Alzheimer's Cured by Methylene Blue Celebration Thread!

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Tue Dec 31, 2019 9:48 pm

Welcome to 2020 everyone!
A world cured of Alzheimer's dementia!

Methylene blue appears to be the cure that we have been waiting for.
If we can operationally define a cure for Alzheimer's as ~80+% reduction in
decline over one year loosely as a "cure", then evidence apparently supports
MB as such a cure.

The MB story has been evolving over a number of years, though we have now reached
the point where a more vigorous statement of efficacy for this treatment should be made.



While the clinical path for MB has been somewhat murky, it has become increasingly clear
that MB is the cure that we have sought.

The phase 2 trial was positive.
The first phase 3 trial was somewhat confused. However, after the statistical
analysis plan for the second phase 3 was updated, it reported out as positive.
A recent article has helped to clarify what occurred during the phase 3s and has
reported the correct treatment dose as 16 mg per day using an LMTM formulation.

After all these years of confusion, we can see the fog lifting.
I now have concerns that continuing yet another phase 3 trial is no longer ethically justified.
Perhaps what should happen is that monthly monitoring should be required for the trial.
Once nominal statistical significance of 5% is reached, the result should be reported.
There are so many millions of people currently afflicted with Alzheimer's dementia,
it no longer seems moral to continue studying what has already been proven.

Let the party begin!

PBW
Senior Contributor
Senior Contributor
Posts: 149
Joined: Fri Aug 25, 2017 8:23 am

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby PBW » Wed Jan 01, 2020 11:01 am

I have been sharing
#38 – Francisco Gonzalez-Lima, Ph.D." Advancing Alzheimer’s disease treatment and prevention – is AD actually a vascular and metabolic disease?" since it aired on Peter Attia's Broadcast. I purchased the Infra red Light and have been using it daily as he described for 3 months. Being that I am a 68 ApoE4/4 who has practiced Bredesens supplement recommendations since August 2017, Gundry's ApoE4/4 diet for a year plus added in this light therapy, I feel better than I have in years...no fogginess, good memory and energy. I am still waiting for improvement in oxLDL and homocysteine(also my TMOA and TSH were high for the first time in Aug) I don't know to what I attribute the energy and brain function....maybe all of the forementioned. I repeated bloodwork 12/15 and have a followup with Gundry 1-19-20. We will see.
Can you send the location of the Phase 2 or 3 trials that include" treatment dose as 16 mg per day "?
thanks

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Wed Jan 01, 2020 10:00 pm

Below tables and figure are from the second phase 3 trial of LMTM with the adjusted statistical plan that read out positive.
I wanted to instill a sense of finality with my original post for this thread: LMTM has already been proven effective in Alzheimer's.
A phase 2 trial and 2 phase 3 trials have provided definitive evidence.

Here's the second phase 3.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734125/

Here's the first phase 3. Figures show the same pattern of homogeneous addons and monotherapy subgroups.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164296/

Yet, I still wanted to crunch some numbers to understand the results better.
What put me off was that Comparison A in Table 2a compared all those on 4 mg bid with those on 100 mg bid monotherapy.

It occurred to me that this was the wrong comparison.
The 4 mg bid group was composed of those on monotherapy and those on add-on therapy.
So, this is a mixture of those who had a response and those who did not have a response.
Here the 4 mg group is supposed to be the "placebo" or non-treatment group.
I am not sure why this comparison was chosen, as the first phase 3 that had already been unlocked
had shown that the composite add on and monotherapy groups had heterogeneous treatment responses.

This can all be seen readily by looking at the figure below.
The 4 mg and 100 mg monotherapy treatment arms had almost the same treatment response.
The 4 mg and 100 mg add-on treatment arms also had almost the same treatment response.

What I found interesting was that I could work back the calculations in Table 2a.
For example, with ADAS-Cog Comparison A, the population standard deviation for the total 4 mg group was = 0.49
The individual SD1(per) = 9.7; likewise for the 100 mg monotherapy arm: SD (pop)= 1.11, SD2(per)= 9.9

When you plug all the values into the equation:

z= D/ [{{(SD1(pop)^^2)/n1} + {(SD2(pop)^^2)/n2}}^^0.5]

You find z= 2.59.
This is the exact result for the p-value presented 0.0047.

After gaining confidence that the expected calculations gave the correct results, I thought it would be interesting to
make what would seem the obvious comparison.

Namely Comparison D: compare the combinations of 4 mg bid and 100 mg bid add on with
4 mg bid and 100 mg bid monotherapy.

When you refer back to the figure below, this combination would seem to be the most rational.
Both pairs in the comparison appear to be very homogeneous.

When I crunched through the numbers using similar formulae as above I found a
z value = 5.1.

This corresponds to a p-value = 0.000 000 2
That is, 2 chances in 10 million.

I did the same calculation for the first phase 3 trial (combining the add ons into one group and then the
monotherapy into another group and then comparing them). This time the z- value was ~7.
The p-value was ~0.000 000 000 01.
1 chance in 100 billion.

The grand z value for both phase 3 trials combined was ~8.
The standard normal values aren't reported for 8 SD.
My best guess is that this p-value might be perhaps 1 in 10 trillion.

What is of additional interest is that we now know that the add-on treatment arms were not a true
non-treatment comparison. Methylene blue actually benefited those on add-on treatment, thus the
differences calculated above are actually underestimates.

When you complete your calculations and you realize that the 1 in 10 trillion p-value is quite probably
a highly conservative estimate, it is probably about time that the 44 million people coping with dementing
illness should be be given access to this treatment to help them.


Phase 3 Comparisons 1 Figure.PNG
[attachment=0]Phase 3 Comparisons 2.PNG

Phase 3 Comparisons 1.PNG
You do not have the required permissions to view the files attached to this post.
Last edited by J11 on Fri Jan 03, 2020 5:24 pm, edited 1 time in total.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Wed Jan 01, 2020 11:19 pm

PBW, here is the reference for 16 mg dosing. ~ 20 - 40 mg daily LMTM appears to provide optimal benefit as an AD therapy.
I discuss the research below.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918900/

An improved understanding of the pharmacokinetics of LMTM is emerging.
The 8 mg LMTM per day dose has a wide range of treatment response and is not optimal for all patients.
In fact, 8 mg appears to be the exact dose at which the dose- treatment response goes vertical.
I wonder whether they did a GWAS for this dose-response?

The current phase 3 trial with LMTM began with a treatment dose of 8 mg, though a 16 mg treatment arm was added to the trial in September 2018. Thus, taurx realized the dosing response implications sometime between February and September of 2018. With a 10 point difference in ADAS-COG with SD(per)= ~10, a 5% significant result would be obtained with a trial of only 20 total patients.

As can be seen from the figure, many patients, even on monotherapy did not derive optimal benefit at this dose as they had widely different effective concentrations which resulted in significantly different responses. Therefore in the recent research patients on the 8 mg dose were divided into 4 (also 5) subgroups based on actual drug exposure. The figure below shows large differences in treatment response at this same dose.

Roughly, 4 ADAS-Cog 11 points variation within the 8 mg subgroups. That is enormous!

This occurred for both the monotherapy group (on the top; black triangles to the left) and the addons (on the bottom to the left; white triangles). Moving all those on 8 mg monotherapy LMTM to ~ 16 mg per day would bring their expected decline in ADAS-COg 11 over 65 weeks to ~0, while removing the cognitive benefit received from the 8 mg LMTM in the add ons (white triangles) to ~0 (i.e., they would decline by ~9-10 decline on ADAS-Cog 11), would result all together in a massive treatment effect of ~ 9-11 ADAS Cog-11 points.

While the ADAS-COG and ADAS-Cog 11 are related they are not identical, even still the z calculations from the previous post would likely be similar with z values somewhat higher than the differences in scores. If this held true for this dataset then a z value of ~10 might be found (reflecting the ~ 9 ADAS Cog-11 difference between mono and addons). That would give a truly minuscule p-value of possibly millionths of trillionths.

Since the figure includes over ~ 1200 patients from the 2 phase 3 trials, it is able to provide a reasonably accurate relationship between dose and response. The treatment response maximum appears to occur somewhere between 10-50 mg/day. They called it 16 mg per day.

They also found that there was a dose response to MB even for those on add-on therapy. As can be seen at the 8 mg dose there is a large change in treatment response in both monotherapy and add-on. If they could move down the placebo dose of MB and move all the patients to a 16 mg per day dose the treatment effect could expand considerably. Those on higher doses (~100 mg) did not appear to derive much incremental benefit.

Of course, all of this is hopelessly confusing because phase 3 trials are not intended to provide active treatment to the placebo group. There should be no dosing curve with the active ingredient as can be seen in the figure with the white triangles and circles. The true comparison that should have been made is with those receiving no benefit from the active treatment. In the figure this is probably even lower than the lowest white triangle on the left. The comparison should then have been made with the patients treated at the maximum of the top black curve.

In the figure the comparison that was made in the trial was roughly the white circle on the right at 200 mg (labeled from the top) with the black triangle also at 200 mg {Call this x}. The true comparison that should have been made was the black triangle on the far right and the white triangle on the far left. Roughly, starting from the reported treatment effect of x, you should add another x to maximize LMTM efficacy to the top of the dose-response curve and then another x to move down the active treatment given to the placebo to find a true no treatment placebo: x + x + x = 3x. Therefore, the "true" (theoretical maximum) treatment effect was actually three times higher than that which was reported.

The fact that the phase 3 trials reported p values in the range of p < 0.0001 using the wrong comparison groups with only a fraction of the true treatment effect (masked by the partial treatment effect in the "non-active" arms) indicates the actual substantial magnitude of the treatment efficacy of LMTM in Alzheimer's.



Dosing 1.PNG



I had not realized that the Lucidity trial has not actually fully enrolled as indicated by clinical trials .gov.
The taurx website is reporting that the trial is now being reorganized and will soon start recruiting again.
Given all that we know now, it is difficult to understand why it is felt worthwhile to continue with a randomized clinical
trial. The treatment effects that they have already demonstrated are simply massive. It was not clear how to interpret the numbers when they were first reported. Yet, now it is becoming obvious that there is a way to describe all that has happened and that very large treatment effects are present (with further extensions to these effects already demonstrated) Simply dosing up patients to
the now recognized optimal dose ~ 16 mg per day should significantly enhance the previously reported results, while perhaps at the same time removing treatment gains from those supposedly on placebo. One of the last uncertainties is trying to figure out why the add-on therapy moderated the gains from LMTM.

With all that has now been presented, I suspect that we already have p-values of 1 in quadrillions or less.

It can be said with equal statistical significance that it is not moral to continue to pursue yet more implausible results
given that tens of millions of people with dementing illness currently face a probability for accessing an effective disease modifying treatment somewhere close to zero.
You do not have the required permissions to view the files attached to this post.

broiler_x
Senior Contributor
Senior Contributor
Posts: 49
Joined: Wed Aug 08, 2018 8:52 am

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby broiler_x » Thu Jan 02, 2020 1:19 pm

Why on earth did they do the trial where the control group was dosed at 8 mg/day? There had to be some rational reason, because these trials are very expensive to run. Sounds like a new trial does need to be done with better controls. I don't think the FDA could approve a treatment based on a trial where the control group was dosed with an active level of the same drug.

broiler_x
Senior Contributor
Senior Contributor
Posts: 49
Joined: Wed Aug 08, 2018 8:52 am

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby broiler_x » Thu Jan 02, 2020 1:48 pm

broiler_x wrote:Why on earth did they do the trial where the control group was dosed at 8 mg/day? There had to be some rational reason, because these trials are very expensive to run. Sounds like a new trial does need to be done with better controls. I don't think the FDA could approve a treatment based on a trial where the control group was dosed with an active level of the same drug.


I just did some digging to find the answer to my question. MB turns your urine blue, and the only way they could "blind" the patients in the trial was to give them a low dose that turned their urine blue. Otherwise, they would have know that they were receiving the placebo if their urine wasn't blue. That's unfortunate. If there is another unrelated and safe compound that turns urine blue, then maybe that would be a better control. Although that could also be seen as a confounding factor since the control could also be having an effect. In this case I'd say that having the patients not be blinded may be the best way to go as there is a ton of clinical trial data from failed drugs and essentially no placebo effect. For other non-AD drugs where a blind placebo is impossible due to similar reasons, they will sometimes just compare to historical data relating to normal progression of disease. Not as satisfying and convincing, but sometimes that's the best you can do.

PBW
Senior Contributor
Senior Contributor
Posts: 149
Joined: Fri Aug 25, 2017 8:23 am

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby PBW » Thu Jan 02, 2020 3:39 pm

J11..Thanks for the info. I willl tackle this reading later. I remember in Francisco's podcast he strongly spoke of mistakes that were made in interpretation of data and recommendations for doses. I think I will review that before I read this newer data....Getsall the wheels warmed up.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Thu Jan 02, 2020 5:58 pm

Phase 2 a.PNG


This figure is from a previous Methylene Blue thread; I am unable to locate it at this time on taurx.
What is of particular interest with this trial was that the placebo was in fact a true 0 mg methylene blue placebo.
Over a 2 year period the 138 mg daily methylene blue dose declined by only ~2 ADAS Cog point in the mild/moderate group, the placebo declined by 10 points! A large effect! The recent phase 3 trials gave me the impression that perhaps the therapeutic effect wore off after about a year; possibly somewhat like the Aricept type drugs that have no (or little) disease modifying power. 2 years of withholding decline is substantial and perhaps it continues to be effective into the future?

So there it is, the phase 2 trial showed that comparing MB with a true placebo the results were quite large over 2 years.
Interestingly, the 138 mg might not have even been the optimal dose. taurx apparently had believed that the 228 mg might have
been more effective. It is not clear; possibly even a higher dose would have been more effective. In some of the research they noted that (I am foggy about this, I think that it was reported in the most recent research article that I cited above {roughly LMTM was 20:1 more effective so a dose of 16 * 20 =320 mg ???}.

Also notable is that the current phase 3 trial with LMTM might actually be using methylene blue as the urine coloring agent. The phase 2 dosing curve suggests that methylene blue at low doses does not have an anti-Alzheimer effect. Figure 8 from the phase 2 trial (see below) suggests that a 10 mg dose of MB would have virtually zero anti-dementing effect. Drawing a straight line and interpolating 10 mg is probably not that accurate, though with this linear approximation there might be a third of a point ADAS-Cog benefit to the placebo group at 24 weeks in the current phase 3 trial (assuming 10 mg of MB is being used). It is only LMTM dosed around 10-20 mg that has a powerful anti-Alzheimer effect. Yet, 10 mg of MB is sufficient to turn urine blue. It would thus not be overly surprising if methylene blue at a low non-therapeutic dose is being used in the current phase 3 trial.

Phase 2 a.PNG



Yes, broiler_x, the more you read about the Methylene Blue/LMTM clinical trials, the more confusing it becomes. It is still a big mystery to me why they compared all those on 4 mg against the 100 mg monotherapy group in the second phase 3 (Comparison A). They already knew from the dataset from the first phase 3 that they had access to that the 4 mg monotherapy was significantly more effective than 4 mg add on(see below). Comparison A in the second phase 3 trial was thus comparing one treatment arm with a placebo arm and another treatment arm. Even with this handicap, the results were very statistically significant.


Figure 2 Phase 3 a.PNG
You do not have the required permissions to view the files attached to this post.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Thu Jan 02, 2020 6:22 pm

PBW, I will need to think about the laser light idea that you mentioned. I have read that some have combined light with MB, though I am unsure whether the research supports the use of non-invasive light. It would be very neat if one could dose with MB and then possibly shine a light on one's leg etc., and then this would activate the MB which could then travel to the brain and have an anti-AD effect. Unclear, though whether this is how it works.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Thu Jan 02, 2020 7:45 pm

This quote is from the phase 2 write-up. The important point mentioned here is that methylene blue is a prodrug for LMTM.
In order for MB to be absorbed it needs to be converted into the LMTM state. We can thus see how a ten fold lower dose of LMTM can be more powerful than MB.

I am somewhat unclear about the redox mechanism. In the blue bottle experiment, MB can constantly cycle back into LMTM and back. What would stop the LMTM from converting to MB at some point in digestion? Absorption requires that it be in the LMRM form, what would keep it in the MB state?

Also the issue of the fed state is noted in the quote. Not sure how this was resolved.

"In summary, MT is a redox molecule and, depending
on environmental conditions (e.g., pH, oxygen, reducing
agents), exists in equilibrium between a reduced
(leuco-methylthioninium, LMT) and oxidized form
(MT+). As the chloride salt (MTC) used in the phase
2 trial, MT exists entirely in the MT+ form in an oxygen
atmosphere. Active conversion to the LMT form
is required to permit absorption by passive diffusion
[17, 26]. This conversion occurs optimally in the stomach,
likely due to the pH dependence of the MT redox
potential [27]. MTC is therefore a pro-drug, and the
absorption and disposition of MT depend both on the
fed/fasting status and on dissolution time of the formulation
administered [17]."


Return to “Prevention and Treatment”

Who is online

Users browsing this forum: No registered users and 16 guests