COVID-19 trial: Remdesivir accelerates recovery and improves survival

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A clinical trial by the US National Institutes of Health found that hospitalised patients with advanced COVID-19 and lung involvement who received remdesivir recovered 31% faster and had better survival than those treated with a placebo. A separate NIH animal study found that early treatment with remdesivir significantly reduced clinical disease and lung damage.

Hospitalised patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo, according to a preliminary data analysis from a randomised, controlled trial involving 1,063 patients, which began on 21 February. The trial (known as the Adaptive COVID-19 Treatment Trial, or ACTT), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is the first clinical trial launched in the US to evaluate an experimental treatment for COVID-19.

An independent data and safety monitoring board (DSMB) overseeing the trial met on 27 April to review data and shared 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, time to recovery, a metric often used in influenza trials. Recovery in this study was 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% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059).

More detailed information about the trial results, including more comprehensive data, will be available in a forthcoming report. As part of the US Food and Drug Administration‘s commitment to expediting the development and availability of potential COVID-19 treatments, the agency has been engaged in sustained and ongoing discussions with Gilead Sciences regarding making remdesivir available to patients as quickly as possible, as appropriate.

The trial closed to new enrollments on 19 April. NIAID will also provide an update on the plans for the ACTT trial moving forward. This trial was an adaptive trial designed to incorporate additional investigative treatments.

The first trial participant in the ACTT trial was an American who was repatriated after being quarantined on the Diamond Princess cruise ship that docked in Yokohama, Japan, and volunteered to participate in the study at the first study site, the University of Nebraska Medical Centre/Nebraska Medicine, in February 2020. A total of 68 sites ultimately joined the study – 47 in the US and 21 in countries in Europe and Asia.

Remdesivir, developed by Gilead Sciences, is an investigational broad-spectrum antiviral treatment administered via daily infusion for 10 days. It has shown promise in animal models for treating SARS-CoV-2 (the virus that causes COVID-19) infection and has been examined in various clinical trials.

Early treatment with the experimental antiviral drug remdesivir significantly reduced clinical disease and damage to the lungs of rhesus macaques infected with SARS-CoV-2, the coronavirus that causes COVID-19, according to NIH scientists.

The study was designed to follow dosing and treatment procedures used for hospitalised COVID-19 patients being administered remdesivir in a large, multi-centre, clinical trial led by NIH’s NIAID. The findings are not yet peer-reviewed and should not be considered clinical advice, but are being shared to assist the public health response to COVID-19.

A study detailing the development of the rhesus macaque model of mild- to-moderate human disease, was conducted by the same team of NIAID scientists.

The current study of remdesivir, a drug developed by Gilead Sciences and NIAID-supported investigators, involved two groups of six rhesus macaques. One group of monkeys received remdesivir and the other animals served as an untreated comparison group. Scientists infected both groups with SARS-CoV-2. Twelve hours later the treatment group received a dose of remdesivir intravenously, and then received a daily intravenous booster dose thereafter for the next six days. The scientists timed the initial treatment to occur shortly before the virus reached its highest level in the animals’ lungs.

Twelve hours after the initial treatment, the scientists examined all animals and found the six treated animals in significantly better health than the untreated group, a trend that continued during the seven-day study. They report that one of the six treated animals showed mild breathing difficulty, whereas all six of the untreated animals showed rapid and difficult breathing. The amount of virus found in the lungs was significantly lower in the treatment group compared to the untreated group, and SARS-CoV-2 caused less damage to the lungs in treated animals than in untreated animals.

The investigators note that the data supports initiating remdesivir treatment in COVID-19 patients as early as possible to achieve maximum treatment effect. The authors, from NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, also note that while remdesivir helped prevent pneumonia, it did not reduce virus shedding by the animals. “This finding is of great significance for patient management, where a clinical improvement should not be interpreted as a lack of infectiousness,” they write.

Abstract
Background: Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection.
Methods: To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy.

Results: In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue.
Conclusions: Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

Authors
Brandi N Williamson, Friederike Feldmann, Benjamin Schwarz, Kimberly Meade-White, Danielle P Porter, Jonathan Schulz, Neeltje van Doremalen, Ian Leighton, Claude Kwe Yinda, Lizzette Pérez-Pérez, Atsushi Okumura, Jamie Lovaglio, Patrick W Hanley, Greg Saturday, Catharine M Bosio, Sarah Anzick, Kent Barbian, Thomas Cihlar, Craig Martens, Dana P Scott, Vincent J Munster, Emmie de Wit

The Guardian reports that head of NIAID, Dr Anthony Fauci called the early results “quite good news”. “What it has proven is that a drug can block this virus,” Fauci said. “This will be the standard of care.”

Professor Mahesh Parmar, director of the MRC Clinical Trials Unit at University College London, who has overseen the trial in the EU, said: “This is the first large-scale international trial to report on the use of the drug remdisivir to treat patients hospitalised with COVID-19.

“These results are very promising indeed. They show that this drug can clearly improve time to recovery. Before this drug can be made more widely available, a number of things need to happen: the data and results need to be reviewed by the regulators to assess whether the drug can be licensed and then they need assessment by the relevant health authorities in various countries. While this is happening we will obtain more and longer-term data from this trial, and other ones, on whether the drug also prevents deaths from COVID-19.”

The report says experts agreed the results were hopeful. Peter Horby, professor of emerging infectious diseases and global health at the University of Oxford, is running the Recovery trial of repurposed drugs that could be useful in COVID-19. He hopes to include remdesivir but has not yet managed to secure supplies because of global demand. He was involved in a trial of the drug in China, however.

“The four days shorter time to clinical improvement in COVID patients receiving remdesivir reported by Dr Fauci from the NIAID trial is similar to the five days difference we saw in our trial in Chinese patients treated within 10 days of illness onset,” he said.

“This suggests that this is a real effect and that remdesivir can help patients with COVID-19. We need to see the full results, but if confirmed this would be a fantastic result and great news for the fight against COVID-19. Our trial and the NIAID trial are quite similar in design and a joint – analysis of the combined data will provide even greater certainty over the effectiveness of remdesivir. The next steps are to get the full data out and work on equitable access to remdesivir.”

Derek Hill, professor of medical imaging at University College London, pointed out that this was a randomised controlled trial, in which half the patients were given placebo, so the results were more reliable than in observational studies where all patients receive the drug.

“These are promising preliminary results,” he said. “In normal times this drug would still be many months or years away from being approved for use on patients. But given these extraordinary circumstances, medicine regulators may decide to provide special fast approval in the near future, provided that there are ongoing controlled studies of its safety and efficacy.”

NIH/National Institute of Allergy and Infectious Diseases

NIH material

bioRxiv abstract

Gilead Sciences material

Full report in The Guardian

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