I’m a housewife and a dog rescuer but even I know to dose dogs according to weight! I would not expect mange mites to die or intestinal worms to die if I gave a reduced dose.
I think what your trying to achieve is an estimate of the number of patients who received less than 400mcg/kg.
I don’t think it is worth pursuing this unless you have the raw data. It is too speculative, could easily be out by 5 patients either way and irrespective, the authors will not respond nor change their paper based on this speculation.
However, all hope is not lost. If a patient is 100kg or greater then they would have received 360mcg/kg or less.
Even without knowing the exact weights of the patients, it is almost certain that at least 1 patient was greater than 100kg (although likely many more). I chose 100kg because this represents a 10% reduction in the stated dose that was supposedly being assessed for effect. As I mentioned previously, you could pick any number under 400mcg/kg but a 10% reduction becomes clearly significant
The mere fact that even a single underdosed patient was included in the study results without mention anywhere in the paper renders the study invalid and requires at the very least a retraction and rewrite.
With raw data you can then start to exclude underdosed patients and reassess the results.
I think the time is right to escalate and insist the NEJM retract the paper and/or grant access to raw data.
Lastly, I know you’re doing it but keep a close eye on the original paper, there is every chance that they’ll change the manuscript again in regards to the dosing regime and its potential failings
Urban Minas Gerais has a population that is typical of Brazil in general. Any BMI distribution data from Brazil could be reasonably extrapolated to the IVM study region. Or if you can't get a Brazilian BMI distribution, how about finding BMI distribution data from Europe or North America and then assume that the Brazilian BMI distribution is of similar shape. You would only need to rescale the distribution to have a mean equal to that of the Brazilian distribution; the Brazilian mean BMI is available; around 26, I believe. Brazilians have an average BMI only slightly lower than the USA, in other words, they are pretty overweight.
Assuming that you don't have the raw data, you could estimate the underdosing by using a Monte Carlo simulation, i.e. drawing a sample of 100,000 heights and weights from data of Central Brazil, and randomly pairing them to generate the probable BMI distribution along with its mean and variance, from which you could determine what portion of the patients likely weighed over 90 kg and so were underdosed.
90 kg is a low cutoff point. I am 76 kg (160 lbs), 5.11", BMI of 22.3. If I weighed 200 lbs (=90.7 kg), I would have a BMI of 27.9, about the middle of the overweight category. I have lived in Brazil and can say that BMIs over 28 are quite common there.
But then you would need to adjust for the fact that those presenting for treatment are more likely to be skewed towards higher BMIs, the thinner persons having dealt with the infection more easily on their own.
your mention of monte carlo simulation was the clue that reminded me of getguesstimate.com. I'm now using it to get the estimate I was looking for. Thank you!!
All I know is that the outcome was likely decided and the study designed to match that desired end. Everything I've read about this confirms this, at least for me.
Honestly this adherence to scientific principles and examination of the trial for methodological flaws seems almost besides the point, now. They could not allow any readily-available therapeutic to appear to work because that would invalidate the EUA. That's it. There was some pretence at testing pharmaceuticals for show purposes, but everyone knew an engineered outcome was essential to prop up mandates and, especially, to frighten people into wanting the vax for their children.
I admire your stamina here and I want every bit of fraud exposed. But, again, we know why it happened, right?
I think understanding the underlying structure of the issue, as well as the response, will teach me a lot about why and how such things happen. Even if nothing ends up happening, I have already learned a huge amount from doing this, and connected with many smart people with integrity.
I can't see how to calculate questions 1 and 2. They screwed up and I don't see how you can go back and get anything meaningful without knowing everyone's weight. The 2 biggest problems to me were that #1. it wasn't early treatment and #2. the IVM was used during the gamma variant whereas the placebo group used had an earlier, less severe variant. The 2 groups were not run concurrently. The problem with RCTs is that in order to do it right for IVM, you need the right dose and to have your cut off for early treatment be early, like Day1 or 2 and that takes tremendous diligence, which these guys don't have because it is in their best interest to have the results be neutral or negative. This is why I find population studies more accurate.
The idea is to use demographic information to make some sane estimates about what the data most likely looks like. Obviously we can't get precise answers, but an estimate should help see the size of the issue.
I think without concrete numbers, it doesn't really matter. I don't think estimates matter. Remember, if they screwed up on one thing, who knows if the numbers you have to get your estimates from are even accurate. They aren't honest or trustworthy people. We already know there is so much evidence IVM works, it's tragic. This is the game they play and yes, it is very frustrating.
Are you kidding? Do you really not know what happened in Peru or Uttar
Pradesh? Most were quickly given access to the drugs - don't think the majority were sick for a week before treatment. How quickly you get the medicine plus the dose you need, and the duration are also dependent on the strain, gamma being the most severe. I guess the dramatic drop off soon after the programs began were just random chance. Most people at this point have either taken or known people who have taken IVM for covid. 6/6 high risk people I know took it and all recovered well with no long covid. That makes my decision to take this safe drug a pretty easy one. You're free to do what you want.
Thank you for including the link. Yes, not only were the people who had Covid treated (and supposedly quickly from what I've read), but their contacts who weren't sick. And as you may recall, our authorities say there is no evidence it works to prevent Covid, either. You can see the pattern in the large crash down in symptomatic cases. That is significant to some of us. And maybe results would have been even better had the dose been doubled. This seems like the best way to deal with a pandemic, which should be the goal. Like I said, many people have taken IVM or known personally those who have and witnessed the help it gives firsthand (seems like a pattern). If you think that is irrelevant, so be it.
Here is the analysis of the population study in the 25 different states of Peru where IVM was introduced at different times, state by state, and the results. https://www.youtube.com/watch?v=d6MZSWXr9Vo
Really? I thought everyone died of Covid! I'll have to write that down.
Fine, don't watch the Peru analysis. You obviously put great faith in scientists - which is not the same as science. As for the 6 high-risk people I know one was my 95 yr old dad who was quickly going downhill by Day 2 and took IVM that night before bed. He was free of fever and pain by morning and feeling better. He spent the next 5 days feeling a little sick and then he was fine. I think we know the Covid pattern by now to know that when you go steeply downhill by Day 2 you don't magically reverse course literally overnight. (His wife took IVM prophylactically, never isolated and never got sick. Coincidence? Maybe. Would you want to risk it? I wouldn't). Obviously, you can be OK without it - most of the world is. But I'd rather not take chances with my friends and family as we are all high-risk. When you add these observations to those of countless others, it is significant. You can listen to many people tell their stories as well as the experience of many treating doctors.
I assume you do know that the studies "showing" IVM and HCQ don't work were funded by organizations such as Unitaid, with money to lose from a positive outcome? Whereas the doctors using IVM to treat covid patients are losing their jobs, risking their licenses - why? Because they are sharing in the same mass hallucination?
Are you aware that the use of penicillin, the use of the triple drug therapy for H. pylori and many things that are still the "gold standard of treatment" today were never verified with an RCT? But there have been RCTs with IVM and Tess Lawrie's meta-analysis showing it works, as well as observational studies but you are being lied to about RCTs being the only way things can yield a meaningful answer.
You could possibly then exclude anyone who received less than 350mcg/kg from the results. Or maybe be more strict and exclude anyone who received less than 375mcg/kg.
If you wanted to go crazy you could also exclude anyone who received their first dose after day 5.
Eventually you would be left with only those who had >375mcg/kg with first dose within 5 days of symptoms versus placebo.
Might give that 17% reduction in hospitalisations that leg up it needs to reach statistical significance
Run it by John Abramson who used to analyze clinical trials for a living. He is an MD and in February, 2022, published "Sickening: How Big Pharma Broke American Health Care and How We Can Repair It." He was interviewed on Tucker Carlson Today on Feb. 14, 2022 in an episode titled, "Exposing Big Pharma."
I know your questions are not specifically addressed to this, but the limitation is likely based on the quantity of 3 mg tablets available. 75 kg would be ten (10) 3 mg tablets. They rationed the tablets out.
I think they backed into an estimate of BMI by determining the maximum dose they would give first and I suspect it was 10 3 mg tablets for ease of distribution, i.e. a 75 kg body weight.
*edit* maybe closer to 80 kg to get to a 30 BMI based on an "average height" across genders? How many 6 mg tablets in a blister pack?
If so, that is poor science. Ivermectin can be compounded to exactly match BMI, as was done by an online practitioner for me. Compounded capsules could be made visually unidentifiable as to content. Alternatively, 6 mg pills could be fractionalized in a pill cutter.
it is incomprehensible to me why anybody would calculate BMI when in fact a far better indicator of proportion of fat is abdominal circumference. Much of the cytokine (IL 6)storm happens in the belly fat.
No, actually, what I wrote is correct. I looked at dosing for parasites.
Secondly, the evidence for dosing requiring scaling with weight is discussed by the authors in their rationale.
However, the problem is none of those things. It's that they *said* they are dosing at 400mcg/kg but actually that wasn't the case for many of the patients, and it also wasn't the average dose.
Why wasn't the dosing weight limit disclosed on the paper itself?
Good scientific standards dictate that a paper discusses its short comings. In this example there are potentially many patients underdosed compared to the desired dose of the trial.
Doesn’t matter whatever other studies showed.
This underdosing was not declared nor discussed.
Do you have a science background?
If yes, surely you must agree this is a massive oversight of the authors, potentially altering the outcome of the study.
I’m a housewife and a dog rescuer but even I know to dose dogs according to weight! I would not expect mange mites to die or intestinal worms to die if I gave a reduced dose.
I think what your trying to achieve is an estimate of the number of patients who received less than 400mcg/kg.
I don’t think it is worth pursuing this unless you have the raw data. It is too speculative, could easily be out by 5 patients either way and irrespective, the authors will not respond nor change their paper based on this speculation.
However, all hope is not lost. If a patient is 100kg or greater then they would have received 360mcg/kg or less.
Even without knowing the exact weights of the patients, it is almost certain that at least 1 patient was greater than 100kg (although likely many more). I chose 100kg because this represents a 10% reduction in the stated dose that was supposedly being assessed for effect. As I mentioned previously, you could pick any number under 400mcg/kg but a 10% reduction becomes clearly significant
The mere fact that even a single underdosed patient was included in the study results without mention anywhere in the paper renders the study invalid and requires at the very least a retraction and rewrite.
With raw data you can then start to exclude underdosed patients and reassess the results.
I think the time is right to escalate and insist the NEJM retract the paper and/or grant access to raw data.
Lastly, I know you’re doing it but keep a close eye on the original paper, there is every chance that they’ll change the manuscript again in regards to the dosing regime and its potential failings
Urban Minas Gerais has a population that is typical of Brazil in general. Any BMI distribution data from Brazil could be reasonably extrapolated to the IVM study region. Or if you can't get a Brazilian BMI distribution, how about finding BMI distribution data from Europe or North America and then assume that the Brazilian BMI distribution is of similar shape. You would only need to rescale the distribution to have a mean equal to that of the Brazilian distribution; the Brazilian mean BMI is available; around 26, I believe. Brazilians have an average BMI only slightly lower than the USA, in other words, they are pretty overweight.
Assuming that you don't have the raw data, you could estimate the underdosing by using a Monte Carlo simulation, i.e. drawing a sample of 100,000 heights and weights from data of Central Brazil, and randomly pairing them to generate the probable BMI distribution along with its mean and variance, from which you could determine what portion of the patients likely weighed over 90 kg and so were underdosed.
90 kg is a low cutoff point. I am 76 kg (160 lbs), 5.11", BMI of 22.3. If I weighed 200 lbs (=90.7 kg), I would have a BMI of 27.9, about the middle of the overweight category. I have lived in Brazil and can say that BMIs over 28 are quite common there.
But then you would need to adjust for the fact that those presenting for treatment are more likely to be skewed towards higher BMIs, the thinner persons having dealt with the infection more easily on their own.
your mention of monte carlo simulation was the clue that reminded me of getguesstimate.com. I'm now using it to get the estimate I was looking for. Thank you!!
All I know is that the outcome was likely decided and the study designed to match that desired end. Everything I've read about this confirms this, at least for me.
Honestly this adherence to scientific principles and examination of the trial for methodological flaws seems almost besides the point, now. They could not allow any readily-available therapeutic to appear to work because that would invalidate the EUA. That's it. There was some pretence at testing pharmaceuticals for show purposes, but everyone knew an engineered outcome was essential to prop up mandates and, especially, to frighten people into wanting the vax for their children.
I admire your stamina here and I want every bit of fraud exposed. But, again, we know why it happened, right?
I think understanding the underlying structure of the issue, as well as the response, will teach me a lot about why and how such things happen. Even if nothing ends up happening, I have already learned a huge amount from doing this, and connected with many smart people with integrity.
Yes, on that I agree, and I admire your own integrity and persistence and that of shared temperament.
I can't see how to calculate questions 1 and 2. They screwed up and I don't see how you can go back and get anything meaningful without knowing everyone's weight. The 2 biggest problems to me were that #1. it wasn't early treatment and #2. the IVM was used during the gamma variant whereas the placebo group used had an earlier, less severe variant. The 2 groups were not run concurrently. The problem with RCTs is that in order to do it right for IVM, you need the right dose and to have your cut off for early treatment be early, like Day1 or 2 and that takes tremendous diligence, which these guys don't have because it is in their best interest to have the results be neutral or negative. This is why I find population studies more accurate.
The idea is to use demographic information to make some sane estimates about what the data most likely looks like. Obviously we can't get precise answers, but an estimate should help see the size of the issue.
I think without concrete numbers, it doesn't really matter. I don't think estimates matter. Remember, if they screwed up on one thing, who knows if the numbers you have to get your estimates from are even accurate. They aren't honest or trustworthy people. We already know there is so much evidence IVM works, it's tragic. This is the game they play and yes, it is very frustrating.
Are you kidding? Do you really not know what happened in Peru or Uttar
Pradesh? Most were quickly given access to the drugs - don't think the majority were sick for a week before treatment. How quickly you get the medicine plus the dose you need, and the duration are also dependent on the strain, gamma being the most severe. I guess the dramatic drop off soon after the programs began were just random chance. Most people at this point have either taken or known people who have taken IVM for covid. 6/6 high risk people I know took it and all recovered well with no long covid. That makes my decision to take this safe drug a pretty easy one. You're free to do what you want.
Thank you for including the link. Yes, not only were the people who had Covid treated (and supposedly quickly from what I've read), but their contacts who weren't sick. And as you may recall, our authorities say there is no evidence it works to prevent Covid, either. You can see the pattern in the large crash down in symptomatic cases. That is significant to some of us. And maybe results would have been even better had the dose been doubled. This seems like the best way to deal with a pandemic, which should be the goal. Like I said, many people have taken IVM or known personally those who have and witnessed the help it gives firsthand (seems like a pattern). If you think that is irrelevant, so be it.
Here is the analysis of the population study in the 25 different states of Peru where IVM was introduced at different times, state by state, and the results. https://www.youtube.com/watch?v=d6MZSWXr9Vo
Really? I thought everyone died of Covid! I'll have to write that down.
Fine, don't watch the Peru analysis. You obviously put great faith in scientists - which is not the same as science. As for the 6 high-risk people I know one was my 95 yr old dad who was quickly going downhill by Day 2 and took IVM that night before bed. He was free of fever and pain by morning and feeling better. He spent the next 5 days feeling a little sick and then he was fine. I think we know the Covid pattern by now to know that when you go steeply downhill by Day 2 you don't magically reverse course literally overnight. (His wife took IVM prophylactically, never isolated and never got sick. Coincidence? Maybe. Would you want to risk it? I wouldn't). Obviously, you can be OK without it - most of the world is. But I'd rather not take chances with my friends and family as we are all high-risk. When you add these observations to those of countless others, it is significant. You can listen to many people tell their stories as well as the experience of many treating doctors.
I assume you do know that the studies "showing" IVM and HCQ don't work were funded by organizations such as Unitaid, with money to lose from a positive outcome? Whereas the doctors using IVM to treat covid patients are losing their jobs, risking their licenses - why? Because they are sharing in the same mass hallucination?
Are you aware that the use of penicillin, the use of the triple drug therapy for H. pylori and many things that are still the "gold standard of treatment" today were never verified with an RCT? But there have been RCTs with IVM and Tess Lawrie's meta-analysis showing it works, as well as observational studies but you are being lied to about RCTs being the only way things can yield a meaningful answer.
I think you need access to the raw data, all of it.
Hopefully they documented the weight of each patient, not just BMI.
Then you can work out the exact mcg/kg dose each participant received.
Then, once known, you can examine outcomes from each subgroup of dosing.
In other words you could divide the Ivermectin arm into groups based on dosing
Ie <200mcg/kg, 201-250mcg/kg, 251-300mcg/kg, 301-350mcg/kg, 351-400mcg/kg.
You could possibly then exclude anyone who received less than 350mcg/kg from the results. Or maybe be more strict and exclude anyone who received less than 375mcg/kg.
If you wanted to go crazy you could also exclude anyone who received their first dose after day 5.
Eventually you would be left with only those who had >375mcg/kg with first dose within 5 days of symptoms versus placebo.
Might give that 17% reduction in hospitalisations that leg up it needs to reach statistical significance
Run it by John Abramson who used to analyze clinical trials for a living. He is an MD and in February, 2022, published "Sickening: How Big Pharma Broke American Health Care and How We Can Repair It." He was interviewed on Tucker Carlson Today on Feb. 14, 2022 in an episode titled, "Exposing Big Pharma."
I know your questions are not specifically addressed to this, but the limitation is likely based on the quantity of 3 mg tablets available. 75 kg would be ten (10) 3 mg tablets. They rationed the tablets out.
Obviously the amount of drug given should not relate to the convenience of the trialists.
6 mg tabs are standard in Brazil. If placebo wasn’t 100% identical with inert ingredients , hard fail. 🛑
Boulware did the same thing in HCQ trial when he gave folate as placebo . Very subtle, but they always find a way to game the system 💰
I think they backed into an estimate of BMI by determining the maximum dose they would give first and I suspect it was 10 3 mg tablets for ease of distribution, i.e. a 75 kg body weight.
*edit* maybe closer to 80 kg to get to a 30 BMI based on an "average height" across genders? How many 6 mg tablets in a blister pack?
If so, that is poor science. Ivermectin can be compounded to exactly match BMI, as was done by an online practitioner for me. Compounded capsules could be made visually unidentifiable as to content. Alternatively, 6 mg pills could be fractionalized in a pill cutter.
it is incomprehensible to me why anybody would calculate BMI when in fact a far better indicator of proportion of fat is abdominal circumference. Much of the cytokine (IL 6)storm happens in the belly fat.
The under-dosing and PK no meal gaffe are inexcusable . Does anyone seriously think this is good science?
Very subtle, but there.
Poorly designed, with an apathetic PI more concerned about hurt feelings than achieving success 💰🤦♀️
No, actually, what I wrote is correct. I looked at dosing for parasites.
Secondly, the evidence for dosing requiring scaling with weight is discussed by the authors in their rationale.
However, the problem is none of those things. It's that they *said* they are dosing at 400mcg/kg but actually that wasn't the case for many of the patients, and it also wasn't the average dose.
Why wasn't the dosing weight limit disclosed on the paper itself?
As explained in the article, they underdosed compared to the dosing they themselves proposed in their protocol and reported in their paper.
Hey Stuart, what do you think about the Together trial including underdosed patients in their analysis?
Obviously anyone over 90kg got less than 400mcg/kg and anyone over 120kg got less than 300mcg/kg.
No mention of this in the discussion...worthy of a retraction or all A-OK?
Yet again Stuart you have dodged the point.
I’m only talking about the Together trial.
Good scientific standards dictate that a paper discusses its short comings. In this example there are potentially many patients underdosed compared to the desired dose of the trial.
Doesn’t matter whatever other studies showed.
This underdosing was not declared nor discussed.
Do you have a science background?
If yes, surely you must agree this is a massive oversight of the authors, potentially altering the outcome of the study.
Underdosed as compared to what everyone under 90kg got.
It was their choice to pick 400mcg/kg so they must have had some rationale for that choice