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Posted

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. 

Posted (edited)

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

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  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.

...

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

Edited by zork
Posted
  On 4/10/2020 at 12:24 AM, 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

  Reveal hidden contents

 

 

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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. 
 

 

Posted

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.

Posted (edited)

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 (note pre-print, this is not peer reviewed.)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 by Anastasis
Posted
  On 4/15/2020 at 1:56 PM, 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.

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

Posted

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.

Posted

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.

Posted

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. 

Posted
  On 4/21/2020 at 5:37 PM, 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.

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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. 

  • Like 1
Posted
  On 4/22/2020 at 11:52 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. 

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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. 

  • Like 1
Posted
  On 4/23/2020 at 12:49 AM, 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. 

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

Posted
  On 4/23/2020 at 1:04 AM, RayDog said:

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

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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/

 

Posted (edited)

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 by Anastasis
  • Like 4
Posted
  On 4/23/2020 at 1:58 AM, 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. 

Expand  

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.

Posted (edited)

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 by Anastasis
Posted
  On 4/24/2020 at 6:08 AM, zork said:
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.
  • 2 weeks later...
Posted

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.

Posted
  On 5/6/2020 at 8:28 PM, 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.

Expand  

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.

  • Like 1
Posted
  On 5/6/2020 at 8:35 PM, 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.

Expand  

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.  

Posted
  On 5/6/2020 at 8:48 PM, Anastasis said:
Expand  

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.

 

  • Like 2
Posted
  On 5/6/2020 at 10:37 PM, Newdoc said:

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

Expand  

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. 

Posted
  On 5/6/2020 at 10:37 PM, 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.

 

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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.

Posted
  On 5/6/2020 at 11:53 PM, 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. 

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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?

Posted
  On 5/7/2020 at 1:10 AM, 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?

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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?

Posted
  On 5/7/2020 at 12:03 AM, 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.

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

Posted
  On 5/7/2020 at 2:01 AM, 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. 

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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

PITTSBURGHUniversity 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.  

 

Falo Gambotto SARS 17 releaseThe 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.

 

Falo Gambatto SARS play“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.
  • Like 2
Posted

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.

Posted

Another piece on challenge trials.

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

  Reveal hidden contents

Posted

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. 

Posted
  On 5/11/2020 at 7:13 PM, Anastasis said:
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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.

Posted
  On 4/22/2020 at 11:52 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. 

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  On 4/23/2020 at 1:04 AM, RayDog said:

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

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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.

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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.  

Posted

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.  

 

Posted

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.  

Posted
  On 5/13/2020 at 3:46 AM, 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.  

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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.

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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.  

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