Methylene Blue Phase 3 failed?

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J11
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

Make a notation on your calendars!
The CTAD conference will help clarify the initial LMTM results (one hopes).

San Diego, USA – December 8-10, 2016

taurx has preannounced that the top line result of the next phase 3 will have a positive primary result.
Obviously want to tune into this one.

"Initial results from the second of the two TauRx Alzheimer’s disease Phase 3 trials (study TRx-237-005) confirm the monotherapy findings discussed in The Lancet publication and will be presented at the 9th Clinical Trials on Alzheimer’s Disease (CTAD) conference in December 2016. It is TauRx’s intention to publish the results of this second study shortly."


http://taurx.com/trx-237-015-publication-update.pdf


Hmm, looks like the Expedition3 presentation will be live streamed to the web.

The CTAD rules appear to prohibit what happened at ICAD with the first LMTM results.
So, no pre-announced press briefing.
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

Perhaps the title for this thread should have been:
Methylene Blue Phase 3 succeeded?

taurx has now released results from the second phase 3 trial in AD.
It was already known that they changed the statistical plan before database lock.
This phase 3 had been preannounced as being positive.

A positive phase 3 in AD is right up there with winning the lottery.

Yet, the press release from taurx is downright sedate.
Nowhere is it even mentioned that the trial was positive.

http://taurx.com/uploads/TRx-237-005-Ph ... -Trial.pdf
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

It ain't never over!

Looks like LMTX is coming back for another round.
Alzheimer News Today is reporting that LMTX will reenter clinical trials soon.

This is becoming super confusing!
I thought this one was over, done, finished.
Apparently not.

Perhaps the title of this thread was even more insightful then we at first realized.

https://content.iospress.com/download/j ... Fjad170560

http://taurx.com/uploads/press%20releas ... ebsite.pdf
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

The Methylene Blue AD Cure Celebration Thread can be devoted more to celebration than intense argumentation and
prolonged debate. The debating and other grumbling can take place more on this thread.

When looking at the results carefully, though it seems clear that MB/LMTX offers substantial anti-dementia effects.
Possibly some sort of breakthrough label from the FDA would now be appropriate. Possibly even a compassionate use/
Right to Try designation for MB would now be reasonable.
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

The complex, confusing and convoluted discussion of the various MB/LMTX trials can take place on this thread.
It will be essential for those commenting to have done all the required readings as there will be a quiz on their
contents.

The first assigned reading is the phase 2 trial article for Methylene Blue.
This does have a migraine inducing quality about it as there are seriously confusing pharmacokinetic issues that arise.

https://content.iospress.com/download/j ... Fjad142874


Briefly, the high dose 228 mg dose turned out not to be so high dosed because of the 100 mg gel caps used.
Of course to really separate the men from the boys, there is also a problem with fed/fasting.

http://jpet.aspetjournals.org/content/352/1/110.long

After a careful and close reading of the phase 2 trial, an article explaining in excruciating detail the deficiencies of the dosing used
in the trial should then be read with equal care.

From these two articles, after having read them thoroughly and thoughtfully, it becomes apparent that methylene blue
has a substantial anti-dementing effect. This can be discussed with others on the forum once the prerequisite thread materials have been explored.

The discussion becomes yet more intense when considering the phase 3 results for LMTX. Something to look forward to as you first contemplate the initial reading list.
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

Remember to post to this thread with all the confusing details of the MB/LMTX trials!
The Celebration thread can be there when we work through everything and we want a party!

Get going on the reading assignment!
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

OK, when you're ready let the conversation begin!
The phase 2 trial with Methylene Blue looks solid.

Methylene Blue is nearly a prehistoric medication.
It predates the FDA!
It was even used as a joke in medical schools due to its property of turning pee blue.
It is FDA approved and has been given in above gram dosing for some conditions.

http://taurx.com/phase-2.html

As can be seen in the Figure for the results from the phase 2 trial, MB had an enormous effect on
cognitive scores. It is difficult to argue with this result. Stabilizing cognitive scores for 2 years or more
has not been achieved in any other reported clinical trial in AD.
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

For starters we can slowly and carefully work through the phase 2 article.
https://content.iospress.com/download/j ... Fjad142874

Line number 1:
"Background:
As tau aggregation pathology correlates with clinical dementia in Alzheimer’s disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models."

We can agree to disagree on whether the question of MOA really should be of central concern for first in human evidence of potential effectiveness of MB. The overriding focus of attention should not be on why it works but instead does it. Considering the very large
effect size claimed determining whether it is effective should not be difficult to answer.

From https://clinicaltrials.gov/ct2/show/NCT ... 333&rank=1 I am now somewhat confused about what placebo was used. The clinicaltrials site says the placebo dose was 0 mg. We will need to keep this in mind when we read on further into the article. (I thought that they used a placebo of 8 mg to maintain blinding)

Quote 2:

"Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and
functional molecular imaging outcomes."

I think it is good to keep in mind that the objective was to find the minimum effective dose. This should not be thought of as the most effective dose of MT. While they dosed up to 200 mg, the actual effective dose that they found was 138 mg. It is entirely possible that a higher effective dose would be more effective.

In the results they report statistically and clinically significant results from the pre-specified analysis (possibly with some wiggle room because the trial did not totally go to plan). The results section of the Abstract notes that there was a problem with the top dosing arm. Also "in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected
p< 0.001).". This is an impressive result! Using a sensitive measure such as cerebral blood flow goes beyond the often erratic cognitive tests to peering at the health of the brain directly. How would one fake a cerebral blood flow test or even have a placebo response on it?

One additional confusion is that the clinical trials site is calling it 30, 60,100 mg tid. Yet, the trial doses were 69,138, 228 mg per day.
Also of note is that all on trial were not on standard of care AD drugs. I would want to see what the expected standard of care cognitive decline trajectory might be.

That is what I can see of interest for page 1. Only 15 pages to go!
Comments please!
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Re: Methylene Blue Phase 3 failed?

Post by J11 »

It is surprising that the phase 2 trial took 8 years to be published. The initial results were reported at ICAD and there was a tremendous amount of media interest in the results, especially as there was no other positive news of note for the amyloid approach at that meeting all those years ago.

The first item that I have encountered in the paper that presents me with a comprehension challenge is:

"This paper reports the primary and secondary outcomes at 24 weeks and a post hoc exploratory analysis at 50 weeks after the first extension of treatment."

I am not sure I understand what this means. The trial was blinded and placebo controlled for 2 years. What does the "post hoc" refer to? While it is true that re-randomizing does change the trial, though the results should still be valid. {I am not sure where the article reports the results for the full two years of the dosing. On the taurx site the phase 2 trial results show a figure in which the results are extended out to two years.

Not sure why they decided not to genotype APOE. APOE4 is a great way of selecting patients who actually have Alzheimer's. Otherwise it is not always easy to know. It is a great way to boost the credibility of any AD trial. Also I think it is fair to say that we are quickly moving to a time when full genome sequencing for all clinical trials will be the norm. I am interested to know which genotypes might especially benefit from MB. The second page also mentions that none of the patients in the trial were on standard of care AD medications. This takes away at least one of the problems that cropped up in the phase 3 trials.

So far so good. The article is reporting a solid result without all the confusions of the later trials. I am not sure what legitimate criticisms can be put forward for this trial.
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Re: Methylene Blue Phase 3 failed?

Post by Harrison »

J11 wrote:"This paper reports the primary and secondary outcomes at 24 weeks and a post hoc exploratory analysis at 50 weeks after the first extension of treatment." I am not sure I understand what this means. The trial was blinded and placebo controlled for 2 years. What does the "post hoc" refer to?
I only ran through the paper briefly, but I think this refers to the fact that pre-specified endpoint was at 24 weeks and people could change doses after that point. Therefore any analysis after that time point would have not been in the original data analysis plan. Many clinical trials have post-hoc analyses (subgroup examinations, etc) that rarely replicate which would explain why they are so careful to point it out.

J11, I appreciate your enthusiasm around this work, but the more I look at it, I see why clinicians are restrained. There are odd things like a 152mg dose being used as placebo in the extension when the most effective dose is 138mg. They claim this is because only 73 mg/day of the 152mg dose was actually bioavailable, but this is still not a placebo. This also explains why the 228mg dose is frequently less efficacious than 138mg: "The100 mg MTC gelatin capsule formulation used to deliver the 152 mg and 228 mg MT/day nominal doses was known, at the time that the study was initiated, to suffer from a dose-dependent dissolution limitation in water and simulated gastric fluid, although not in simulated intestinal fluid. There explains why there is no dose linearity, but why go with this formulation then if you know up front it has problems. I think the field is waiting for TauRx to run a complete study without all these caveats, subgroup analyses, etc.
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