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Thursday, April 30, 2020

Clinical trial launched testing convalescent plasma in COVID-19

Montefiore Health System, Albert Einstein College of Medicine and NYU Langone have initiated a clinical trial evaluating the efficacy of convalescent plasma in COVID-19 patients.
Convalescent plasma is derived from patients who have recovered from the infection and have subsequently produced antibodies against the coronavirus.
The randomized study will enroll 300 patients who have had respiratory symptoms for less than one week, require some supplemental oxygen or have been hospitalized for less than four days. 50% will receive plasma containing anti-SARS-CoV-2 antibodies while 50% will receive a placebo.
Plasma therapy-related tickers: XBiotech (XBIT +5.9%), Cerus (CERS +1.7%), ThermoGenesis (THMO -6.2%), Kamada (KMDA +2.6%)
https://seekingalpha.com/news/3566136-clinical-trial-launched-testing-convalescent-plasma-in-covidminus-19-patients

Lockdown panic syndrome, and how to fix it

The worldwide pandemic over COVID-19, and the heavy-handed government response to it, has generated a wide range of reaction among patients. As a family physician and a psychiatrist, we have seen some patients adapting well. On the other hand, many feel anxious over the thought of getting the illness or experience other negative emotional responses resulting from the lockdown. Invasive public policy intervention always comes with a host of unanticipated consequences.
Politicians initially gave into their usual impulses to reassure rather than inform, calling for “business as usual,” and “nothing to see here.” But it quickly became evident that the disease spread fast and could be life-threatening in a minority of cases. In response, federal and state entities called for “social distancing, “hand and surface washing, and “hands off the face,” all of which seemed reasonable. Then, as the news media sensationalized their coverage, public officials became anxious and fell back on their all-time favorite method of problem-solving: risk management. Emergency statutes and orders have mandated masks, closings, and in some states, curfews.
Governors are deeming which businesses and services are to be considered essential or not. Some of our neighbors are mandated to work, despite the risk, while others are now unemployed or are forced to stay home and lose income. Other consequences of mandatory “stay at home” measures and deferred medical care include mental health and substance use disorders, other illnesses, and domestic violence. And of course, the economic damage caused by the lockdowns will also degrade patients’ ability to obtain medical care in the future.
In our practices, we are seeing patients make health compromises that might increase their susceptibility to the viral scourge. Some have become so anxious or depressed, due to fear stoked by the media, that they are unable to work. One potty-trained four-year-old patient had a curious manifestation. In the last month, as her entire routine changed, she had daily unpredictable urination, or incontinence: probably a disorder driven by all of the media blitz, adult anxiety, and related disruption.
Physicians, guided by the principle of “do no harm,” are always on the alert to side effects and unexpected reactions to their interventions. Physicians are expected to take responsibility for the “iatrogenic” harms they cause.
The side effects of government intervention might be dubbed “solonogenic” (after the historic Greek lawgiver), although accountability in a political context does not reach the standard of the medical model. Economist and philosopher Thomas Sowell put it this way: “It is hard to imagine a more stupid or more dangerous way of making decisions than by putting those decisions in the hands of people who pay no price for being wrong.” Patients beware: Politicians are not your doctors!
As a family physician and a psychiatrist with more than fifty years, collectively, of clinical experience, we are not the only ones to observe that the current intervention in the name of public health is so invasive and far-reaching that it has caused considerable amount of preventable mental illness in adults and children alike. Our colleagues are, no doubt, also spending considerable time treating patients’ mental health symptoms stemming from the government-caused crisis.
It is imperative to recognize these solonogenic harms so they can be treated properly by clinicians. It may not be possible to remove the mental irritant of public health orders right now, but their effects can be mitigated if we distance our minds from the parts of the guidance that irritate.
We propose the name “lockdown panic syndrome,” in order to highlight the public health intervention as the etiology of the mental disorder. Put simply, this syndrome consists of anxiety about the coronavirus and confinement at home that leads to paralysis rather than productive problem-solving. In some cases, it even results in loss of sphincter control — a rather transparent metaphor for the general problem we face. It is inherently anxiety-provoking and fatiguing to have one’s own judgment about managing the risks of everyday life preempted by the micro-risk-managing directives of public officials who are remote and unaccountable.
As physicians, we grapple with the same mental challenges as our patients. It is anxiety-provoking to be faced with the possibility of punishment if one does not practice medicine according to government edict, particularly when the authors of those directives are nonclinicians, remote, unaccountable, and concerned with the well-being of populations rather than individuals. Physicians beware: public officials will not be responsible for the clinical outcomes resulting from your compliance with their guidance!
How can lockdown panic syndrome be treated? Encourage patients to take back control over their own daily lives as much as they safely can. Tell patients that their own judgment about protecting themselves will be sound once they have vetted their information carefully and sought individualized guidance from their personal physicians. Patients can also be supported in taking the initiative to rebuild their own lives on their own terms, in safe and realistic ways, rather than waiting for the go-ahead from public officials.
Physicians can heal themselves by staying in charge of their own clinical decisions. As always, doctors interpret the scientific literature in the context of their own unique practice experiences.  Individualize treatment plans to the needs and values of each patient. Physicians will feel less anxious, and their morale will improve when they remind themselves that they are servants of their patients, not the state.
Public officials and the media could stop lockdown panic syndrome in its tracks by allowing physicians to treat the clinical problems created by COVID-19, and empowering patients to use their individual judgment and take responsibility for themselves and their families. Unfortunately, it may be too much to ask public officials to shelve their partisan agendas, but the rest of us, practicing physicians and patients, can partner together to make America a healthy nation again, mentally, physically, and perhaps we can learn to put politics in places less central in our minds.
Craig M. Wax is a family physician. Robert Emmons is a psychiatrist.
Lockdown panic syndrome, and how to fix it

Remdesivir results pile up, but what do they all mean?

The latest addition to remdesivir’s Covid-19 dataset paints a confusing picture, but it’s not necessarily bad.
In a market desperate for news of progress against the coronavirus pandemic even highly equivocal results are hailed as a triumph. Gilead’s 6% rise yesterday, plus another 3% after close, was down to the dubious result of the NIAID’s remdesivir trial as much as the uncontrolled data from the company’s own study of this antiviral.
Taken at face value, together with the failed but immature Chinese remdesivir data, Gilead looks to have gone two for three – a bald view that plays down the latest results’ shortcomings. But the NIAID and Gilead data are not a failure, either; detailed comparison of the findings does show hints of a benefit, and this could be enough.
For those struggling to keep up with this daily-shifting drama, there are now three remdesivir datasets out, in some form: a Chinese study, rigorously blinded and placebo-controlled but terminated prematurely; Gilead’s uncontrolled study; and the NIAID study, which was double-blind and placebo-controlled, but which had an adaptive design that to an extent undermines its findings.
The first reports of remdesivir’s activity in Covid-19, revealed separately, concerned compassionate use in 61 hospitalised subjects in a paper published in the NEJM in April; and a leak published in Stat of an internal meeting from a US hospital participating in Gilead’s studies. However, neither amounted to anything more than anecdotal case reports from which little definite could be gleaned.
Blinded dataset
This is why formal clinical trial data are important. Those from NIAID’s trial, toplined yesterday, showed remdesivir subjects recovering 31% faster than placebo recipients, which was said to be statistically significant. Confusingly, however, this contradicts the China trial, which showed no difference in time to clinical improvement between remdesivir and placebo.
The Chinese study had been powered to show a 15 versus 21-day improvement, and being terminated early is not a wholly convincing reason for its failure: numerically the difference was a highly disappointing 21 versus 23 days.
A crucial consideration when comparing across trials is that recruitment criteria differ. While both studies concerned hospitalised subjects, those in the NIAID trial look like they were less severe overall, something that the relatively better performance of its control arm seems to bear out.
Gilead’s own severe Covid-19 study, unveiled yesterday, muddies the waters further since it did not even have a control cohort (The winds change again for Gilead and remdesivir, April 29, 2020). And nothing is known about whether subjects’ baseline characteristics were balanced across cohorts, either in the Gilead or NIAID trial.
Cross-trial comparisons of remdesivir’s three datastes

China trial Gilead trial NIAID trial
Trial ID NCT04257656 NCT04292899 NCT04280705
Enrolment Halted at 237 (target 453)* 397 (target 6,000) 1,063
Covid-19 severity Hospitalised, confirmed lung involvement, ≤12 days since illness onset Hospitalised, severe, ≤4 days since PCR confirmation of disease** Hospitalised, ≤72 hours (some exceptions) since PCR confirmation of disease
Design Quadruple-blinded, placebo-controlled Open-label, uncontrolled, 2-cohort (5-day/10-day) Double-blinded, placebo-controlled
Primary endpoint Time to clinical improvement at day 28 Odds ratio for improvement at day 14^ Time to recovery^^
Result 21 days vs 23 days (HR=1.23, not stat sig) 54-65% had ≥2-point improvement 11 days vs 15 days (p<0.001)
Mortality result  14% vs 13% (not stat sig) 8-11% (no control group) 8% vs 12% (not stat sig)
*Terminated early because, China’s Covid-19 epidemic having been brought under control, no further eligible patients could be enrolled; **cohort of mechanically ventilated subjects was added in Apr; ^changed from normalisation of fever and oxygen saturation at day 14; ^^changed from disease severity improvement at day 15.
Indeed, the only hard (secondary) endpoint common to all three studies is mortality, and crucially none of the three has been able to show a statistically significant improvement, though numerically subjects on remdesivir tend to have a better chance of survival.
Rather, it is tinkering with trial design that could be most revealing: the Gilead study added mechanically ventilated subjects, perhaps because the effect in less severe patients was insufficiently pronounced, while the NIAID primary endpoint was changed from improvement on a scale that included death.
This is not to imply shenanigans, as one study was open-label and the other deliberately had an adaptive design. But the hints are that remdesivir might not, after all, have a major impact on preventing the death of people infected with Covid-19.
However, the fact that this is not on the cards need not spell disaster, and perhaps investors are right in not looking for a home run. At this stage of the pandemic, when some countries’ hospitals risk being overwhelmed by patient numbers, a drug that merely reduces the severity of disease could make a real difference.
Remdesivir might, just about, be capable of that.
https://www.evaluate.com/vantage/articles/news/trial-results/remdesivir-results-pile-what-do-they-all-mean

BofA cautions on Teladoc on potential competitive encroachment

In a note, Bank of America analyst Allen Lutz (Neutral/$194) warns clients that Teladoc’s (TDOC -6.2%) potential reach in the academic medical center market may be constrained after software developer Epic Systems chose Twilio (TWLO +2.3%) to power its telehealth app.
Shares are under pressure despite the company’s bullish forecast on revenue and visits.
https://seekingalpha.com/news/3567051-bofa-cautions-on-teladoc-on-potential-competitive-encroachment

Aveo Pharma up 40% after business update

AVEO Pharmaceuticals (AVEO +40.2%), fresh off a volatility halt, is up on a 15x surge in volume after its business update today. Key points:
Final survival data from its Phase 3 study, TIVO-3, of tivozanib in third- and fourth-line renal cell carcinoma (RCC) will be presented at the ASCO Virtual Scientific Program in late May/early June. [In December 2019, The Lancet Oncology published data from the study that showed a greater overall survival (OS) benefit for Bayer’s Nexavar (sorafenib)].
Last month it filed a U.S. marketing application for tivozanib for relapsed/refractory RCC. Per an agreement with the FDA, it will withdraw the application if the OS hazard ratio is greater than 1.00.
On the capital front, it says it had ~$33.6M in quick assets at the end of March, enough, along with payments from cost-sharing obligations and Fotivda royalties, to fund operations into Q2 2021.
Baird is one of the company’s bulls. It recently added it as a Fresh Pick and reiterated its Outperform rating and $15 (103% upside) price target.
https://seekingalpha.com/news/3567033-aveo-pharma-up-40-after-business-update

Gilead to be challenged to meet demand for remdesivir

Gilead Sciences (GILD +0.9%) will be hustling to produce sufficient quantities of antiviral remdesivir after the expected nod from regulators after two successful trials in COVID-19 patients.
It started with an inventory of ~5K doses when studies ramped up and now has ~50K which should fly off the shelves as soon as emergency use is authorized. It says its goal is to have “multiple millions” of courses by year-end.
Production is apparently no walk in the park, involving a series of chemical steps, a range of components and manual inspection of each filled vial, the last a labor-intensive step considering the volumes planned. It has been procuring raw materials for some time and has condensed the manufacturing process to 6-8 months from 9-12 months.
Initial quantities will be generally reserved for seriously ill patients.
https://seekingalpha.com/news/3567039-gilead-to-be-challenged-to-meet-demand-for-remdesivir

Retracted Study Claimed Broader Spread of Aerosolized Coronavirus

A study which found that aerosolized novel coronavirus could be spread nearly 15 feet — twice what health officials had believed — has been retracted, but the journal isn’t saying why.
Practical Preventive Medicine published the paper in early March. Titled “An epidemiological investigation of 2019 novel coronavirus diseases through aerosol-borne transmission by public transport,” the authors, from institutions in China, looked at the spread of the virus on a bus linked to one infected passenger.
According to the abstract:
This COVID-19 outbreak was transmitted by a public transport resulting in 11 confirmed cases including one asymptomatic case and two third-generation cases.The farthest transmission distance of COVID-19 in the airtight air-conditioning bus reached 4.5 meters. This contagious virus could float in the air for 30 minutes at least and cause infection.
The researchers concluded:
The COVID-19 has strong transmissibility and can be transmitted by aerosol in a closed environment. To prevent infection, personal protection should be done well when taking public transports,and the ventilation and fresh air volume in public transports should be guaranteed, and the cleaning and disinfection in the carriage should be done well.
Not surprisingly, the article received a significant amount of attention in the media, including coverage in the South China Morning Post and the Daily Mail , among other outlets. The two papers even published a schematic of the bus the researchers described.
The Chinese-language journal has stated that it retracted the paper, but the notice doesn’t say why. We emailed the publisher for more information but haven’t heard back. The corresponding author on the paper did not immediately respond to a request for comment.
There have been a handful of COVID-19 studies from China retracted, and speculation that at least some of the moves came after government pressure. Nature reported last week that:
Over the past two months, it appears to have quietly introduced policies that require scientists to get approval to publish — or publicize — their results, according to documents seen by Nature and some researchers.
As we wrote last month in Wired , articles about Covid-19 are coming in a torrent. We’re willing to bet the latest retraction won’t be the last.
https://www.medscape.com/viewarticle/929663