproductive-aged non-pregnant women) with laboratory confirmed COVID-19. The median age of pregnant women was 30 (interquartile range [IQR] = 26.75-32) years that was similar to that of non-pregnant women of 31 (IQR = 28-35) years. The median gestational age of the pregnant women on admission was 38 (IQR = 36.5-39) weeks. Comorbidities were not frequently reported in both groups.

According to study data, the severity of disease was comparable in the two groups. Apart from 2 (7.1%) patients in pregnant women presented as mild type, most patients were categorized as moderate pneumonia (24 in pregnant women (85.7%) vs. 53 in non-pregnant women (98.1%)) and only 2 (7.1%) patients in pregnant women and 1 (1.9%) in non-pregnant women were classified as severe pneumonia. 

Univariate regression indicated no association between pregnancy and the severity of disease (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.08-5.15; p = 0.76), virus clearance time (hazard ratio [HR] 1.16; 95% CI, 0.65-2.01; p = 0.62), and length of hospital stay (HR 1.10, 95% CI 0.66-1.84; p = 0.71). 

Of those pregnant women, 3 (10.7%) were in the first trimester, 1 (3.6%) in the second trimester and 24 (85.7%) in the third trimester. All pregnant women in the first and second trimester terminated pregnancy due to concerns of radiological examination and COVID-19. Two pregnant women in early third trimester continued pregnancy (30, and 33 gestational weeks, respectively). There were 22 pregnant women who delivered 23 live births either by cesarean section (17, 60.7%) or vaginal delivery (5, 17.9%) and no neonate was infected with SARS-CoV-2. The authors noted that the potential of vertical transmission is still uncertain due to the limited data and further study is warranted.

The authors noted several limitations including the majority of the patients included were presented as mild to moderate, which limited the interpretation of the results, and that more severe patients might be admitted to other hospitals, other than the study hospital.

The authors also added that all the pregnant women who delivered were infected with SARS-CoV-2 in the late stage of pregnancy, and the probability of vertical transmission during the early trimesters could not be assessed. 

Reference: https://www.ijidonline.com/article/S1201-9712(20)30280-0/fulltext

SOURCE: International Journal of Infectious Diseases

Herd immunity’ without a vaccine could mean 840,000 coronavirus deaths in California

• Lisa M. Krieger
• PUBLISHED: April 16, 2020 at 11:39 a.m. | UPDATED: April 16, 2020 at 1:45 p.m.
• Categories:California News, News

Gov. Gavin Newsom provides an update on the coronavirus situation in California.

Amid Gov. Gavin Newsom’s scenario of a post-sheltering world, there are two chilling words: herd immunity.

Tomorrow’s tableau — waiters with masks, distant desks, split-shift schools — will be the new normal, he told reporters in his Tuesday press briefing, “at least until we have herd immunity.”

The phrase came up again as he explained what’s ahead, as “we begin to transition into suppression, ultimately, on our way to herd immunity” and then a vaccine. He repeated it later, describing progress “towards herd immunity.”

What’s herd immunity? It’s when so many people have been infected and develop protective antibodies that a virus runs out of hosts. That’s likely what happened in the 1918-1919 flu pandemic, which killed 20 to 40 million people and then vanished.

What does “herd immunity” look like in the age of COVID-19? Without a vaccine, about 28 million infected Californians.

Based on current estimates, about 5 percent of infected people — or roughly 1.4 million Californians — would get severely ill. Of these, 840,000 could die, although there’s hope of holding that number down.

This bleak strategy may be the only way through a pandemic that is causing profound economic, social and education paralysis. A vaccine, which also could provide herd immunity, is 12 to 18 months away, with likely additional months needed to scale up manufacturing and distribution.

It’s also very scary. The governor’s promised “light at the end of the tunnel” could instead be the glaring halogens over an ICU bed.

As if in synchrony, on Tuesday scientists at Harvard’s prestigious Harvard T.H. Chan School of Public Health also conceded the inevitability of continued infections.

In a set of mathematical models published in the journal Science, they proposed a strategy of intermittent restrictions that would help us approach herd immunity as slowly as possible, so hospitals aren’t overwhelmed.

Rather than hiding from the virus, a goal is to spread out the number of infections at any one time, so fewer people die, they concluded.

“Several rounds of social distancing will be required to get us to ‘herd immunity’ in the absence of vaccination,” said Harvard epidemiologist and study co-author Dr. Marc Lipsitch.

This is the concept: If a large number of people — the “herd” — are immune, then a vulnerable person in the middle of the herd is unlikely to be exposed. Life goes on.

Based on early estimates of this virus’s infectiousness, we likely will need at least 70% of the population to be immune to have herd protection, according to Johns Hopkins School of Public Health epidemiologists Gypsyamber D’Souza and David Dowdy.

Why 70%? The more contagious the virus, the more people need to be vaccinated for herd immunity to work; contagious viruses are more likely to find that unprotected person in the herd. Immunity to measles is reached at 90-95%; for polio, it’s 80-85%.

Right now, we’re nowhere near that. It’s unclear exactly how far away we are, because COVID-19 antibody tests just now are coming online. Back in late February and early March, only two out of nearly 3,000 people with respiratory symptoms were later found to have had the virus, according to a Stanford study.

There’s a lot else we still don’t know. For instance, how many Californians would die with this strategy? We can only make estimates.  So far, the virus has killed 3% of Californians known to be infected. But the true death rate is almost certainly much lower, because many of those infected haven’t been tested. The vast majority of infected people – 80%, it is estimated – have only mild symptoms.

How much protection do antibodies confer on people who have recovered? The jury is still out on that.

When will new medicines blunt the impact of illness? We don’t know that, either.

Could we reach that magic 70% target by infecting just young people, segregating the sick and elders? Perhaps. But they’d pay a price. New data show that youth aren’t invincible; up to one-fifth of infected people ages 20-44 have been hospitalized — and 2%-4% required an ICU rescue.

The goal is to reach “herd immunity” without overshooting it, incurring unnecessary heartbreak, the Harvard experts said.

Dr. Sonia Angell, director of the California Department of Public Health, seems braced for this hard choice — and rather than denying it, is preparing.

“As we change interventions, as we make it possible for people to move around more freely, we do know that infections could increase,” she said Tuesday. “And indeed, there may be more demands on our hospitals. So it is essential that we ensure our ability to care for the sick.”

Diplomatically, she warned: “As we start to loosen up, there is the possibility for more movement of COVID-19. And we need to make sure that our hospitals are prepared. Some of the key questions we’ll be asking ourselves include, do we have adequate bed capacities, staff and supplies such as ventilators and masks?”
It would be easy to create herd immunity very quickly. Lifting all restrictions now would accelerate the process. It would also swamp our hospitals and fill our cemeteries.

A go-slow approach means that more of us will survive to join the herd. Studies show that death rates are highest — surpassing 10% — in Italy and Spain, where health systems were overwhelmed by a huge explosion of cases. In contrast, the death rate is 2.4% in Germany, 2.1% in South Korea and 0.5% in Iceland.

The goal is to infect the most while killing the least. That demands an exquisitely calibrated state strategy: counting each illness, then lifting or imposing very targeted restrictions to create smaller and better-managed outbreaks.

To reach herd immunity, “there’s no light switch here” of all-or-nothing restrictions, said Newsom. “It’s more like a dimmer … toggling back and forth.”