UK Gov Approves as U.S. HHS Places Dexamethasone on Treatment Guidelines; Demand Soars & More Data Needed

Jun 29, 2020 | ARDS, Blog, Corticosteroid, COVID-19, Dexamethasone, News, Positive Results, Respiratory, SARS-CoV-2

UK Gov Approves as U.S. HHS Places Dexamethasone on Treatment Guidelines; Demand Soars & More Data Needed

The government of the United Kingdom (UK) approved dexamethasone, a commonly prescribed steroid treatment, as a COVID-19 therapy thanks to the successful University of Oxford RECOVERY trial evidencing that low doses of the steroid reduce deaths in hospitalized COVID-19 patients who were on ventilators by one third or receiving oxygen support by one fifth. Although, the Oxford investigators found that the steroid failed to benefit those COVID-19 patients that were hospitalized but not requiring respiratory support. Approved for use across the UK National Health Service, dexamethasone is the first drug worldwide to evidence a reduction of deaths among severely ill COVID-19 patients. The U.S. Health and Human Services has placed the drug in its COVID-19 treatment guidelines. Now market demand appears to soar while more data is required to better understand the impact of this low-cost, generally available corticosteroid.

Approval in the UK & Acceptance in the U.S.

Although the UK government has stockpiled enough dexamethasone doses to treat about 200,000 people, the UK is a near epicenter of the global contagion with 311,151 cases as of June 29, 2020 and 43,550 deaths. The UK has the third highest death rate after Brazil and the United States.

The United States, the world’s largest market for pharmaceutical products, has recently added both dexamethasone and remdesivir to the U.S. Health and Human Services (HHS) treatment guidelines reported HHS Secretary Alex Azar at a coronavirus task force briefing. Secretary Azar declared, “We’ve added dexamethasone, a very low-cost steroid, to our treatment guidelines, and we believe its reasonable to assume that other corticosteroids which may be more readily accessible in some places would have similar immunological effects,” as reported by Bloomberg Law.

Not a Panacea

This low-cost steroid only helps patients that are hospitalized and that are in need of help breathing through ventilation and oxygen assistant. The study revealed dexamethasone didn’t help hospitalized patients without such needs which is the majority. Moreover, the drug will do nothing to help individuals with mild COVID-19 infection, which is by far the majority of cases. Dexamethasone doesn’t prevent an individual from contracting the virus either.

The BMJ summarized the June 22 preprint paper, noting that out of the 2104 patients studied in the RECOVERY trial 454 (21.6%) o 2104 patients allocated to dexamethasone and 1065 of 4321 (24.6%) patients allocated to usual care died within 28 days (age adjusted rate ration 0.83 (95% CI (0.74 to 0.92); P <0.001). Launched in March 2020, the RECOVERY trial’s dexamethasone arm involves 176 NHS hospitals.

The RECOVERY trial dexamethasone arm ended recruitment June 8, 2020. Eligible and consenting patients were allocated in a 2:1 ration to a usual standard of care or to a usual standard of care plus dexamethasone 6 mg once daily (oral or intravenous) for a 10 day maximum (or till discharge if sooner).

Among the group of patients receiving oxygen, 275 of the 1279 taking the steroid died compared with 650 of the 2604 receiving standard of care. This is a reduction in mortality from 25.0% to 21.5% (0.80(0.70 to 0.92); P=0.002). The researchers found that in the group of patients receiving no respiratory support the steroid did not reduce mortality rate.

600%+ Increase in Demand

Not surprisingly, within days of the Oxford report, demand for dexamethasone in the United States exploded by more than 600%, according to data from health care performance company Vizient. Consequently, Vizient member hospitals are seeing fill rates for the products at 54%.

Physicians charged with treating the most severely ill COVID-19 patients take note of news that a drug is effective for treating patients requiring oxygen or a ventilator, reports Dan Kistner, PharmD, group senior vice president, pharmacy solutions at Vizient. Kistner reported that on the day of the announcement demand for dexamethasone vials and tablets spiked 183% and just a week later aggregate demand boomed 610% and the fill rate metric lowered from 97% down to 54%.

Are there Shortages of Dexamethasone?

Thus far, it appears there won’t be any material shortages and Vizient’s Kistner remains cautiously optimistic that drug manufactures and distributors can adjust to increase the availability of the drug and manage the unfolding situation. But the growing orders evidence the need for manufacturers’ resiliency into pharmaceutical inventory capacity. Vizient’s Kistner calls the drug a “Workhorse drug for hospitals” and notes that several manufacturers and distributors operate in the supply chain. The situation undoubtedly is being monitored by health systems (public and private) and hospitals as cases of COVID-19 continue to rise.

Dexamethasone

This corticosteroid has been in use since the 1960s to reduce inflammation in a wide array of conditions from inflammatory disorders to certain cancers. First made in 1957 by Philip Showalter Hench and initially approved in 1961, the drug is on the World Health Organization’s List of Essential Medicines. By 2017, it was the 321st most commonly prescribed medication in the United States with over one million prescriptions.

Dexamethasone is used to treat many conditions from rheumatic problems and skin diseases to severe allergies, asthma and chronic obstructive lung disease to many other use cases. It is often used with a medication that has greater mineralocorticoid effects such as fludrocortisone. It can be taken orally, injected into the muscle or used intravenously.

Proceed with Caution

In a recent ABC report, Dr. Todd Ellerin, director of infectious diseases at South Shore Health, warned that those patients with milder COVID-19 illness should stay away from this drug, noting the “risk of the medication likely outweighs the benefits.” University of Utah’s Erin Fox, a drug shortage expert, suggested that in fact there is lots of data demonstrating the benefit and risks steroids can bring to critically ill patients, hence “many doctors may want to wait for additional data.” Dr. Rajesh T. Gandhi implores people to help behave in such as ways as to “flatten the curve” from wearing masks and practice social distancing to frequent hand-washing, commenting for ABC, “We know how to prevent the cases.”

Ongoing Clinical Trials Targeting use of Dexamethasone & COVID-19 Patients

Erin Fox from the University of Utah suggests more data is needed; who could argue with that? Interestingly, 13 clinical trials involving dexamethasone and COVID-19 in some way, are now disclosed in Clincaltrials.gov website. TrialSite News offers a brief summary of few relevant studies below.

A recently completed observational study (limited case series) may not be considered evidence to  support the University of Oxford findings but nonetheless is notable. Clinical trial NCT04445506 is sponsored by The Miriam Hospital in Rhode Island; investigators reviewed the charts of 50 SARS-CoV02 patients with pneumonia and moderate to severely elevated CRP and worsening hypoxemia who were treated with early, short-term dexamethasone. The results were recently uploaded to preprint server medRxiv by principal investigators Vijairam Selvaraj, MD, Kwame Dapaah-Afriyie, MD, Arkadiy Finn, MD, and Timothy Flanigan, MD. The study authors report that they demonstrate that timely, short-term use of systemic corticosteroids among hospitalized patients with hypoxic respiratory failure due to SARS-CoV-2 was well tolerated with good outcomes including the reduction in inpatient mortality, CRP levels, requirement for mechanical ventilation and escalation of care. However, the investigators acknowledge as this is a limited case series (not a randomized controlled trial) that the results may not offer concrete evidence toward the benefit of corticosteroids in COVID-19 patients.

In Spain, Dr. Negrin University Hospital initiated a Phase 4 clinical trial titled “Efficacy of Dexamethasone Treatment for Patients with ARDS caused by COVID-19” targeting 200 patients. The study runs through till October 2020. See NCT04325061. The study is led an international expert in ARDS and lung protection ventilation, Dr. Jesus Villar, Group Chief of the Center for Biomedical Research in Respiratory Diseases in Madrid and Senior Scientists of the Research Unit at the Hospital Universitario Dr. Negrin in Las Palmas, Spain.

University of Colorado initiated a Phase 2a clinical trial NCT04360876 titled “Targeted Steroids for ARDS Due to COVID-19 Pneumonia: A Pilot Randomized Clinical Trial,” which runs from May to December 2020. Targeting 90 patients, the study team investigates the safety and efficacy of targeted corticosteroids in mechanically ventilated patients with the hyper-inflammatory sub phenotype of ARDS due to COVID-19. For those that fit the inclusion criteria, investigators will administer dexamethasone intravenous 20mg daily for 5 days followed by 10mg daily for 5 days.

While in France, Assistance Publique – Hôpitaux de Paris sponsors this study led by principal investigator Jean François, TIMSIT, Pr, with two hypothesis, including 1) that corticosteroid therapy benefits patients with severe COVID-19 infection admitted in ICU in terms of survival, and 2) that in the subset of patients free of mechanical ventilation  at admission, either Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) allows to reduce intubation rate safely during COVID-19 related acute hypoxemic respiratory failure. Enrolling 550 patients, the French trial NCT04344730 runs from April 2020 through December 2020.

Call to Action: It would appear Dexamethasone may help reduce mortality in severe COVID-19 cases involving ventilation or oxygen support, however more data would certainly support the claims. TrialSite News monitors Dexamethasone studies ongoing and will update the TrialSite Network. Sign up for the daily newsletter.

Source: Vizient

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