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Just early results, but this from Gilead sure sounds promising: a survival rate of over 98% for severely ill patients (already a subset of those infected.) Still need more testing, obviously, and we'd also obviously still have a long haul for a full economic recovery, but if this is for real, current market prices would make a lot more sense.
This sounds Promising but the report is only anecdotal at this point. We need to see the full results from the clinical trials that are ongoing. This is information from one site in Chicago and there are 152 clinical trial sites around the world for this drug. We should learn more in the next couple of weeks.
This sounds Promising but the report is only anecdotal at this point. We need to see the full results from the clinical trials that are ongoing.
Unfortunately, "anecdotal" is one of those words that is bandied about without clear meaning. I'm afraid that Gilead muddied the waters further with its statement (from the ZeroHedge piece):
Anecdotal reports, while encouraging, do not provide the statistical power necessary to determine the safety and efficacy profile of remdesivir as a treatment for Covid-19. We expect the data from our Phase 3 study in patients with severe Covid-19 infection to be available at the end of this month ...
Contrast this with Dr. Fauci's use of "anecdotal" where he draws a distinction between anecdotal stories and clinical trials:
"Many of the things out there are what I have called 'anecdotal reports,'" he told reporters at a press briefing. “The information that you’re referring to specifically is anecdotal. It was not done in a controlled clinical trial, so you really can’t make any definitive statement about it."
No one other than business "analysts" is suggesting that this was not a clinical trial. Hence (following Dr. Fauci's use of the word), this is not merely anecdotal. As Gilead noted, what was reported did not constitute a phase 3 clinical trial. It sounds like a phase 2 clinical trial.
The first phase of a clinical trial doesn't even use sick people. It uses healthy ones to test safety. The second phase uses small samples of sick people to test whether a drug works at all, i.e. to test whether it might be efficacious. Unlike what the ZeroHedge hack wrote, these are usually not double blind.
Gilead is correct in saying that one needs a phase 3 test with many more people to be statistically meaningful. About 30% of drugs that make it through phase 2 ultimately make it through phase 3.
Here's a New Yorker article discussing testing of hydroxychloroquine. We were given the article in our health economics class. What it calls "anecdotal" are beliefs of individual doctors, not studies . It goes on to observe that
a careful reading of the [supposedly positive Marseille] study reveals a striking finding: eighty-five per cent of the treated patients had no fever. Ninety-two per cent were in the lowest category for clinical deterioration. We know that many people with the virus have no symptoms at all, while others have mild to moderate ones, and that, in such people, their own immune systems can purge the microbe in a matter of days or weeks.
Contrast this with the patients involved in the remdesivir study.
I'm not saying I expect remdesivir to prove out or not to. Just that based only on the sketchy information provided, it sounds like the drug is progressing successfully through the standard FDA clinical testing process. Which means that it hasn't yet been rejected.
@msf If you look at the original article, this was from a phase 3 trial. But yes, it's only one small part of that trial, so Gilead is correctly saying it's promising but too soon to be sure.
Poking around a bit further, it seems that even if it works, they could produce a million doses by the end of the year.
That wouldn't be enough to end this pandemic, though it would save a lot of lives.
Seems to me the market is betting that something is on the way, whether this drug or something else or a comob, so the end is in sight.
I don't disagree that it is promising. Which is another way of saying that it hasn't flunked a trial yet.
What these drugs do is treat a disease, not end a pandemic. Though in shortening the period of time that someone has a disease it can have the side effect of slowing transmission.
@msf +1, I agree. I wonder if this development might actually hurt the recovery: by encouraging a too-early easing of social distancing and by making it seem less urgent for Congress to pass more stimulus.
I don't know, too many variables for me, which is why whenever I try market timing (like right now, when I'm sitting on a bunch of dry powder that I wished I'd used a couple weeks ago) I strike out.
It seems the folks were appropriate for compassionate use... that is they were doing very poorly 34 were on ventilators and 3 on heart lung bypass machines
The available studies from China and Italy and Seattle have different criteria for hospital admission so I looked just at the patients on ventilators from their studies. . They also mix in "non invasive mechanical ventilation" which is hard to tell what that means without digging thru the supplements, presumably BiPap.
Of the patients on ventilators in Redesivir study the mortality thus far is 18% ( 6 of 34) but only 24% ( 8 of 34) are out of the hospital so 58% are still hospitalized. So highest mortality if all remaining in hospital died would be 76%
They were able to reduce their oxygen requirements by 2 steps ( from ventilator to nasal oxygen for example) in 56 % of patients which implies that they are getting much better
There are very few studies I have seen to compare.
had 67% mortality with 24% still "critically ill" ( so possibly up to 91% dead) but these patients had more comorbidities ( 85% vs 68% with one coexisting condition, and 10% organ transplants, 42% heart failure, and 10% on dialysis. I doubt patients this sick were considered for compassionate use.
had 31/32 patients who needed ventilators die and 24/26 patients who needed non invasive mechanical ventilation die. This is a general population and maybe more comparable to Remdisivir
To compare Redesivir and Wuhan numbers, let us assume the only survivors are those currently discharged ( and none of them go on to die), and anyone left in hospital at time of publication dies, AND THAT WUHAN AND USA PATIENTS AND HOSPITAL ARE SIMILAR
Comparing 8/34 survivors (Redesivir) vs 3/58 (Wuhan) or 24% survival vs 5%.
The chi-square statistic is 11.139. The p-value is .000845. Significant at p < .05.
But this is a very very marginal way to determine health policy!!! This is why we need controlled trial in the same institution. We need to know if the patients are similar, and even if they are, the controls should be chosen at the same time as the treatment group , chosen in a randomized fashion and in the same country and health system. I doubt any of us would want to rely on a drug that was proven to work only in Wuhan China. The opposite should be true.
Hopefully we will not get to the point where like Hydroxychloroquine,no o ne will want to participate in such a study, fearing they will not get a life saving drug. Consequently this type of study should be the only way this drug is available.
Do you think / know whether ongoing studies will be affected by mid-treatment changes in clinical practice of ventilation and treatment indications (changed oxygen threshold, length of time, levels of pressure, etc.)?
I assume that the studies will have enough patients in them so eventually we will have lots of data on effectiveness on patients in hospital. I do not know what egibility criteria they are using to add a patient to the study; presumably on assisted ventilation ( ie at least BiPap) or significant oxygenation or other measures of severity but if they are smart they have included patietns in early stages to see if it prevents deterioration
Keep in mind thought that even if it is extremely effective and say reduces mortality or deterioration by 50% it will not stop transmission or new cases. People will still be worried about getting sick and the still increased ( if lower) risk of death.
Thus a wildly successful drug may lessen the panic and fear, but may not do as much to reopen things as people will still be worried about getting sick
I very much doubt Hydroxychloroquine will do much, but we will know more shortly.
Several small better studies than the one Trump touts have shown little to some smaller benefits
But we need to know all of data definitions and how studies were done. For example in latter study what does "improved pneumonia" mead? Did the doctors who read the patients xrays know the patient was taking hydroxychloroquine?
These are standard protocols that must be followed if we are to have confidence these drugs will be effective.
Without this is as if Trump had decided that Boeing had "done enough" to fix the Max 737, certified it to fly by presidential edict and told the FAA to stop the investigation.
I've been going through the NEJM paper and have some clarifying questions about the oxygen support figures. From a high level perspective, this detail doesn't matter, but I do try to understand various figures.
With respect to invasive/non-invasive mechanical/non-mechanical ventilation, the NEJM study seems to characterize ventilators as invasive mechanical, and ECMOs ("similar to the heart-lung by-pass machine used in open-heart surgery") as invasive non-mechanical ventilation.
So of the total 34 patients receiving invasive ventilation, it appears that 30 were on ventilators and 4 on ECMOs. That's out of the 53 that completed the study.
The text talks about "a decrease of at least 2 points from baseline on a modified ordinal scale (as recommended by the WHO R&D Blueprint Group) ... The six-point scale consists of the following categories: 1, not hospitalized; 2, hospitalized, not requiring supplemental oxygen; 3, hospitalized, requiring supplemental oxygen; 4, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 5, hospitalized, requiring invasive mechanical ventilation, ECMO, or both; and 6, death."
Looking at Figure 1, first column (invasive oxygen support at baseline), I see "only" 16 patients (48%) dropping at least two points. So I'm puzzled by this line in the post above: "They were able to reduce their oxygen requirements by 2 steps ( from ventilator to nasal oxygen for example) in 56 % of patients which implies that they are getting much better."
The paper also describes a finer granularity of oxygen support, including "low-flow oxygen, nasal high-flow oxygen, [and] noninvasive positive pressure ventilation [NIPPV]", Perhaps sma3 is using another scale where high-flow oxygen and NIPPV are counted as separate levels. If so, it would help to see what that scale looks like.
None of this changes the generally positive results reported in the paper. I'm just trying to understand the definitions and numbers.
Details covered well by previous posters, but notably absent in clinical characteristics was BMI as obesity is an identified risk factor. However, other than an observational assessment, generally difficult to elucidate in a severely ill bedridden patient unless you have recent input from an EMR.
With the Gilead drug, I agree with several posters that the ongoing, better controlled study will offer much more granularity.
Concerning Hydroxychloroquine/Azithromycin, as a pharmacist in my area I saw very few attempts at inappropriate "just in case" prescribing. I know it was a much bigger issue in other areas of the country particularly early in the evolution of the breadth of infections, but professional discretion by colleagues and restrictions installed by many Boards of Pharmacy or Governors limited the overreach. Often forgotten was the potential overuse of Azithromycin, as an emergent bacteria that develops resistance due to indiscriminate antibiotic prescribing could pose a threat that dwarfs Corona.
Comments
https://www.zerohedge.com/health/gilead-pours-cold-water-report-sent-market-soaring-anecdotal-reports-no-statistical-power
https://www.cnbc.com/2020/04/17/gilead-drug-remdesivir-investors-should-be-cautious-analysts-says.html
The first phase of a clinical trial doesn't even use sick people. It uses healthy ones to test safety. The second phase uses small samples of sick people to test whether a drug works at all, i.e. to test whether it might be efficacious. Unlike what the ZeroHedge hack wrote, these are usually not double blind.
https://www.clinicaltrials.gov/ct2/help/glossary/phase
https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/what-you-need-to-know/phases-of-clinical-trials.html
Gilead is correct in saying that one needs a phase 3 test with many more people to be statistically meaningful. About 30% of drugs that make it through phase 2 ultimately make it through phase 3.
Here's a New Yorker article discussing testing of hydroxychloroquine. We were given the article in our health economics class. What it calls "anecdotal" are beliefs of individual doctors, not studies . It goes on to observe that https://www.newyorker.com/news/daily-comment/a-new-study-questions-the-effectiveness-of-a-potential-game-changer-against-the-coronavirus
Contrast this with the patients involved in the remdesivir study.
I'm not saying I expect remdesivir to prove out or not to. Just that based only on the sketchy information provided, it sounds like the drug is progressing successfully through the standard FDA clinical testing process. Which means that it hasn't yet been rejected.
Poking around a bit further, it seems that even if it works, they could produce a million doses by the end of the year.
That wouldn't be enough to end this pandemic, though it would save a lot of lives.
Seems to me the market is betting that something is on the way, whether this drug or something else or a comob, so the end is in sight.
What these drugs do is treat a disease, not end a pandemic. Though in shortening the period of time that someone has a disease it can have the side effect of slowing transmission.
As illustration, consider that the world still has an HIV pandemic. Treatment, not vaccine.
https://www.businessinsider.com/pandemics-that-changed-the-course-of-human-history-coronavirus-flu-aids-plague
I don't know, too many variables for me, which is why whenever I try market timing (like right now, when I'm sitting on a bunch of dry powder that I wished I'd used a couple weeks ago) I strike out.
Better data is published from the compassionate use study in the NEJM
https://www.nejm.org/doi/full/10.1056/NEJMoa2007016
It seems the folks were appropriate for compassionate use... that is they were doing very poorly 34 were on ventilators and 3 on heart lung bypass machines
The available studies from China and Italy and Seattle have different criteria for hospital admission so I looked just at the patients on ventilators from their studies. . They also mix in "non invasive mechanical ventilation" which is hard to tell what that means without digging thru the supplements, presumably BiPap.
Of the patients on ventilators in Redesivir study the mortality thus far is 18% ( 6 of 34) but only 24% ( 8 of 34) are out of the hospital so 58% are still hospitalized. So highest mortality if all remaining in hospital died would be 76%
They were able to reduce their oxygen requirements by 2 steps ( from ventilator to nasal oxygen for example) in 56 % of patients which implies that they are getting much better
There are very few studies I have seen to compare.
Seattle ventilator patients https://jamanetwork.com/journals/jama/fullarticle/2763485
had 67% mortality with 24% still "critically ill" ( so possibly up to 91% dead) but these patients had more comorbidities ( 85% vs 68% with one coexisting condition, and 10% organ transplants, 42% heart failure, and 10% on dialysis. I doubt patients this sick were considered for compassionate use.
Wuhan https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
had 31/32 patients who needed ventilators die and 24/26 patients who needed non invasive mechanical ventilation die. This is a general population and maybe more comparable to Remdisivir
To compare Redesivir and Wuhan numbers, let us assume the only survivors are those currently discharged ( and none of them go on to die), and anyone left in hospital at time of publication dies, AND THAT WUHAN AND USA PATIENTS AND HOSPITAL ARE SIMILAR
Comparing 8/34 survivors (Redesivir) vs 3/58 (Wuhan) or 24% survival vs 5%.
The chi-square statistic is 11.139. The p-value is .000845. Significant at p < .05.
But this is a very very marginal way to determine health policy!!! This is why we need controlled trial in the same institution. We need to know if the patients are similar, and even if they are, the controls should be chosen at the same time as the treatment group , chosen in a randomized fashion and in the same country and health system. I doubt any of us would want to rely on a drug that was proven to work only in Wuhan China. The opposite should be true.
Hopefully we will not get to the point where like Hydroxychloroquine,no o ne will want to participate in such a study, fearing they will not get a life saving drug. Consequently this type of study should be the only way this drug is available.
Do you think / know whether ongoing studies will be affected by mid-treatment changes in clinical practice of ventilation and treatment indications (changed oxygen threshold, length of time, levels of pressure, etc.)?
Keep in mind thought that even if it is extremely effective and say reduces mortality or deterioration by 50% it will not stop transmission or new cases. People will still be worried about getting sick and the still increased ( if lower) risk of death.
Thus a wildly successful drug may lessen the panic and fear, but may not do as much to reopen things as people will still be worried about getting sick
I very much doubt Hydroxychloroquine will do much, but we will know more shortly.
Several small better studies than the one Trump touts have shown little to some smaller benefits
https://www.medrxiv.org/content/10.1101/2020.04.10.20060699v1
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
But we need to know all of data definitions and how studies were done. For example in latter study what does "improved pneumonia" mead? Did the doctors who read the patients xrays know the patient was taking hydroxychloroquine?
These are standard protocols that must be followed if we are to have confidence these drugs will be effective.
Without this is as if Trump had decided that Boeing had "done enough" to fix the Max 737, certified it to fly by presidential edict and told the FAA to stop the investigation.
Who would get on such an aircraft?
I've been going through the NEJM paper and have some clarifying questions about the oxygen support figures. From a high level perspective, this detail doesn't matter, but I do try to understand various figures.
With respect to invasive/non-invasive mechanical/non-mechanical ventilation, the NEJM study seems to characterize ventilators as invasive mechanical, and ECMOs ("similar to the heart-lung by-pass machine used in open-heart surgery") as invasive non-mechanical ventilation.
So of the total 34 patients receiving invasive ventilation, it appears that 30 were on ventilators and 4 on ECMOs. That's out of the 53 that completed the study.
The text talks about "a decrease of at least 2 points from baseline on a modified ordinal scale (as recommended by the WHO R&D Blueprint Group) ... The six-point scale consists of the following categories: 1, not hospitalized; 2, hospitalized, not requiring supplemental oxygen; 3, hospitalized, requiring supplemental oxygen; 4, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 5, hospitalized, requiring invasive mechanical ventilation, ECMO, or both; and 6, death."
Looking at Figure 1, first column (invasive oxygen support at baseline), I see "only" 16 patients (48%) dropping at least two points. So I'm puzzled by this line in the post above: "They were able to reduce their oxygen requirements by 2 steps ( from ventilator to nasal oxygen for example) in 56 % of patients which implies that they are getting much better."
The paper also describes a finer granularity of oxygen support, including "low-flow oxygen, nasal high-flow oxygen, [and] noninvasive positive pressure ventilation [NIPPV]", Perhaps sma3 is using another scale where high-flow oxygen and NIPPV are counted as separate levels. If so, it would help to see what that scale looks like.
None of this changes the generally positive results reported in the paper. I'm just trying to understand the definitions and numbers.
With the Gilead drug, I agree with several posters that the ongoing, better controlled study will offer much more granularity.
Concerning Hydroxychloroquine/Azithromycin, as a pharmacist in my area I saw very few attempts at inappropriate "just in case" prescribing. I know it was a much bigger issue in other areas of the country particularly early in the evolution of the breadth of infections, but professional discretion by colleagues and restrictions installed by many Boards of Pharmacy or Governors limited the overreach. Often forgotten was the potential overuse of Azithromycin, as an emergent bacteria that develops resistance due to indiscriminate antibiotic prescribing could pose a threat that dwarfs Corona.