COVID: remdesivir helps a little, costs a lot; and convalescent plasma??

 A new trial of remdesivir for treatment of patients with moderate Covid-19 pneumonia found a statistically significant difference in clinical status with the medication, though the difference was of uncertain clinical importance (see covid remdesivir review jama2020 in dropbox, or doi:10.1001/jama.2020.16349) 

 

Details:

-- 580 for patients with confirmed SARS-CoV-2 infection by PCR and moderate Covid-19 pneumonia (pulmonary infiltrates and room air oxygen saturation >94%) were randomized to receive a 10-day course of remdesivir, a 5-day course of remdesivir, or standard care. Remdesivir was dosed at 200 mg on day one followed by 100 mg per day IV, in an open label trial in 105 hospitals in the US, Europe, and Asia between March 15 and April 18

-- median age 57, 39% women, 58% white/18% black/18% Asian/18% Hispanic, BMI 27, 84% were at clinical status 5 (see below)

-- 56% had cardiovascular disease at baseline, 42% hypertension, 40% diabetes, and 14% asthma

-- duration of hospitalization before the 1^st dose of medication: 2 days; duration of symptoms before 1^st dose: 8 days

-- concomitant medications: steroids 17%; hydroxychloroquine in 10% in the remdesivir groups, but 45% in standard care; lopinavir/ritonavir 5% of remdesivir groups vs 22% in standard care

-- primary endpoint was clinical status on day 11 on the 7-point ordinal scale:

    -- 1: death

    -- 2: hospitalized, requiring invasive mechanical ventilation or ECMO

    -- 3: hospitalized, requiring noninvasive ventilation or use high flow oxygen devices

    -- 4: hospitalized requiring low-flow supplemental oxygen

    -- 5: hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related or not to Covid-19)

    -- 6: hospitalized, not requiring supplemental oxygen or ongoing medical care

    -- 7: not hospitalized

-- secondary endpoint was proportion of patients with adverse events throughout the duration of the study

-- median length of treatment was 5 days for patients in the 5-day group and 6 days for those in the 10-day group

  

Results:

-- on day 11:

    -- remdesivir 5-day group: statistically significant higher odds of better clinical status distribution vs standard care, OR 1.65 (1.09-2.48), p=0.02

    -- no difference in the 10-day group vs standard care

-- by day 28: 9 patients had died (2 in the 5-day remdesivir group, 3 in the 10-day group, and 4 in the standard care group)

-- 76% of those on the 5-day remdesivir group completed the assigned treatment duration (most discontinuing treatment because of earlier hospital discharge); 38% of the 10-day group completed treatment, also mostly because of the hospital discharge

-- on exploratory efficacy endpoints, no significant differences between the 5-day or 10-day remdesivir groups and standard care for any of these endpoints:

    -- time to a 2-point or greater improvement in clinical status

    -- time to a 1-point of greater improvement in clinical status

    -- time to recovery

    -- time to discontinuation of oxygen support

    -- also, no difference in duration of oxygen therapy or hospitalization or in all-cause mortality

-- adverse events, remdesivir vs standard care: overall, 51% in the 5-day remdesivir group, 59% in the 10-day group, and 47% in the standard care group, with statistically significant difference between 10-day remdesivir group and standard care for nausea 10% vs 3%, hypokalemia in 6% vs 2%, and headache 5% vs 3%

 

Commentary:

-- it was notable in the study that there was a significant shift in clinical outcomes overall in those on remdesivir, though it was not clear of any real clinical benefit for any of the more specific endpoints

-- a prior double-blind randomized controlled trial of patients with severe Covid-19 treated with a 10-day course of remdesivir did find a significantly shorter time to recovery than placebo (11 days vs 15 days), and there was a strong trend towards mortality benefit that was not statistically significant. This trial did not show significant benefit for those with less severe disease. See http://gmodestmedblogs.blogspot.com/2020/05/covid-remdesivir-rct-finally.html

    -- as a result of this and another trial, the FDA granted Emergency Use Authorization of remdesivir for patients with severe Covid

 

Limitations of study:

-- the standard care group received many more potentially effective Covid medications, potentially distorting the effect of remdesivir and/or affecting the clinical endpoints differentially

-- this was an open label study, and there may have been conscious or unconscious differences in the non-study-based treatment of patients. Discharge decisions might also have been influenced by the group (e.g. were those on the 10-day IV remdesivir group kept longer in the hospital to receive their continued IV therapy?, did they get more attention from the staff overall??)

-- There may well have been very different criteria in different hospitals in different countries in terms of ancillary treatments, usual care treatments, decisions regarding use of oxygen or mechanical ventilation, lengths of stay in the intensive care unit: all of which might have affected outcomes

-- there were no data on virologic outcomes during the study

-- pretty much all of the patients were in ordinal scale clinical status 5 (hospitalized, not requiring supplemental oxygen by requiring ongoing medical care).  how does this study then generalize to those presenting with different clinical status?

    -- though, of note, 15% of them did receive supplemental oxygen on day one, prior to starting the study drug, so they actually received the meds at a different real clinical stage....

 

-- The Public Citizen just sent out a twitter reminder that Gilead is charging $3000 for remdesivir, though the drug was developed with more than $70 million of taxpayer dollars and costs them less than $10 to produce (see https://www.citizen.org/news/gileads-remdesivir-price-is-offensive/ )

    -- Gilead will be charging $3120 for typical patient with insurance

    -- public financial support for the development of remdesivir has been at least $70.5 million through federal grants and clinical trials

        -- based on available public data: Gilead received $34.5 million for the initial development of remdesivir, initially for Ebola virus; another $6 million of taxpayer support went to accelerate the development of remdesivir against coronaviruses (also with lots of help from publicly-supported NIH researchers); and at least $30 million went into public funding around the world to begin clinical trials (the NIH is running a trial that will cost at least $30 million this fiscal year alone). See https://www.citizen.org/article/the-real-story-of-remdesivir/

    -- based on these numbers, the Public Citizen suggests that the cost for treatment should be $1 per day; the cost-effective benchmark price would be $310 a day as suggested by the Institute for Clinical and Economic Review (ICER)

        -- but the typical charges will be 10 times that!!!!!

 

So, a not so impressive result for remdesivir in those with Covid-19 pneumonia, at least in the group not requiring supplemental oxygen. this study reinforces a few points:

-- we really do need RCTs to determine drug efficacy. Earlier observational studies for remdesivir did suggest more benefit (eg, see http://gmodestmedblogs.blogspot.com/2020/04/covid-remdesivir-may-help-asymptomatic.html). And, early observational studies on hydroxychloroquine did as well  (eg see http://gmodestmedblogs.blogspot.com/2020/07/covid-hydroxychloroquine-works-at-least.html).

    --and, the recent Trump administration pushing for convalescent plasma transfusion was also only based on observational studies such as http://gmodestmedblogs.blogspot.com/2020/06/covid-convalescent-plasma-seems-to-help.html.  Ongoing RCTs will hopefully elucidate whether convalescent plasma will go the same way as remdesivir and hydroxychloroquine or will actually be a useful therapy beyond its intended political consequences of making Trump look like he’s actually doing something against this pandemic 

        --for the FDA statement, which basically does comment that convalescent plasma is not approved but will have expanded access, see https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma ). their strong statement is that convalescent plasma "may be effective" (https://www.fda.gov/media/141480/download). 

        --for the FDA noting that the emergency use authorization is “another achievement in administration’s fight against pandemic” : https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment (still unclear this is an achievement.  and, what exactly were the other achievements???? seems like there have been >30,000 excess US deaths because Trump minimized/denied/suppressed/lied about the seriousness of Covid-19. is that an achievement???)

        -- it should be noted that the 37% reduction in mortality with convalescent plasma, as touted by Trump, is actually a relatively small absolute difference of about 11% vs 7% (i.e. 4% different). And the results of RCTs tend to be less impressive than observational studies...

-- and, as noted above, Gilead pharmaceuticals is going to be more than double-dipping: getting taxpayers to fund over $70 million for drug development, then effectively charging taxpayers really high rates, about 300 times the cost of the production of the medication...

geoff

 

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