COVID-19 medical discussion

[naija 2868]

some humor

 

[Skipper 6136]

More Attia medical stuff way over my head:  https://threader.app/thread/1248626276794949632

[Txzen 498]

It's pretty dubious - basically, someone did some molecular modeling and said that Covid could bind heme in red blood cells, and that would be a major mechanism for the clinical outcome. It hasn't been proven that this is occurring, it's not very likely based on current understanding of the mechanism of coronoviruses, and the research is a bit shite. 

[Homercles 10206]

So does this mean Ann Margaret’s not coming?

[zork 629]

possible lab success, from 4-6-20 report

Quote

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

 

Quote

...

Herein, we show that the ribonucleoside analog β-D-N⁴-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir.

...

https://stm.sciencemag.org/content/early/2020/04/03/scitranslmed.abb5883

Edited April 11, 2020 by zork

[Anastasis 23475]

20 minutes ago, zork said:

possible lab success, from 4-6-20 report

 

https://stm.sciencemag.org/content/early/2020/04/03/scitranslmed.abb5883

N=0 humans involved. 

[GRHorn 105]

On 4/9/2020 at 7:24 PM, GringoSalado said:

Siap

https://www.statnews.com/2020/04/08/doctors-say-ventilators-overused-for-covid-19/

 

With ventilators running out, doctors say the machines are overused for Covid-19

By SHARON BEGLEY @sxbegle

APRIL 8, 2020

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HEALTH

With ventilators running out, doctors say the machines are overused for Covid-19

By SHARON BEGLEY @sxbegle

APRIL 8, 2020

A fuel cell stack testing engineer tests ventilator oxygen at Bloom Energy in Sunnyvale, Calif. The company has switched over to refurbishing ventilators as an increasing number of patients experience respiratory issues as a result of Covid-19.BETH LABERGE/POOL PHOTO VIA AP

Even as hospitals and governors raise the alarm about a shortage of ventilators, some critical care physicians are questioning the widespread use of the breathing machines for Covid-19 patients, saying that large numbers of patients could instead be treated with less intensive respiratory support.

If the iconoclasts are right, putting coronavirus patients on ventilators could be of little benefit to many and even harmful to some.

What’s driving this reassessment is a baffling observation about Covid-19: Many patients have blood oxygen levels so low they should be dead. But they’re not gasping for air, their hearts aren’t racing, and their brains show no signs of blinking off from lack of oxygen.

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That is making critical care physicians suspect that blood levels of oxygen, which for decades have driven decisions about breathing support for patients with pneumonia and acute respiratory distress, might be misleading them about how to care for those with Covid-19. In particular, more and more are concerned about the use of intubation and mechanical ventilators. They argue that more patients could receive simpler, noninvasive respiratory support, such as the breathing masks used in sleep apnea, at least to start with and maybe for the duration of the illness.

Support STAT: If you value our coronavirus coverage, please consider making a one-time contribution to support our journalism.

“I think we may indeed be able to support a subset of these patients” with less invasive breathing support, said Sohan Japa, an internal medicine physician at Boston’s Brigham and Women’s Hospital. “I think we have to be more nuanced about who we intubate.”

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That would help relieve a shortage of ventilators so critical that states are scrambling to procure them and some hospitals are taking the unprecedented (and largely untested) step of using a single ventilator for more than one patient. And it would mean fewer Covid-19 patients, particularly elderly ones, would be at risk of suffering the long-term cognitive and physical effects of sedation and intubation while being on a ventilator.

None of this means that ventilators are not necessary in the Covid-19 crisis, or that hospitals are wrong to fear running out. But as doctors learn more about treating Covid-19, and question old dogma about blood oxygen and the need for ventilators, they might be able to substitute simpler and more widely available devices.

An oxygen saturation rate below 93% (normal is 95% to 100%) has long been taken as a sign of potential hypoxia and impending organ damage. Before Covid-19, when the oxygen level dropped below this threshold, physicians supported their patients’ breathing with noninvasive devices such as continuous positive airway pressure (CPAP, the sleep apnea device) and bilevel positive airway pressure ventilators (BiPAP). Both work via a tube into a face mask.

In severe pneumonia or acute respiratory distress unrelated to Covid-19, or if the noninvasive devices don’t boost oxygen levels enough, critical care doctors turn to mechanical ventilators that push oxygen into the lungs at a preset rate and force: A physician threads a 10-inch plastic tube down a patient’s throat and into the lungs, attaches it to the ventilator, and administers heavy and long-lasting sedation so the patient can’t fight the sensation of being unable to breathe on his own.

 

In this video, we look at how ventilators work, and how they are used to treat patients with Covid-19.

But because in some patients with Covid-19, blood-oxygen levels fall to hardly-ever-seen levels, into the 70s and even lower, physicians are intubating them sooner. “Data from China suggested that early intubation would keep Covid-19 patients’ heart, liver, and kidneys from failing due to hypoxia,” said a veteran emergency medicine physician. “This has been the whole thing driving decisions about breathing support: Knock them out and put them on a ventilator.”

To be sure, many physicians are starting simple. “Most hospitals, including ours, are using simpler, noninvasive strategies first,” including the apnea devices and even nasal cannulas, said Greg Martin, a critical care physician at Emory University School of Medicine and president-elect of the Society of Critical Care Medicine. (Nasal cannulas are tubes whose two prongs, held beneath the nostrils by elastic, deliver air to the nose.) “It doesn’t require sedation and the patient [remains conscious and] can participate in his care. But if the oxygen saturation gets too low you can achieve more oxygen delivery with a mechanical ventilator.”

The question is whether ICU physicians are moving patients to mechanical ventilators too quickly. “Almost the entire decision tree is driven by oxygen saturation levels,” said the emergency medicine physician, who asked not to be named so as not to appear to be criticizing colleagues.

That’s not unreasonable. In patients who are on ventilators due to non-Covid-19 pneumonia or acute respiratory distress, a blood oxygen level in the 80s can mean impending death, with no room to give noninvasive breathing support more time to work. Physicians are using their experience with ventilators in those situations to guide their care for Covid-19 patients. The problem, critical care physician Cameron Kyle-Sidell told Medscape this week, is that because U.S. physicians had never seen Covid-19 before February, they are basing clinical decisions on conditions that may not be good guides.

“It’s hard to switch tracks when the train is going a million miles an hour,” said Kyle-Sidell, who works at a New York City hospital. “This may be an entirely new disease,” making ventilator protocols developed for other conditions less than ideal.

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As doctors learn more about the disease, however, both frontline experience and a few small studies are leading him and others to question how, and how often, mechanical ventilators are used for Covid-19.

The first batch of evidence relates to how often the machines fail to help. “Contrary to the impression that if extremely ill patients with Covid-19 are treated with ventilators they will live and if they are not, they will die, the reality is far different,” said geriatric and palliative care physician Muriel Gillick of Harvard Medical School.

Researchers in Wuhan, for instance, reported that, of 37 critically ill Covid-19 patients who were put on mechanical ventilators, 30 died within a month. In a U.S. study of patients in Seattle, only one of the seven patients older than 70 who were put on a ventilator survived; just 36% of those younger than 70 did. And in a study published by JAMA on Monday, physicians in Italy reported that nearly 90% of 1,300 critically ill patients with Covid-19 were intubated and put on a ventilator; only 11% received noninvasive ventilation. One-quarter died in the ICU; 58% were still in the ICU, and 16% had been discharged.

Older patients who do survive risk permanent cognitive and respiratory damage from being on heavy sedation for many days if not weeks and from the intubation, Gillick said.

To be sure, the mere need for ventilators in Covid-19 patients suggests many in the studies were so critically ill their chances of survival were poor no matter what care they received.

But one of the most severe consequences of Covid-19 suggests another reason the ventilators aren’t more beneficial. In acute respiratory distress syndrome, which results from immune cells ravaging the lungs and kills many Covid-19 patients, the air sacs of the lungs become filled with a gummy yellow fluid. “That limits oxygen transfer from the lungs to the blood even when a machine pumps in oxygen,” Gillick said.

As patients go downhill, protocols developed for other respiratory conditions call for increasing the force with which a ventilator delivers oxygen, the amount of oxygen, or the rate of delivery, she explained. But if oxygen can’t cross into the blood from the lungs in the first place, those measures, especially greater force, may prove harmful. High levels of oxygen impair the lung’s air sacs, while high pressure to force in more oxygen damages the lungs.

Related: 

A system to allocate scarce ventilators and ICU beds gains traction for not counting any group out

In a letter last week in the American Journal of Respiratory and Critical Care Medicine, researchers in Germany and Italy said their Covid-19 patients were unlike any others with acute respiratory distress. Their lungs are relatively elastic (“compliant”), a sign of health “in sharp contrast to expectations for severe ARDS.” Their low blood oxygen might result from things that ventilators don’t fix. Such patients need “the lowest possible [air pressure] and gentle ventilation,” they said, arguing against increasing the pressure even if blood oxygen levels remain low. “We need to be patient.”

“We need to ask, are we using ventilators in a way that makes sense for other diseases but not for this one?” Gillick said. “Instead of asking how do we ration a scarce resource, we should be asking how do we best treat this disease?”

Researchers and clinicians on the front lines are trying. In a small study last week in Annals of Intensive Care, physicians who treated Covid-19 patients at two hospitals in China found that the majority of patients needed no more than a nasal cannula. Among the 41% who needed more intense breathing support, none was put on a ventilator right away. Instead, they were given noninvasive devices such as BiPAP; their blood oxygen levels “significantly improved” after an hour or two. (Eventually two of seven needed to be intubated.) The researchers concluded that the more comfortable nasal cannula is just as good as BiPAP and that a middle ground is as safe for Covid-19 patients as quicker use of a ventilator.

“Anecdotal experience from Italy [also suggests] that they were able to support a number of folks using these [non-invasive] methods,” Japa said.

To be “more nuanced about who we intubate,” as she suggests, starts with questioning the significance of oxygen saturation levels. Those levels often “look beyond awful,” said Scott Weingart, a critical care physician in New York and host of the “EMCrit” podcast. But many can speak in full sentences, don’t report shortness of breath, and have no signs of the heart or other organ abnormalities that hypoxia can cause.

“The patients in front of me are unlike any I’ve ever seen,” Kyle-Sidell told Medscape about those he cared for in a hard-hit Brooklyn hospital. “They looked a lot more like they had altitude sickness than pneumonia.”

Because U.S. data on treating Covid-19 patients are nearly nonexistent, health care workers are flying blind when it comes to caring for such confounding patients.  But anecdotally, Weingart said, “we’ve had a number of people who improved and got off CPAP or high flow [nasal cannulas] who would have been tubed 100 out of 100 times in the past.” What he calls “this knee-jerk response” of putting people on ventilators if their blood oxygen levels remain low with noninvasive devices “is really bad. … I think these patients do much, much worse on the ventilator.”

That could be because the ones who get intubated are the sickest, he said, “but that has not been my experience: It makes things worse as a direct result of the intubation.” High levels of force and oxygen levels, both in quest of restoring oxygen saturation levels to normal, can injure the lungs. “I would do everything in my power to avoid intubating patients,” Weingart said.

One reason Covid-19 patients can have near-hypoxic levels of blood oxygen without the usual gasping and other signs of impairment is that their blood levels of carbon dioxide, which diffuses into air in the lungs and is then exhaled, remain low. That suggests the lungs are still accomplishing the critical job of removing carbon dioxide even if they’re struggling to absorb oxygen. That, too, is reminiscent of altitude sickness more than pneumonia.

The noninvasive devices “can provide some amount of support for breathing and oxygenation, without needing a ventilator,” said ICU physician and pulmonologist Lakshman Swamy of Boston Medical Center.

One problem, though, is that CPAP and other positive-pressure machines pose a risk to health care workers, he said.  The devices push aerosolized virus particles into the air, where anyone entering the patient’s room can inhale them. The intubation required for mechanical ventilators can also aerosolize virus particles, but the machine is a contained system after that.

“If we had unlimited supply of protective equipment and if we had a better understanding of what this virus actually does in terms of aerosolizing, and if we had more negative pressure rooms, then we would be able to use more” of the noninvasive breathing support devices, Swamy said.

About the Author

Sharon Begley

Senior Writer, Science and Discovery

Sharon covers science and discovery.

 sharon.begley@statnews.com

 @sxbegle

Tags

CORONAVIRUS

HOSPITALS

INFECTIOUS DISEASE

RESPIRATORY

Republish this article 

 

 

An interview I shared a while back with Italian Er doc said they were having success with Cpap but patients wore hoods to protect against aerosolization. I have never seen those in the wild in the Us though. 
 

 

[Bruno Sardine 147]

Doomsayer alert. Yes, it's the South China Morning Post.

https://www.scmp.com/news/china/society/article/3079443/coronavirus-could-target-immune-system-targeting-protective

But the story’s source is a peer-reviewed article (I think) in a reputable scientific journal.

https://www.nature.com/articles/s41423-020-0424-9

It's a Chinese study with one researcher based in the US. Says the disease attacks the immune system itself. MERS does the same thing, but less effectively.

[Anastasis 23475]

Pretty good graphic from JAMA review that summarizes the different therapeutics being explored. 

 

[Bevo Num1 1021]

Pretty good graphic from JAMA review that summarizes the different therapeutics being explored. 
 

Is there a Karen virus in there too?

[Anastasis 23475]

Negative results from open-label randomized controlled trial of HCQ. (note pre-print, this is not peer reviewed.)

https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1 

Participants 150 patients hospitalized with COVID-19. 75 patients were assigned to HCQ plus SOC and 75 were assigned to SOC alone (control group).

Interventions HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). 

Main outcome measures The primary endpoint was the 28-day negative conversion rate of SARS-CoV-2. The assessed secondary endpoints were negative conversion rate at day 4, 7, 10, 14 or 21, the improvement rate of clinical symptoms within 28-day, normalization of C-reactive protein and blood lymphocyte count within 28-day. Primary and secondary analysis was by intention to treat. Adverse events were assessed in the safety population.

Results The overall 28-day negative conversion rate was not different between SOC plus HCQ and SOC group (Kaplan-Meier estimates 85.4% versus 81.3%, P=0.341). Negative conversion rate at day 4, 7, 10, 14 or 21 was also similar between the two groups. No different 28-day symptoms alleviation rate was observed between the two groups.

Edited April 15, 2020 by Anastasis

[Shaddie 1651]

8 hours ago, Anastasis said:

Negative results from open-label randomized controlled trial of HCQ. (note pre-print, this is not peer reviewed.)

https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1 

Participants 150 patients hospitalized with COVID-19. 75 patients were assigned to HCQ plus SOC and 75 were assigned to SOC alone (control group).

Interventions HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). 

Main outcome measures The primary endpoint was the 28-day negative conversion rate of SARS-CoV-2. The assessed secondary endpoints were negative conversion rate at day 4, 7, 10, 14 or 21, the improvement rate of clinical symptoms within 28-day, normalization of C-reactive protein and blood lymphocyte count within 28-day. Primary and secondary analysis was by intention to treat. Adverse events were assessed in the safety population.

Results The overall 28-day negative conversion rate was not different between SOC plus HCQ and SOC group (Kaplan-Meier estimates 85.4% versus 81.3%, P=0.341). Negative conversion rate at day 4, 7, 10, 14 or 21 was also similar between the two groups. No different 28-day symptoms alleviation rate was observed between the two groups.

So your saying I should steal my dogs heart worm medicine? 

[Anastasis 23475]

11 minutes ago, Shaddie said:

So your saying I should steal my dogs heart worm medicine? 

On to the next. 

[Shaddie 1651]

1 minute ago, Anastasis said:

On to the next. 

Shit!!! I know who the wife likes more so the meds will be gone by the time I get home. 

[Captainant 27680]

Crossposting from the shitposting thread:

Haven't seen anything on surly yet about the new data coming in from France on HCQ treatment for COVID-19, but it looks like it's ineffective against Rona at the hospitalization stage. From the abstract:

This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47-1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation. Interpretation These results do not support the use of HCQ in patients hospitalised for documented SARS-CoV-2-positive hypoxic pneumonia.

[Anastasis 23475]

Pretty well executed retrospective analysis of VA data.

https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf

 

ABSTRACT BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence.

METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARSCoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented.

RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group.

CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

[Nice Guy Eddie 13515]

In short, the initial US studies are that hydroxychloroquine appears to have a higher fatality rate than patients not treated with it? Who saw that one coming...

[UT_OB1 2224]

This seems like it should be a straightforward answer to get, but I’m having trouble finding it. What is the % hospitalized by age group. Everything I’ve read indicates odds are very low for the 30-40 age group and high for 65+, but I’ve only found it expressed as hospitalization rate per 100k, and I don’t think that is the number I’m looking for. About the best I could find was the overall at 15% of people who get covid get hospitalized. 

[RayDog 682]

On 4/22/2020 at 1:37 AM, Anastasis said:

Pretty well executed retrospective analysis of VA data.

https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf

 

ABSTRACT BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence.

METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARSCoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented.

RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group.

CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

Given that the zinc ionophore mechanism may be how chloroquine works it takes a real idiot to run such a study and not have a group that receives zinc supplements. 

[Anastasis 23475]

2 minutes ago, RayDog said:

Given that the zinc ionophore mechanism may be how chloroquine works it takes a real idiot to run such a study and not have a group that receives zinc supplements. 

LOL. It was a retrospective analysis of EMR data collected in real world setting, not an interventional study. You don't get to travel back through time to make sure that you have a Zn arm in the cohort. 

[RayDog 682]

14 minutes ago, Anastasis said:

LOL. It was a retrospective analysis of EMR data collected in real world setting, not an interventional study. You don't get to travel back through time to make sure that you have a Zn arm in the cohort. 

So no doctors included zinc? I don't believe that.

[Anastasis 23475]

3 minutes ago, RayDog said:

So no doctors included zinc? I don't believe that.

It's not mentioned in most (any?) of the treatment guidelines. There are a few trials underway that co-administer zn and vitamins with HCQ. There are many that do not. 

http://www.med.umich.edu/asp/pdf/adult_guidelines/COVID-19-treatment.pdf

https://covid19treatmentguidelines.nih.gov/introduction/

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

 

[RayDog 682]

Chris Martenson does a good critique of the VA study. He gets into detail starting around the 15 minute mark.

 

 

[Anastasis 23475]

Not sure who that is, what he training is, or what his motivations are, but he is way out of his element.  He doesn't even know what propensity score adjustment is, and suggests that the authors do not describe their PS methodology (20:30).  These are pretty common, if not basic, methods used in pharmacoepidemiology. The PS methodology are described in sufficient detail on page 9.  That is a garbage review, convincing only to people who share some non-reality based optimism re: HCQ and don't know enough to recognize his basic lack of understanding of the study methods, strengths and limitations.

The VA study has strengths and weaknesses just like every study.  The primary limitation in my estimate would be the limited generalizability. VA setting, all males, race breakdown. It is not definitive in any regard. But it is one more negative study to add to the pile for HCQ, and a US-based one at that. 

Edited April 23, 2020 by Anastasis

[zork 629]

On 4/22/2020 at 8:58 PM, Anastasis said:

Not sure who that is, what he training is, or what his motivations are, but he is way out of his element.  He doesn't even know what propensity score adjustment is, and suggests that the authors do not describe their PS methodology (20:30).  These are pretty common, if not basic, methods used in pharmacoepidemiology. The PS methodology are described in sufficient detail on page 9.  That is a garbage review, convincing only to people who share some non-reality based optimism re: HCQ and don't know enough to recognize his basic lack of understanding of the study methods, strengths and limitations.

The VA study has strengths and weaknesses just like every study.  The primary limitation in my estimate would be the limited generalizability. VA setting, all males, race breakdown. It is not definitive in any regard. But it is one more negative study to add to the pile for HCQ, and a US-based one at that. 

Just an interesting, to me, anecdotal set of images:(try and open both pictures on the screen at the same time:

https://ourworldindata.org/grapher/total-covid-deaths-per-million

https://ourworldindata.org/grapher/incidence-of-malaria

Maybe it is just a coinkydink or possibly just a non-sequitor to this thread.  To me though it is stunning the near mirror of the two pictures.  Seems like there might be something going on or maybe it is just a lack of world travelers to the malaria regions or some other things perhaps.

[Anastasis 23475]

How could anyone have ever predicted these problems?  Can't wait to get a hot take from PeakProsperity.com.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2765270

Abstract

Importance  There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug.

Objective  To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19.

Design, Setting, and Participants  This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon.

Interventions  Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days).

Main Outcomes and Measures  Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4.

Results  Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).

Conclusions and Relevance  The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19.

Edited April 24, 2020 by Anastasis

[bluto 4932]

Just an interesting, to me, anecdotal set of images:(try and open both pictures on the screen at the same time:
https://ourworldindata.org/grapher/total-covid-deaths-per-million
https://ourworldindata.org/grapher/incidence-of-malaria
Maybe it is just a coinkydink or possibly just a non-sequitor to this thread.  To me though it is stunning the near mirror of the two pictures.  Seems like there might be something going on or maybe it is just a lack of world travelers to the malaria regions or some other things perhaps.

I’m gonna go with 3rd world countries not having shit for testing to confirm the positivity of the deaths. Look at how much of a total shit show it’s been here. One African city burned a damn center to the ground bc they didn’t want it as a neighbor.

[Horn Dog 9875]

This stroke shit in young/ middle age healthy, sometimes asymptomatic patients is freaking me out

https://www.washingtonpost.com/health/2020/04/24/strokes-coronavirus-young-patients/

[Anastasis 23475]

Curious as to thoughts on the board regarding potential strategies to speed vax develop, and the potential ethical implications?

We hear 18 months or longer for vax development, but there are potentially ways to speed the development. Creates an interesting dilemma. 

 

https://www.usatoday.com/story/news/health/2020/05/05/coronavirus-vaccine-challenge-trial-ethics-covid-19/3061009001/

Vaccine trials can take decades. In the race against COVID-19, we don’t even have years.

To have a vaccine by next summer will require both luck and cutting corners never cut before, putting once seemingly academic questions about vaccine testing suddenly front and center.

Current rules are meant to protect volunteers from harm, but with the global death count from the coronavirus over 250,000, scientists are asking: Is it acceptable to deliberately infect healthy people with a disease that could kill them, and for which there is no cure?

It's called a challenge trial, and increasing scientists say the answer is yes.

The tried and true method would be to vaccinate tens of thousands of people, let them go about their daily, socially distanced lives and see who gets sick, knowing some small number would have anyway. That takes time. 

To speed up the process, some researchers are planning to give volunteers experimental vaccines and then infect them with SARS-CoV-2, the virus that causes COVID-19. 

“You’re weighing risks and benefit to the individual versus benefit to society as a whole,” said David Magnus, director of the Stanford Center for Biomedical Ethics at Stanford University.

The ethical quandary will be fast upon us. As of Tuesday, eight candidate vaccines were in clinical evaluation, four in China, one in Britain, one in the European Union and two in the United States, according to the World Health Organization. None are yet at Phase III trials, in which a vaccine is tested on large numbers of people to see if it works, is safe or has side effects.

Typically, such trials would be years away. Now, they could begin this year. Last week the Trump administration created Operation Warp Speed to cut development of a vaccine by at least eight months.

The Food and Drug Administration, which regulates vaccines, is looking hard at the scientific, ethical and feasibility questions raised by such a drastically shortened schedule.

"A formal determination about any specific human challenge trial proposal would be made by the FDA in the context of all the information that is available at that time," said spokesman Michael Felberbaum. 

Exactly when challenge trials will happen or what guidelines will be changed to make them possible have not been revealed.

One thing, however, is certain. To meet such a timeline, what happens next will be extraordinary.

...

COVID-19 challenge trials

Scientists hope to speed up the process for the coronavirus vaccine by running tests for each phase at the same time. In a normal scenario, each part of each phase of testing would be completed and carefully analyzed before the next one was begun. That’s partly for safety and effectiveness but also to save money by not continuing down paths that lead to dead ends.

This time, companies and nonprofits are pouring billions into the search. The rules also are being loosened. The FDA is working closely with companies that have SARS-CoV-2 vaccine trials underway to streamline the process as much as possible.

Phase III is the conundrum. Usually, researchers watch tens of thousands of volunteers as they go about their normal lives to see if they become infected. With COVID-19, because volunteers would still be following social distancing guidelines, few of them would even be exposed to the virus. That's partly why the group must be so large.

“Then we would use statistical techniques to see if there were fewer cases than we would expect there should have been among those vaccinated,” said Paul Root Wolpe, director of the Center for Ethics at Emory University.

In a challenge trial, volunteers are purposefully infected with the virus. The number could be much smaller because most would get sick. The time would be shorter because COVID-19 appears within two weeks.

It’s an ethical minefield. Some percentage of the volunteers, no matter how young and healthy, could die.

For that reason challenge trials are done only with diseases where there’s a 100% cure, said Susan Ellenberg,a professor of biostatistics, medical ethics and health policy at the University of Pennsylvania School of Medicine.

Even when there is a cure, taking part is no fun. When challenge trials were launched for malaria and cholera, participants got very sick.

“The volunteers had lots of diarrhea and vomiting, but they were standing by with IV fluids and antibiotics. so the people who took part were miserable but there was very low risk of actual permanent harm or death,” said Stanford’s Magnus.

With COVID-19, the death rates aren’t even known, and the one current potential treatment, remdesivir, appears only to lessen the duration of the illness.

[Brisketexan 105157]

4 minutes ago, Anastasis said:

Curious as to thoughts on the board regarding potential strategies to speed vax develop, and the potential ethical implications?

We hear 18 months or longer for vax development, but there are potentially ways to speed the development. Creates an interesting dilemma. 

 

https://www.usatoday.com/story/news/health/2020/05/05/coronavirus-vaccine-challenge-trial-ethics-covid-19/3061009001/

Vaccine trials can take decades. In the race against COVID-19, we don’t even have years.

To have a vaccine by next summer will require both luck and cutting corners never cut before, putting once seemingly academic questions about vaccine testing suddenly front and center.

Current rules are meant to protect volunteers from harm, but with the global death count from the coronavirus over 250,000, scientists are asking: Is it acceptable to deliberately infect healthy people with a disease that could kill them, and for which there is no cure?

It's called a challenge trial, and increasing scientists say the answer is yes.

The tried and true method would be to vaccinate tens of thousands of people, let them go about their daily, socially distanced lives and see who gets sick, knowing some small number would have anyway. That takes time. 

To speed up the process, some researchers are planning to give volunteers experimental vaccines and then infect them with SARS-CoV-2, the virus that causes COVID-19. 

“You’re weighing risks and benefit to the individual versus benefit to society as a whole,” said David Magnus, director of the Stanford Center for Biomedical Ethics at Stanford University.

The ethical quandary will be fast upon us. As of Tuesday, eight candidate vaccines were in clinical evaluation, four in China, one in Britain, one in the European Union and two in the United States, according to the World Health Organization. None are yet at Phase III trials, in which a vaccine is tested on large numbers of people to see if it works, is safe or has side effects.

Typically, such trials would be years away. Now, they could begin this year. Last week the Trump administration created Operation Warp Speed to cut development of a vaccine by at least eight months.

The Food and Drug Administration, which regulates vaccines, is looking hard at the scientific, ethical and feasibility questions raised by such a drastically shortened schedule.

"A formal determination about any specific human challenge trial proposal would be made by the FDA in the context of all the information that is available at that time," said spokesman Michael Felberbaum. 

Exactly when challenge trials will happen or what guidelines will be changed to make them possible have not been revealed.

One thing, however, is certain. To meet such a timeline, what happens next will be extraordinary.

...

COVID-19 challenge trials

Scientists hope to speed up the process for the coronavirus vaccine by running tests for each phase at the same time. In a normal scenario, each part of each phase of testing would be completed and carefully analyzed before the next one was begun. That’s partly for safety and effectiveness but also to save money by not continuing down paths that lead to dead ends.

This time, companies and nonprofits are pouring billions into the search. The rules also are being loosened. The FDA is working closely with companies that have SARS-CoV-2 vaccine trials underway to streamline the process as much as possible.

Phase III is the conundrum. Usually, researchers watch tens of thousands of volunteers as they go about their normal lives to see if they become infected. With COVID-19, because volunteers would still be following social distancing guidelines, few of them would even be exposed to the virus. That's partly why the group must be so large.

“Then we would use statistical techniques to see if there were fewer cases than we would expect there should have been among those vaccinated,” said Paul Root Wolpe, director of the Center for Ethics at Emory University.

In a challenge trial, volunteers are purposefully infected with the virus. The number could be much smaller because most would get sick. The time would be shorter because COVID-19 appears within two weeks.

It’s an ethical minefield. Some percentage of the volunteers, no matter how young and healthy, could die.

For that reason challenge trials are done only with diseases where there’s a 100% cure, said Susan Ellenberg,a professor of biostatistics, medical ethics and health policy at the University of Pennsylvania School of Medicine.

Even when there is a cure, taking part is no fun. When challenge trials were launched for malaria and cholera, participants got very sick.

“The volunteers had lots of diarrhea and vomiting, but they were standing by with IV fluids and antibiotics. so the people who took part were miserable but there was very low risk of actual permanent harm or death,” said Stanford’s Magnus.

With COVID-19, the death rates aren’t even known, and the one current potential treatment, remdesivir, appears only to lessen the duration of the illness.

The ethical balance here is so tough.  And as treatments are getting refined to reduce death rates (and there's reason to believe they are), does the urgency in developing a vaccine go down?  Does the fact that we are comfortable treating people if they do end up sick make the challenge trial LESS daunting?  Can we limit the risk by conducting the challenge trial mostly on people in non-vulnerable age groups?  Lotta questions....moving target answers.

[Anastasis 23475]

1 minute ago, Brisketexan said:

The ethical balance here is so tough.  And as treatments are getting refined to reduce death rates (and there's reason to believe they are), does the urgency in developing a vaccine go down?  Does the fact that we are comfortable treating people if they do end up sick make the challenge trial LESS daunting?  Can we limit the risk by conducting the challenge trial mostly on people in non-vulnerable age groups?  Lotta questions....moving target answers.

Yeah.

It would be interesting if someone could actually put a number to the potential acceleration a challenge trial would provide.  If are are talking like shaving something like 12 months off the development time, fuck that's real. 

I think that I would fall back to a strong deference to informed consent.  If the subjects are fully consented and appreciate the risks involved, go for it.  But then layer in the current economic situation, many people out of jobs, what would likely be a very lucrative payment for providing consent, and man it just adds another angle. Arguably they are vulnerable population created by the virus itself, requiring additional ethical protections.

Bottom line, I think if someone is adequately informed to the risks and consents to participate, let's roll.  

[Anastasis 23475]

background piece from WHO.

https://www.who.int/biologicals/expert_committee/Human_challenge_Trials_IK_final.pdf

 

[Newdoc 3448]

1 hour ago, Anastasis said:

background piece from WHO.

https://www.who.int/biologicals/expert_committee/Human_challenge_Trials_IK_final.pdf

 

The interesting thing is that we are developing a vaccine for an RNA virus which truly uses more modern technology than we ever have before. 
It appears that the safety profile of these can be relatively beneficial vs older ways of vaccine development and production can be ramped up quickly.

However, it is perplexing that you could create a vaccine and test it against placebo using challenge trials of exposing test patients to Covid. Of course this gives us the most accurate scientific data but is extremely ethically challenging.

And sometimes good safety data does not come until post marketing after the medicine/vaccine has been approved.

If somebody is going to actually run a challenge trial and purposely expose these test subjects to Covid then I think there should be some type of significant benefit whether that be monetary or some other reward for the people in the testing group.

 

[Anastasis 23475]

1 hour ago, Newdoc said:

And sometimes good safety data does not come until post marketing after the medicine/vaccine has been approved.

Yeah, I was thinking about that aspect as well.  The challenge method might actually have a negative impact on safety assessment during the registration trial. 

You are 100% correct that the safety profile cannot be definitely established until you are rolling the drug out in post-marketing phase. If the benefit of challenge protocols is that you can complete the study quicker and with smaller sample size, you actually reduce your ability to detect safety signals during the trials. That is a serious concern.

We will be looking to deploy the vax in hundreds of millions of people, if not billions worldwide, in a very compressed timeframe.  This is a terrible set up for a potential safety problem.  Layer in that as you point out some of the tech involved here has never been widely used in humans, e.g. adenovirus vectors for vaccines.  Do we actually have a strong sense of the safety profile with adenovirus vectors used in broad populations of patients? Say there is some unforeseen small to moderate increase in cancer risk with a moderate latency period, it's gonna be a fucking shit show.

I wonder if it is not in fact a safer approach to use old tech inactivated virus like the Chinese are doing. 

[PenelopeWitherspoon 19104]

1 hour ago, Newdoc said:

The interesting thing is that we are developing a vaccine for an RNA virus which truly uses more modern technology than we ever have before. 
It appears that the safety profile of these can be relatively beneficial vs older ways of vaccine development and production can be ramped up quickly.

However, it is perplexing that you could create a vaccine and test it against placebo using challenge trials of exposing test patients to Covid. Of course this gives us the most accurate scientific data but is extremely ethically challenging.

And sometimes good safety data does not come until post marketing after the medicine/vaccine has been approved.

If somebody is going to actually run a challenge trial and purposely expose these test subjects to Covid then I think there should be some type of significant benefit whether that be monetary or some other reward for the people in the testing group.

 

In a trial, can't you control the virus load?  Also, as it seems that some people are genetically predisposed to worse cases, those people cannot be part of the study.  As many have said, genetics and virus load are probably the two things that contribute most to this being worse in some patients vs. others.  If you are in a controlled test environment, I would argue you should be able to control that.

[Bevo 13579]

1 hour ago, Anastasis said:

Yeah, I was thinking about that aspect as well.  The challenge method might actually have a negative impact on safety assessment during the registration trial. 

You are 100% correct that the safety profile cannot be definitely established until you are rolling the drug out in post-marketing phase. If the benefit of challenge protocols is that you can complete the study quicker and with smaller sample size, you actually reduce your ability to detect safety signals during the trials. That is a serious concern.

We will be looking to deploy the vax in hundreds of millions of people, if not billions worldwide, in a very compressed timeframe.  This is a terrible set up for a potential safety problem.  Layer in that as you point out some of the tech involved here has never been widely used in humans, e.g. adenovirus vectors for vaccines.  Do we actually have a strong sense of the safety profile with adenovirus vectors used in broad populations of patients? Say there is some unforeseen small to moderate increase in cancer risk with a moderate latency period, it's gonna be a fucking shit show.

I wonder if it is not in fact a safer approach to use old tech inactivated virus like the Chinese are doing. 

The Pittsburgh vaccine does not use an adenovirus vector. It may not work, but it is a pretty elegant approach and I doubt it would have adverse outcomes. Can someone posts the various vaccines that are in clinical trials to refresh my memory?

[Anastasis 23475]

48 minutes ago, Bevo said:

The Pittsburgh vaccine does not use an adenovirus vector. It may not work, but it is a pretty elegant approach and I doubt it would have adverse outcomes. Can someone posts the various vaccines that are in clinical trials to refresh my memory?

https://blogs.sciencemag.org/pipeline/archives/2020/04/23/a-close-look-at-the-frontrunning-coronavirus-vaccines-as-of-april-23

 

Not sure I have seen a description of the Pittsburgh approach, can you share?

[Anastasis 23475]

quick search indicates it is the patch spike protein microarray, like a bandaid with needles that inserts spike protein to elicit immune response. 

[Newdoc 3448]

2 hours ago, PenelopeWitherspoon said:

In a trial, can't you control the virus load?  Also, as it seems that some people are genetically predisposed to worse cases, those people cannot be part of the study.  As many have said, genetics and virus load are probably the two things that contribute most to this being worse in some patients vs. others.  If you are in a controlled test environment, I would argue you should be able to control that.

Yes. Most can control viral load but how much is needed is a murky question. 

[Bevo 13579]

24 minutes ago, Anastasis said:

quick search indicates it is the patch spike protein microarray, like a bandaid with needles that inserts spike protein to elicit immune response. 

Yeah, here is the basic info., but for some reason, I thought it used both the spike protein and the helicase as targets:

https://www.upmc.com/media/news/040220-falo-gambotto-sars-cov2-vaccine

4/2/2020

PITTSBURGH – University of Pittsburgh School of Medicine scientists today announced a potential vaccine against SARS-CoV-2, the new coronavirus causing the COVID-19 pandemic. When tested in mice, the vaccine, delivered through a fingertip-sized patch, produces antibodies specific to SARS-CoV-2 at quantities thought to be sufficient for neutralizing the virus. 

 

The paper appeared today in EBioMedicine, which is published by The Lancet, and is the first study to be published after critique from fellow scientists at outside institutions that describes a candidate vaccine for COVID-19. The researchers were able to act quickly because they had already laid the groundwork during earlier coronavirus epidemics.   

 

“We had previous experience on SARS-CoV in 2003 and MERS-CoV in 2014. These two viruses, which are closely related to SARS-CoV-2, teach us that a particular protein, called a spike protein, is important for inducing immunity against the virus. We knew exactly where to fight this new virus,” said co-senior author Andrea Gambotto, M.D., associate professor of surgery at the Pitt School of Medicine. “That’s why it’s important to fund vaccine research. You never know where the next pandemic will come from.”

 

“Our ability to rapidly develop this vaccine was a result of scientists with expertise in diverse areas of research working together with a common goal,” said co-senior author Louis Falo, M.D., Ph.D., professor and chair of dermatology at Pitt’s School of Medicine and UPMC.

 

Compared to the experimental mRNA vaccine candidate that just entered clinical trials, the vaccine described in this paper — which the authors are calling PittCoVacc, short for Pittsburgh Coronavirus Vaccine — follows a more established approach, using lab-made pieces of viral protein to build immunity. It’s the same way the current flu shots work.  

 

The researchers also used a novel approach to deliver the drug, called a microneedle array, to increase potency. This array is a fingertip-sized patch of 400 tiny needles that delivers the spike protein pieces into the skin, where the immune reaction is strongest. The patch goes on like a Band-Aid and then the needles — which are made entirely of sugar and the protein pieces — simply dissolve into the skin. 

 

“We developed this to build on the original scratch method used to deliver the smallpox vaccine to the skin, but as a high-tech version that is more efficient and reproducible patient to patient,” Falo said. “And it’s actually pretty painless — it feels kind of like Velcro.”

 

The system also is highly scalable. The protein pieces are manufactured by a “cell factory” — layers upon layers of cultured cells engineered to express the SARS-CoV-2 spike protein — that can be stacked further to multiply yield. Purifying the protein also can be done at industrial scale. Mass-producing the microneedle array involves spinning down the protein-sugar mixture into a mold using a centrifuge. Once manufactured, the vaccine can sit at room temperature until it’s needed, eliminating the need for refrigeration during transport or storage.

 

“For most vaccines, you don’t need to address scalability to begin with,” Gambotto said. “But when you try to develop a vaccine quickly against a pandemic that’s the first requirement.”

 

When tested in mice, PittCoVacc generated a surge of antibodies against SARS-CoV-2 within two weeks of the microneedle prick. 

 

Those animals haven’t been tracked long term yet, but the researchers point out that mice who got their MERS-CoV vaccine produced a sufficient level of antibodies to neutralize the virus for at least a year, and so far the antibody levels of the SARS-CoV-2 vaccinated animals seem to be following the same trend. 

 

Importantly, the SARS-CoV-2 microneedle vaccine maintains its potency even after being thoroughly sterilized with gamma radiation — a key step toward making a product that’s suitable for use in humans.  

 

The authors are now in the process of applying for an investigational new drug approval from the U.S. Food and Drug Administration in anticipation of starting a phase I human clinical trial in the next few months. 

 

“Testing in patients would typically require at least a year and probably longer,” Falo said. “This particular situation is different from anything we’ve ever seen, so we don’t know how long the clinical development process will take. Recently announced revisions to the normal processes suggest we may be able to advance this faster.”

 

Additional authors on the study are Eun Kim, Geza Erdos, Ph.D., Shaohua Huang, Thomas Kenniston, Stephen Balmert, Ph.D., Cara Donahue Carey, Michael Epperly, Ph.D., William Klimstra, Ph.D., and Emrullah Korkmaz, Ph.D., all of Pitt; and Bart Haagmans, of Erasmus Medical Center.

[Anastasis 23475]

A glimpse inside the remdesivir trial. Some controversial decisions during the execution of the study. 

https://www.statnews.com/2020/05/11/inside-the-nihs-controversial-decision-to-stop-its-big-remdesivir-study/

The ACTT study (short for Adaptive Covid-19 Treatment Trial) began in late February. The first patient dosed in the study was an American repatriated from the Diamond Princess, a British cruise ship where there was an outbreak of more than 800 Covid-19 cases. By the terms of the study, hospitalized patients were randomly assigned to receive either intravenous remdesivir or a placebo. On day 15, the study would score patients on a scale from 1 (dead) to 8 (not hospitalized, with no restrictions on activities).

As results from other Covid-19 studies conducted in China started to trickle in, Lane and his team began to worry that looking at the outcome on only the 15th day could lead the study to fail even if the drug was effective. On March 22, with only 77 patients enrolled in the study, members of the NIAID team had a conference call on which they decided to change the measure that would be used. Instead of measuring patients on an eight-point scale on one day, the study would measure the time until the patients scored one of the best three outcomes on the scale. This decision was finalized on April 2; it was posted to clinicaltrials.gov, a government registry of clinical trials, on April 16.

Ironically, Lane said, the study would still have been positive if the change had not been made. But the change in the study’s main goal also changed the way the study would be analyzed. Now, the NIAID decided, the analysis would be calculated when 400 patients out of the 1,063 patients the study enrolled had recovered. If remdesivir turned out to be much more effective than expected, “interim” analyses would be conducted at a third and two-thirds that number.

The job of reviewing these analyses would fall to a committee of outside experts on what is known as an independent data and safety monitoring board, or DSMB. Though they generally go unseen, DSMBs are among the most important and powerful forces in medical research. They are allowed to analyze the data from a trial while it’s ongoing, even as drug companies, doctors, and patients are kept from knowing who is getting the medicine and who is getting placebo. These boards have two jobs: to make sure that patients aren’t being harmed by the experimental drug, and to ensure that it’s not already clear beyond a doubt that a medicine is effective.

...

But the DSMB for the remdesivir study did not ever meet for an interim efficacy analysis, Lane said. All patients had been enrolled by April 20. The data for a DSMB meeting was cut off on April 22. The DSMB met and, on April 27, it made a recommendation to the NIAID.

That recommendation was not about whether the patients on placebo should receive remdesivir. Instead, the DSMB recommended that in the next phase of the study, testing Eli Lilly’s arthritis drug Olumiant against remdesivir, there was no need for a placebo-only group. 

That decision, Lane said, led the NIAID to conclude that patients who had been given placebo should be offered remdesivir, something that started happening after April 28.

This is where Nissen and Bach disagree. There were 1,063 patients in the study, but only 480 had recovered at the time of the analysis. Researchers could have collected more data, they argue, and perhaps have learned if remdesivir saves lives. They were already close, both note. Results are considered “significant” if a measure called a p-value is less than 0.05; the value for mortality in the preliminary analysis was 0.059. “How many patients would we want to put at risk of dying to get that 0.01 on the p-value,” Lane retorted.

[Anastasis 23475]

Another piece on challenge trials.

https://www.wsj.com/articles/one-idea-for-speeding-a-coronavirus-vaccine-deliberately-infecting-people-11589221164

One Idea for Speeding a Coronavirus Vaccine: Deliberately Infecting People

Debate is rising among scientists about whether a so-called human challenge trial is worth the risk

A big part of preparing for a human challenge trial is developing a strain of the virus that is safe but will infect most participants. Here is a version of influenza that researchers used in November to infect participants with the ultimate goal of creating a universal flu vaccine.

PHOTO: ERIC KAYNE FOR THE WALL STREET JOURNALBy 

Sumathi Reddy

May 11, 2020 2:19 pm ET

PRINT

TEXT

4

It’s a controversial idea: Intentionally infect people with the virus that causes Covid-19 to test the effectiveness of a potential vaccine.

The approach is called a human challenge trial, and it’s not the usual way a vaccine is tested. More commonly, researchers track thousands of people, some of whom receive a vaccine, and others a placebo, and then see who becomes infected in the natural course of their lives. It’s a slower process, but poses fewer risks than deliberately infecting people after they’ve received a vaccine.

But some scientists now argue the risks of such a challenge trial are worth taking if it could potentially speed the development of a vaccine. Three groups of health experts have recently published articles advocating for the idea. And the World Health Organization last week published a document outlining criteria for the “ethical acceptability” of a Covid-19 human challenge study.

Vaccines usually take decades to manufacture but experts are looking for ways to shorten the entire process with Covid-19 to perhaps 12 to 18 months. There’s no guarantee they will be able to do so. It’s unclear how much a challenge trial could potentially accelerate the timetable. Experts say the trial itself might take only a couple of months, but creating a version of the virus to infect people with—a crucial part of any challenge—would likely take at least six months.

Kathleen Neuzil is principal investigator for the influenza study and director of the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine.

PHOTO: ERIC KAYNE FOR THE WALL STREET JOURNAL

“We have to look at ways that are not typical vaccine development,” says Stanley Plotkin, a professor emeritus of pediatrics at the University of Pennsylvania and vaccine expert who co-authored an article in the journal Vaccine earlier this month advocating for a human challenge trial.

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“I think that a human challenge could contribute greatly and unless we start preparing for it now it will not be available when we need it,” added Dr. Plotkin, who consults with vaccine manufacturers. “If problems don’t arise along the way, I think it would be reasonable to hope that one could do a human challenge trial in about four months.”

Dr. Plotkin says the immediate objective isn’t a vaccine for the general public, but rather to expedite approval of a vaccine for emergency use in high-risk groups. Experts agree that even if a challenge trial were used to accelerate a vaccine, a broader trial would still ultimately need to take place.

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Several potential coronavirus vaccines have entered human testing. But none have announced that they will be doing human challenge testing.

Any human challenge would be done in a highly controlled setting. When used in vaccine and drug development previously, challenge trials have tended to be done with diseases whose behavior and effects are better understood than Covid-19. Researchers have done challenges with the flu, for instance, to try to develop a better, longer-lasting vaccine. Influenza is a well-studied, well-known virus, and scientists are confident they can give a precise amount of it to young, healthy volunteers without killing them.

Challenge trials are also considered when traditional vaccine development isn’t possible. In 2017 the National Institutes of Health recommended against a human challenge trial for a Zika virus based on ethical concerns. But now that traditional vaccine trials would be difficult in part because Zika outbreaks are so unpredictable, researchers are preparing for a human challenge trial, though one hasn’t been formally approved.

With the coronavirus, there are many risk factors and uncertainties. “You’re starting with this whole new virus that we don’t know a lot about,” says Kathleen Neuzil, director of the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine. She’s also the principal investigator of a government-funded influenza human challenge study that launched last year.

Dr. Neuzil doesn’t think a human challenge trial would speed up the vaccine development process. That’s partly because of the time it could take to create a version of the virus to be used in the testing. That strain has to be manufactured according to government standards and tested to find the right dose.

David Magnus, director of the Stanford Center for Biomedical Ethics at Stanford University, says another problem of doing a Covid-19 human challenge trial is that there are no effective treatments available if a volunteer becomes sick. Most other human challenge trials are done with diseases where there is very low risk of serious illness and there are good treatments when people become sick. “We can’t even get adequate consent right now because we can’t really tell people what the risks are or if immunity is conferred,” he says.

Josh Morrison started a website where people can express interest in participating in a future human challenge trial for Covid-19.

PHOTO: JOSH MORRISON

Still, some people say they would be willing to volunteer. Josh Morrison, a 34 year old in New York City, has started a group called 1Day Sooner where people can express interest in participating in a future challenge trial for Covid-19.

So far around 15,000 people from more than 100 countries have signed up, including him, despite the fact that he donated a kidney in 2011.

“Obviously I would prefer not to get Covid-19,” he says. “But I also felt like this was a chance to be part of saving thousands or even hundreds of thousands of lives. And I felt so powerless at the time that being able to take action and do something meaningful was a strong motivator to me.”

SHARE YOUR THOUGHTS

Would you be willing to take part in a Covid-19 vaccine “challenge”? Why or why not? Join the discussion below.

Conor Barnes, a 27-year-old library technician in British Columbia, Canada, has also expressed interest on the website. He says he weighed the risks and benefits for a week. “There isn’t much else I can do to help,” he says. “It’s a big decision because it is a risk but just looking at the numbers of people who die every day, the idea of contributing to that reduction I think is huge,” he said.

In the U.S., the Food and Drug Administration regulates vaccines. “Because these [challenge] studies involve exposing volunteers to the virus, the studies raise a variety of potential scientific, feasibility and ethical issues. The FDA will work with those who are interested in conducting human challenge trials to help them evaluate these issues,” says an FDA spokesman.

A company in London called hVIVO that specializes in human challenge trials is “very actively looking into how we could build a Covid-19 challenge study to help speed up the world wide development of an effective vaccine,” said Cathal Friel, executive chairman of Open Orphan, a clinical trials company that acquired hVIVO earlier this year. He says at least 10 pharmaceutical companies have already expressed interest in them potentially conducting a challenge trial of their vaccine candidates.

Seema Shah, a bioethicist at Lurie Children’s Hospital of Chicago, is first author of a study published recently in the journal Science which concluded that there are two big questions that need to be answered before launching a human challenge study.

First, it needs to be determined that a trial would lead to some benefit, be it a better vaccine or treatment or a shortened timetable. Second, the risks must be minimized. “Right now there are still young, healthy people who are having strokes or having serious complications,” says Ms. Shah, who is also part of the WHO’s working group.

Still, because it would take several months to set up a challenge study, the authors concluded that it’s a smart idea to get ready for the possibility now. “It’s worth preparing to do one and laying the groundwork while waiting to make that final decision when we have more information,” she says.

Write to Sumathi Reddy at sumathi.reddy@wsj.com

[Liquor and Poker 3659]

We need a thread summarizing each post in this thread.  
 

Has anyone hypothesized or done any work on the efficacy of PrEP drugs on COVID?  Seems like a somewhat similar thing to a guy who has no scientific training. 

[wild_turkey 3167]

On 5/11/2020 at 2:13 PM, Anastasis said:

Another piece on challenge trials.

https://www.wsj.com/articles/one-idea-for-speeding-a-coronavirus-vaccine-deliberately-infecting-people-11589221164

The ethics of a challenge trial are very interesting. It would obviously be detrimental on the individual level because some otherwise healthy people will likely die from participation in the study, but the benefit to society as a whole may justify that cost.

[triplehorn 2664]

On 4/22/2020 at 4:52 PM, RayDog said:

Given that the zinc ionophore mechanism may be how chloroquine works it takes a real idiot to run such a study and not have a group that receives zinc supplements. 

 

On 4/22/2020 at 6:04 PM, RayDog said:

So no doctors included zinc? I don't believe that.

An NYU retrospective study of 900 cases, zeroing in on HCQ/AZ, with and without zinc.  The inclusion of zinc to HCQ and AZ apparently reduced the risk of death by 44%. 

Zinc-hydroxychloroquine found effective in some COVID-19 patients:

https://news.yahoo.com/zinc-hydroxychloroquine-found-effective-covid-19-patients-study-215732283.html?bcmt=1

 

Quote

Washington (AFP) - The antimalarial drug hydroxychloroquine has shown mixed results against the coronavirus in early studies, but a new paper out of New York suggests combining it with the dietary supplement zinc sulfate could create a more effective treatment.

The research by the NYU Grossman School of Medicine was posted on a medical preprint site on Monday, meaning it hasn't yet been peer reviewed.

Records of about 900 COVID-19 patients were reviewed in the analysis, with roughly half given zinc sulfate along with hydroxychloroquine and the antibiotic azithromycin.

The other half only received hydroxychloroquine and azithromycin.

Those receiving the triple-drug combination had a 1.5 times greater likelihood of recovering enough to be discharged, and were 44 percent less likely to die, compared to the double-drug combination.

It did not, however, change the average time patients spent in hospital (six days), the time they spent on the ventilator (five days), or the total amount of oxygen required.

Senior investigator and infectious disease specialist Joseph Rahimian told AFP it was the first study to compare the two combinations.

But he cautioned that a controlled experiment would be needed to prove the benefits beyond doubt.

"The next logical step would be to do a prospective study to see if this holds up in people that you give zinc to, and then you watch and compare," he said.

Hydroxychloroquine has been proposed as a treatment against the SARS-CoV-2 virus because it has antiviral properties that have been proven in lab settings, but not in people.

It interferes with the virus' ability to enter the cells -- and also seems to block them from replicating once they are already inside.

Zinc itself has antiviral properties and past research has suggested it may reduce the time people suffer from common colds.

Rahimian said that it may be that when used to treat coronavirus patients, it is the zinc that does the heavy lifting and is the primary substance attacking the pathogen.

Hydroxychloroquine, on the other hand, acts as an agent that transports the zinc into cells, increasing its efficacy, he suggested.

So adding zinc to HCQ/AZ could make a real difference relative HCQ/AZ alone.  Add to that targeting use for early-as-possible intervention.  

[Anastasis 23475]

7 minutes ago, triplehorn said:

So adding zinc to HCQ/AZ could make a real difference relative HCQ/AZ alone.  Add to that targeting use for early-as-possible intervention.  

[triplehorn 2664]

It's known.  When your words fail, you deploy .gifs.  soooo

 

Anyway, @RayDog, you raised a highly relevant question about whether specifically raising zinc levels could augment results when combined with HCQ/AZ.  This new study supports that zinc warrants serious consideration as a key element in this cocktail.  

 

[Anastasis 23475]

This should be good.  Bat signal RayDog to come educate us about HCQ and the PRRA fusin cleavage site.

Maybe you should read around the board for a bit since you took a little hiatus about the time that the CV risk associated with HCQ, which were pointed to you a long time ago, started playing out in the clinical data.  

[triplehorn 2664]

19 minutes ago, Anastasis said:

This should be good.  Bat signal RayDog to come educate us about HCQ and the PRRA fusin cleavage site.

Maybe you should read around the board for a bit since you took a little hiatus about the time that the CV risk associated with HCQ, which were pointed to you a long time ago, started playing out in the clinical data.  

CV risk associated with HCQ?  I saw this published less than two weeks ago:

The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection

Quote

Conclusions - In the largest reported cohort of COVID-19 patients to date treated with chloroquine/hydroxychloroquine {plus minus} azithromycin, no instances of TdP or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy. Further study of the need for QT interval monitoring is needed before final recommendations can be made.

I guess , don't know (words), you're thinking of the study of people with HCQ being more likely to die ?  If so, I don't recall if there was a cause/effect determined.  Was it due to arrhythmogenic causes?  Was Zinc provided to those HCQ subjects?  

Things have progressed from the last month, and a lot of it was not touched on over the course of the last page.  

[Anastasis 23475]

JFC.