U.K. approves steroid after master protocol shows survival benefit in COVID-19

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The U.K. has approved dexamethasone to treat COVID-19, the same day an adaptive trial based in the country demonstrated the anti-inflammatory steroid increased survival. It is the first therapy to show a mortality benefit in a randomized, controlled trial.

The approval covers patients hospitalized with COVID-19 who require oxygen. The U.K. said it has stockpiled enough doses of the steroid to treat over 200,000 patients.

The rapid approval is a strong validation that master protocols provide the fastest path to definitive answers on COVID-19 treatments and vaccines. Master protocol trials enable multiple treatments to be evaluated in parallel using the same endpoints, data analysis methods and other protocol parameters. The trial arms share resources, such as a single control arm, and the structure’s adaptive design employs Bayesian statistics to get an early read on which treatments are working (see “U.K. Sets the Bar”).

A master protocol could also be the best way to establish a standardized treatment paradigm -- such as using antiviral remdesivir earlier in disease course, and reserving dexamethasone for sicker patients -- by determining the benefits of the two agents alone and in combination in different COVID-19 patient populations.

Remdesivir from Gilead Sciences Inc. (NASDAQ:GILD) was granted Emergency Use Authorization in the U.S. on the basis of data from NIH’s ACTT master protocol, and approved in Japan as Veklury. The antiviral is also under EMA review.

Reducing mortality

The RECOVERY trial, sponsored by the University of Oxford, enrolled 2,104 patients hospitalized with COVID-19 to receive 6 mg of dexamethasone either orally or intravenously for 10 days. The comparator arm consisted of 4,321 patients given standard-of-care treatment.

Dexamethasone reduced deaths by 35% in ventilated patients (rate ratio=0.65, 95% CI: 0.48, 0.88; p=0.0003) and by 20% in patients on oxygen support (rate ratio=0.80, 95% CI: 0.67, 0.96; p=0.0021). It had no benefit in patients who did not require respiratory support (rate ratio=1.22, 95% CI: 0.86,1.75; p=0.14).

For the two benefiting patient populations, Oxford also reported the number needed to treat (NNT) -- a statistic that describes how many people need to receive a treatment for one person to live instead of die.

To prevent one death, 25 patients receiving oxygen would need to be treated with dexamethasone; ventilated patients had an NTT of eight.

No other therapy has shown a mortality benefit to date.

Remdesivir did not lead to a statistically significant survival improvement in the ACTT trial, which enrolled 538 hospitalized patients to receive the antiviral, and 521 to receive placebo. The remdesivir arm had a mortality rate of 7.1%, vs. 11.9% for placebo (rate ratio=0.74, 95% CI: 0.50 to 1.10).

Additionally, subgroup analyses showed that remdesivir vs. placebo led to no difference in patients receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) as well as high-flow oxygen or non-invasive mechanical ventilation (see “NIH’s Detailed Remdesivir Data Show Ventilated COVID-19 Patients Unlikely to Benefit”).

NIH did not report an NNT for ACTT, but a rough calculation based on the difference between the two mortality rates suggests about 21 hospitalized patients would need to be treated with remdesivir to prevent one death. Data from Gilead’s 584-patient Phase III SIMPLE study in moderate COVID-19, however, suggests an NTT of 400 (see “More Data Needed to Determine Best Use of Remdesivir”).

Establishing a COVID-19 treatment paradigm will need to take into account when the two therapies are most effective, and in which patients. Antivirals are typically more effective the earlier they are given; and dexamethasone showed the most benefit in the sickest patients.

While there are at least eight adaptive master protocol trials for COVID-19, RECOVERY is the only with a dexamethasone arm. The trial is focused on repurposed therapies and does not have a remdesivir arm.

According to ClinicalTrials.gov, there are no studies under way comparing dexamethasone to remdesivir or testing a combination of the two.

Eight groups besides Oxford have started clinical trials of the steroid to treat COVID-19, and according to BioCentury’s COVID-19 Resource Center, there are at least 94 other immunosuppressants in the clinic to treat COVID-19.

Dexamethasone, an approved steroid, could also be a more inexpensive and readily available option than remdesivir. A 10-day treatment course costs about $15, based on a $150 wholesale acquisition cost for a 100-count supply of 6 mg pills.

Based on an assessment from ICER, assuming that remdesivir doesn’t show a mortality benefit, the antiviral could be cost effective at $390 per treatment course to meet the standard $50,000 per quality-adjusted life year threshold.

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