Alzheimer's Cured by Methylene Blue Celebration Thread!

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J11
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Fri Jan 03, 2020 6:31 pm

Dosing 1 Compare.png



My understanding of the analysis of the methylene blue results continues to evolve.

I no longer believe that a 9 point difference in ADAS- COG will plausibly be reported for the ongoing
phase 3 study. Typical mild-moderate trials report a decline in placebo of roughly 4 points on ADAS-COG
at 52 weeks. It is unclear to me how the article cited above developed a model in which addons with 0 MB
had declines of 11 ADAS COG at 65 weeks. How did they find 11 points when placebo decline is known to ~4?

With all the information that we now have, a reasonably accurate estimate can be made for what the
current phase 3 trial will report.


Using the formula:



D
z= -------------------------------------------------------------------

{[ (SD1(per) ^^2 /n1) + (SD2(per)^^2/n2)]^^0.5}


There are good estimates or known values for all the quantities in the above equation.

We know n1 and n2.

taurx has reported: n1 = 150
n2 = 300


SD1(per) will represent the placebo standard deviation at week 52 for individuals.
Large studies have reported values = ~ 8 in mild moderate patients.

SD2(per) will represent the methylene blue standard deviation at week 52 for individuals.
Using the error bars in the figure above my estimate is SD2(per) = ~8.5
(though this is at week 65 and perhaps with a different mix of mild moderate patients)


D With optimal dosing of LMTM, there appears to a stabilization of cognitive ability through at least week 52.
The sub-optimal dosing in the phase 2 with 138 mg of MB demonstrated a point or two of decline in ADAS-COG.
The article cited above found in the combined phase 3 samples high dose monotherapy arms a slight improvement
in two of the 3 arms. A zero change from baseline in ADAS-COG at week 52 is a good estimate. Those patients
who might try some of the ideas found on this forum might do somewhat better.

The change from baseline in placebo in mild moderate Alzheimer's patients from large studies has been found
to be ~ 4 ADAS-COG points (as noted above).



Putting this all together:
(We'll start by using SD1(per) =10 and SD2(per)=10 because the numbers are easier.)

z = 4 / ( (100/150) + (100/300))

z = 4 / 1 = 4

This is a quite good estimate of what the current LMTM phase 3 trial with 150 placebo and 300 LMTM 16 mg patients
should report in 2-3 years time. Almost all of the above numbers are known to reasonable precision. There is some
wiggle room, though as the trial started dosing at 8 mg which we now know is not an optimal dose. There is also
some uncertainty in the effect size. However, even here such uncertainty is not very large. The placebo decline
in ADAS-COG is a known quantity. The treatment group should roughly stop declining when the tau process is interrupted
yet probably would not do much better than achieving stasis.

Given the above the trial should be expected to report a p-value of 0.000 03.
30 chances in a million.


With the more accurate values of SD1(per) = 8 and SD2(per) = 8:

z= 4 / 0.8 = 5
p-value = 0.000 000 3

3 chances in 10 million.


These updated and more accurate estimates for the statistical readout of the current LMTM
phase 3 trial, highlight once again that the trial should be concluded. The treatment effect of
optimally dosed LMTM is clearly overwhelming. Stopping progression of Alzheimer's dementia
is impressive now as it was 12 years ago when it was first reported. However, now the
uncertainties that originally confused the discussion have been clarified and the many
patients that could benefit from this treatment should be quickly given access to it.
a much better understanding of
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J11
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Sat Jan 04, 2020 2:56 pm

I have investigated the ADAS-COG scores further.
It appears that 4.5 ADAS-COG is roughly the expected decline at 52 weeks.

Yet, many of the previous large AD studies went to 78 weeks.
At 78 weeks the ADAS-COG typically declined by ~ 4-6 points in mild patients and ~10-12 points in moderate patients.

taurx has recently amended the phase 3 trial protocol to include moderate AD patients.
A trial with moderate patients would double the z-value on ADAS-COG at 52 compared to mild patients resulting in a dramatically reduced p-value.

If the current taurx phase 3 trial were to have continued past 52 weeks, then the p-values would have become even more infinitesimally small than what I have already suggested. In the formula noted before, the z-value depends almost entirely on the value of D (the numerator). The denominator which is roughly equal to 1 can laregly be ignored. Thus, if the trial had been composed of moderate patients treated to 78 weeks, the z value would have been roughly 10. Standard normal tables only typically report up to ~5. There is no 10 z. The z value would continue to increase through time as AD patients continue to lose ~ 4 (mild) - ~7 (moderate) ADAS-COG points every year.


When the LMTM phase 3 trials first reported the p-values had seemed implausibly small to me. Even without maximizing the comparisons, they were still reporting values as small as p<0.0001. Yet, with most other AD trials even with a thousand+ patients treated for 78 weeks it was still not possible to hit a statistically significant result at p<0.05 and an effect size on ADAS-COG of much more than 1.

However, here we are now with a trial of 450 patients treated for 52 weeks which will report a p value << ~10-5 and an effect size of at a minimum 4 ADAS-COG, completely stopping AD progression. Understanding how the numbers are derived is helpful to develop confidence that these seemingly absurdly small values are in fact completely validated by theory.


In this New Year, given the extremely low p-values that have already been achieved in the trial, I hope that the phase 3 trial can be soon converted to an open label extension for all the patients and that there is rapid access of LMTM to help all those coping with Alzheimer's dementia and their caregivers. We can then move forward and find treatments that can reverse Alzheimer's!

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

Postby J11 » Sat Jan 04, 2020 8:34 pm

Phase 3 ADAS-COG.PNG


Notice that in the middle panel of the figure that the 75 mg monotherapy
dose in the Mild-Moderate phase 3 showed a 2.5 point ADAS-COG benefit at the middle
hash mark which represents week 40 and is still significantly greater than zero on the
green circle one to the right which is week 52. The far right hash mark is week 64.
Absolute improvement is not entirely unexpected, though the previous dosing curve
indicated that the benefit would fall just below zero for monotherapy at all doses.

Given the results from this figure with 75 mg dosing, this assumption perhaps could
be questioned. Choosing the 16 mg dose instead of a higher dose of ~ 75 mg might lose this incrementally gain.
Notably previous trials have been unable to even attain a 2.5 point ADAS-COG gain.

The monotherapy doses at week 64 did not show decline over baseline. This is a substantial preservation
of cognition over a time period exceeding one year. This is very impressive. Having better insight into how
mild versus moderate AD patients respond would be welcome.
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby Sam-J » Sun Dec 20, 2020 11:05 am

PBW wrote: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


Hi PBW,
I have also listened and interview with Dr. Gonzalez-Lima on the Podcast Evolving Past Alzheimer and learned about the Laser light treatment that could be applied to the forehead to stimulate neurons. So I was curious to know where did you purchase the "Infra red light" you mention and how do you apply it?

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

Postby PBW » Sun Dec 20, 2020 1:03 pm

I have 2 lights , RedRush 360 and RedRush720now so I can do full body. My neighbor has JOOV panels(4) so he and his family can also do full body. Both of those companies are quality although JOOV is pricier. I use it 20-30 minutes per day about 5 times per week. Don't know how it is working for my brain because I am also on Bredeson's supplement protocol, fast 36 hours 1X per week, eat a basic keto diet and exercise regularly. I have also added Vit K Complete to possible help my body remove LDL's instead of recirculating them (N-1 study for 3 months). So any of these changes could be the reason I am feeling clear and healthy. Both my siblings are progressing rapidly into dementia(neither have completed genetic testing but since I am a 4/4 they have to have at least one 4. I continue to have difficulty with very short term memory...where did I put those keys...kinda stuff. However I am studying chemistry for the first time, learning to create things with natural wood and driving myself and my dogs to florida solo from Colorado once a year. So hanging in trying to do everything I can to prevent or slow down onset. Fog was pretty bad 3 years ago...now gone.

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

Postby Sam-J » Mon Dec 28, 2020 6:58 am

PBW wrote:I have 2 lights , RedRush 360 and RedRush720now so I can do full body. My neighbor has JOOV panels(4) so he and his family can also do full body. Both of those companies are quality although JOOV is pricier. I use it 20-30 minutes per day about 5 times per week. Don't know how it is working for my brain because I am also on Bredeson's supplement protocol, fast 36 hours 1X per week, eat a basic keto diet and exercise regularly. I have also added Vit K Complete to possible help my body remove LDL's instead of recirculating them (N-1 study for 3 months). So any of these changes could be the reason I am feeling clear and healthy. Both my siblings are progressing rapidly into dementia(neither have completed genetic testing but since I am a 4/4 they have to have at least one 4. I continue to have difficulty with very short term memory...where did I put those keys...kinda stuff. However I am studying chemistry for the first time, learning to create things with natural wood and driving myself and my dogs to florida solo from Colorado once a year. So hanging in trying to do everything I can to prevent or slow down onset. Fog was pretty bad 3 years ago...now gone.


Thanks so much for replying PBW, and for sharing your story. It sounds like you are doing pretty good so congratulation for that!
I am trying to help my Mom who has one copy of APOE4 and is experiencing a lot short time memory difficulties.
The Red lights you mentioned can do full body which confuses me a little because in the interview I heard with Dr. Gonzalez-Lima, he said the light he was using was applied to the forehead only (as a way to reach neurons) which make sense to me. However I am not too sure if he was using the red lights or other kind of light, in any case, it seems to be worth to try the lights you mentioned.
Do you use something to protect your eyes when you apply the light?

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

Postby PBW » Sun Jan 10, 2021 3:14 pm

Sorry for the delay. D r Gonzalez-Lima may have using the very costly light that enters into the brain through the naval cavity. I can't afford that light and am going on the research that it easily passes through dense particles and energizes the mitochondria much like plugging into an electrical socket. So I am hoping that utilizing the light on my head as well as using it all over my body along with MSN and resveratol daily and fasting 36 hours weekly, I am doing everything I can to maximize the aging process of my brain cells and all other cells. Just purchasing the smaller red light might be just fine for your mom. I also do not remember if the good doc used light therapy concurrently with methylene Blue. Hope this helps. We are all flying by our gut using what science we have .

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

Postby J11 » Sat Jan 30, 2021 6:22 pm

Yea, taurx!

OK time for some multiple posts. I know I know the people can't take anymore of these posts, well what needs to be done needs to be done. taurx is really stepping up for the AD community. This needs to be a headline for us.

The below post with Braak Stage is suggesting that LMTM is being thought of as a population scale anti-dementing agent.
"48% of over-45 population have brain tau pathology 26% are at Braak stage 2 or beyond= 70 million in EU/US alone in 2020"
Basically everyone should be dosing with it through out their lives.
And...

"Current expensive diagnostic work up and ineffective treatments need to be replaced by early economical diagnostics and early disease modifying treatment" Basically this is going to be an epic money drop. They are thinking of this in terms of mass scale and at prices that make sense at the consumer level. This is a blueprint for a money printing press. I have talked to those who likely need aducan and their response was even if it worked 100K per yearly treatment did not work them. Developing an effective treatment is only stage one, stage two is an effective treatment that is realistically affordable LMTM check 1 check 2. taurx could put a big Goodwill entry on their balance sheet if they go with the low cost huge revenue strategy.

Probably would be good to bring taurx to the capital markets sooner than later. It is always nice to have capital markets confirm what seems to be obvious. Yet, those who are close to the research probably want to hold this until all the inherent value of the company is fully disclosed in clinical studies. Perhaps an aducan approval could force their hand to stop the Lucidity trial early.
If they only need 5% nominal statistical significance they have probably already achieved this. No great reason to show off a great number of leading zeros in the p-value. I am glad that they went with p<0.0001, as I posted somewhat relentlessly about this, it is on a pro calculated basis probably a great deal lower than 0.0001, but at some point it is much more realistic to simply truncate some leading zeros, as the constraints of reality intrude more so than the theoretical stats.



https://taurx.com/media-news/taurx-to-p ... conference

https://ts-assets.ams3.cdn.digitalocean ... an2021.pdf
Last edited by J11 on Sat Jan 30, 2021 6:48 pm, edited 2 times in total.

J11
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Sat Jan 30, 2021 6:28 pm

Evidence.GIF
Pathology Market.GIF
Timeline.GIF
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Postby J11 » Sat Jan 30, 2021 6:28 pm

Clinical 3.GIF
Clinical 2.GIF
Clinical 1.GIF
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