Primary analysis was negative.
Those not taking AD drugs appeared to benefit.
http://www.multivu.com/players/English/ ... 511063.pdf
Here's the taurx take.
taurx is calling the Phase 3 trials with methylene blue in those not taking AD drugs an unequivocal success.
See first July 27 1:00 PM
The press release talks of disclosing results "27 July 2016, 16:15-17:45"
Toronto time? or Aberdeen?
http://taurx.com/press-releases/
We want methylene blue for our loved one NOW!
The phase 3 FTD trial result analysis seems to be extremely complex.
The trial ended months and months ago and the results were expected to be presented in Toronto.
They are now expected in Munich in late August.
Requiring such a long analysis time hints that this analysis truly is extremely complex.
http://taurx.com/taurx-phase-3-trial-tr ... mentia.pdf
taurx is a private company.
One way to get a feel for what the market thinks of this is to look at the companies with standard of care treatment.
If LMTX only works as a monotherapy, then it suggests that these other treatments will no longer be the standard of care.
Apparently due to the length of time these drugs have been on the market, they all have generic forms.
The nearly 7 point change in ADAS-ADL scores represents a nearly complete halt to AD progression.
If this result can be further clarified, then this could be what we have been waiting for.
http://jama.jamanetwork.com/article.asp ... id=1810379
Problem here might be that the subgroup they are talking about is likely quite small.
I wonder if this means another study will be needed to confirm the result?
It appears though that Taurx has already proven it's point.
Why do another study?
Looks like the main event is 4:15-5:45 today!
Would love to know how many people were in the monotherapy subgroup.
I would think it would be smallish.
We really need to push for this presentation to be live streamed on the net.
Perhaps one of the delegates could use their cell phone?
The online press reports seem to be headlining the result as a success and only noting not hitting the
primary endpoints in the small print.
Methylene Blue Phase 3 failed?
Methylene Blue Phase 3 failed?
Last edited by J11 on Fri Dec 08, 2017 11:56 pm, edited 1 time in total.
Re: Methylene Blue Phase 3 failed?
An update on the results from the LMTX phase 3 trial in mild to moderate AD (MMSE 14-26) announced today at ICAD.
This randomized trial with a posted enrollment on clinical trials.gov of 891 had 2 LMTX treatment arms of 150 and 250 mg / day along with a placebo group that took a small amount of LMTX to remain blinded.
It is not clear how many patients were in each of these three arms.
Media reports are suggesting that 15% of those treated were on monotherapy. These were the responders.
Assuming that this is 15% of the 50% in the treatment group(?), then 70 patients would have received monotherapy treatment with LMTX, or 135 if the 15% were meant to apply to the entire clinical trial (this is not clear).
Another large Phase 3 trial this time in mild AD (MMSE 20-26) apparently also saw a benefit for those on monotherapy. It would be quite possible that these patients should have done even better than the patients reported in the trial today as it was thought that milder AD patients would more respond to tau drugs.
Will greatly look forward to seeing a better crunching of the numbers.
There is still yet another phase 3 trial in FTD that will also be soon reported.
Media is also questioning why the full placebo group was used that is placebo group included those who were
not taking any AD medications (this would have been a fairly small number). The idea would be that
the monotherapy LMTX group should have been tested against the best standard of care and not those
receiving no treatment.
This randomized trial with a posted enrollment on clinical trials.gov of 891 had 2 LMTX treatment arms of 150 and 250 mg / day along with a placebo group that took a small amount of LMTX to remain blinded.
It is not clear how many patients were in each of these three arms.
Media reports are suggesting that 15% of those treated were on monotherapy. These were the responders.
Assuming that this is 15% of the 50% in the treatment group(?), then 70 patients would have received monotherapy treatment with LMTX, or 135 if the 15% were meant to apply to the entire clinical trial (this is not clear).
Another large Phase 3 trial this time in mild AD (MMSE 20-26) apparently also saw a benefit for those on monotherapy. It would be quite possible that these patients should have done even better than the patients reported in the trial today as it was thought that milder AD patients would more respond to tau drugs.
Will greatly look forward to seeing a better crunching of the numbers.
There is still yet another phase 3 trial in FTD that will also be soon reported.
Media is also questioning why the full placebo group was used that is placebo group included those who were
not taking any AD medications (this would have been a fairly small number). The idea would be that
the monotherapy LMTX group should have been tested against the best standard of care and not those
receiving no treatment.
Last edited by J11 on Fri Dec 08, 2017 11:58 pm, edited 1 time in total.
Re: Methylene Blue Phase 3 failed?
FWIW, here's MedPage Today's commentary.
Re: Methylene Blue Phase 3 failed?
Oh, you mean the most suspicious company in the world turned out to be a scam?
viewtopic.php?f=18&t=1184&p=13283&hilit ... ous#p13283
viewtopic.php?f=18&t=1184&p=13283&hilit ... ous#p13283
Re: Methylene Blue Phase 3 failed?
This could soon become a whole bunch more suspiciouser.
Yesterday taurx said that the second phase 3 also showed the monotherapy effect.
However, here is the interesting part.
taurx changed the primary endpoint and the statistical plan on the second phase 3 trial before database lock.
The big question is: Did they change the primary endpoint to the monotherapy group?
I sure would have done that if I were them.
If they have done this, then the next headline from taurx will be " Success! Second Phase 3 trial of LMTX hits primary endpoint"
I am starting to have some doubts, though because the monotherapy group really isn't blinded.
People knew whether they were taking other AD drugs or not and so did the doctors who were caring for them.
This seems to add quite a bit of possible confounding.
https://www.thestreet.com/story/1365308 ... ilure.html
This is excellent news about taurx moving these phase 3 into an open label extension.
Perhaps they could move the entire extension into a placebo controlled trial of monotherapy LMTX versus best standard of care.
Yesterday taurx said that the second phase 3 also showed the monotherapy effect.
However, here is the interesting part.
taurx changed the primary endpoint and the statistical plan on the second phase 3 trial before database lock.
The big question is: Did they change the primary endpoint to the monotherapy group?
I sure would have done that if I were them.
If they have done this, then the next headline from taurx will be " Success! Second Phase 3 trial of LMTX hits primary endpoint"
I am starting to have some doubts, though because the monotherapy group really isn't blinded.
People knew whether they were taking other AD drugs or not and so did the doctors who were caring for them.
This seems to add quite a bit of possible confounding.
https://www.thestreet.com/story/1365308 ... ilure.html
This is excellent news about taurx moving these phase 3 into an open label extension.
Perhaps they could move the entire extension into a placebo controlled trial of monotherapy LMTX versus best standard of care.
Re: Methylene Blue Phase 3 failed?
It is not clear to me why so many have considered the taurx trial a failure.
We are now only months away from the results of the second AD phase 3 that has already been reported to be positive in the
monotherapy subgroup. Why have so many called this a failure when the rebuttal is so close at hand?
I think it is good to go to the primary sources.
From the taurx press release:
"Study TRx-237-015, was a randomised double-blind placebo-controlled study in 891 subjects with mild or moderate Alzheimer’s disease that compared treatment for 15 months with LMTX® with placebo.
... in the pooled analysis, the primary analysis model showed a highly significant effect of treatment in the patients taking LMTX® as monotherapy. This treatment benefit was confirmed in a prespecified supportive analysis of all of the study’s primary and secondary outcomes. This is the first treatment in which a clinical effect has been supported by evidence in delay of progression in brain atrophy shown by MRI scans. ...
The results we have seen in this study confirm the results we saw in our Phase 2 study, where an earlier version of the drug was also given as monotherapy. The results we see in those patients not taking Alzheimer’s disease medications show the considerable potential of LMTX® as a monotherapy for both mild and moderate Alzheimer’s disease. ...
An initial analysis of data from the second of TauRx’s two Phase 3 trials in Alzheimer’s disease, study TRx-237-005 undertaken in 800 patients with the mild form of the disease, confirms the findings of study TRx-237-015 and supports the potential of LMTX® as monotherapy. ...
The ADAS-cog decline analysis produced highly statistically significant treatment effects of -6.3 +/-1.4 (p<.0001) and -5.8 +/-1.4 (p<.0001) units after taking 75mg b.i.d or 125mg b.i.d of LMTX® as monotherapy respectively, while the ADCS-ADL decline analysis produced a statistically significant treatment effect of 6.5 +/-1.8 (p=.0013) and 6.9 +/-1.9 (p=.0007) following treatment of 75mg b.i.d or 125mg b.i.d of LMTX® as monotherapy respectively.
LMTX® taken as monotherapy also slowed down the rate of progression of brain atrophy as measured by LVV derived from MRI scans. There was a reduction in the expansion of the LVV by 38%+/-9% (p=.0023) and 33%+/-9% (p=.0014) for 75mg twice a day and 125mg twice a day, respectively, compared to the control in these patients. These reductions in LVV expansion were statistically significant and confirmed by corresponding increases in the whole brain volumes in the same patient groups."
Those p values on the two treatments arms are small p<.0001,p<.0001, 0.0013, 0.0007, p<0.0001, p<0.0001, p=0.0023, p=0.0014. This isn't even for the combined treatment group!
There were 135 patients on the monotherapy so this is not an exercise of speculation based on very small numbers. With the
bapineuzumab phase 2 subgroup analysis there might have been less than ten in the different dosing arms and subgroupings by
APOE4 status. The APOE4 numbers on monotherapy for the first phase 3 of LMTX might even be worth looking at.
We know that the second phase 3 was also positive. I am greatly looking forward to the meta-analysis of all the studies.
The phase 3 trial yesterday included several Eastern European nations which are thought to have uncertain quality control in their clinical trial process. This was mentioned in the coverage as one possible reason why the monotherapy subgroup might have shown the strong result reported yesterday. However, the second phase 3 trial that is to be disclosed more fully later this year did not include Eastern European nations. The result for the second phase 3 trial has already been disclosed as positive in the monotherapy subgroup. The second phase 3 trial will be in mild AD whereas the first was in mild-moderate AD. In the phase 2 trial the mild AD patients showed less of a benefit at some of the early time points.
In the second trial the mild patients will be treated for longer 78 weeks (versus 65 in the first trial). There were 19% (150) versus 15% (135) patients on monotherapy in the first and second phase 3 trials respectively. Each of these trials might have roughly equal power to detect changes in mental status.
As I mentioned above, if taurx has changed the primary endpoint as the monotherapy subgroup on the second trial, then the headline statement for the trial will be Success.
Of course the first phase 3 trial is already 35 weeks past the time of the datalock. If those patients have continued to be treated, then there will already be a huge dataset that has accumulated on them. Of additional note, is that this first phase 3 trial also included APOE genotyping (while the second one did not). I am sure many on the forum will be interested to see how this sub subgroup fared in the different treatment arms.
I am now fairly encouraged that the answer either yeah or nay is now within sight. With 2000 patients in the 3 phase 3 trials, it should not be unexpected that a truly definitive answer will be presented at ICAD 2017 in London. The effect size that taurx is claiming will be too large to ignore in even a smallish follow on study. We should know soon.
We are now only months away from the results of the second AD phase 3 that has already been reported to be positive in the
monotherapy subgroup. Why have so many called this a failure when the rebuttal is so close at hand?
I think it is good to go to the primary sources.
From the taurx press release:
"Study TRx-237-015, was a randomised double-blind placebo-controlled study in 891 subjects with mild or moderate Alzheimer’s disease that compared treatment for 15 months with LMTX® with placebo.
... in the pooled analysis, the primary analysis model showed a highly significant effect of treatment in the patients taking LMTX® as monotherapy. This treatment benefit was confirmed in a prespecified supportive analysis of all of the study’s primary and secondary outcomes. This is the first treatment in which a clinical effect has been supported by evidence in delay of progression in brain atrophy shown by MRI scans. ...
The results we have seen in this study confirm the results we saw in our Phase 2 study, where an earlier version of the drug was also given as monotherapy. The results we see in those patients not taking Alzheimer’s disease medications show the considerable potential of LMTX® as a monotherapy for both mild and moderate Alzheimer’s disease. ...
An initial analysis of data from the second of TauRx’s two Phase 3 trials in Alzheimer’s disease, study TRx-237-005 undertaken in 800 patients with the mild form of the disease, confirms the findings of study TRx-237-015 and supports the potential of LMTX® as monotherapy. ...
The ADAS-cog decline analysis produced highly statistically significant treatment effects of -6.3 +/-1.4 (p<.0001) and -5.8 +/-1.4 (p<.0001) units after taking 75mg b.i.d or 125mg b.i.d of LMTX® as monotherapy respectively, while the ADCS-ADL decline analysis produced a statistically significant treatment effect of 6.5 +/-1.8 (p=.0013) and 6.9 +/-1.9 (p=.0007) following treatment of 75mg b.i.d or 125mg b.i.d of LMTX® as monotherapy respectively.
LMTX® taken as monotherapy also slowed down the rate of progression of brain atrophy as measured by LVV derived from MRI scans. There was a reduction in the expansion of the LVV by 38%+/-9% (p=.0023) and 33%+/-9% (p=.0014) for 75mg twice a day and 125mg twice a day, respectively, compared to the control in these patients. These reductions in LVV expansion were statistically significant and confirmed by corresponding increases in the whole brain volumes in the same patient groups."
Those p values on the two treatments arms are small p<.0001,p<.0001, 0.0013, 0.0007, p<0.0001, p<0.0001, p=0.0023, p=0.0014. This isn't even for the combined treatment group!
There were 135 patients on the monotherapy so this is not an exercise of speculation based on very small numbers. With the
bapineuzumab phase 2 subgroup analysis there might have been less than ten in the different dosing arms and subgroupings by
APOE4 status. The APOE4 numbers on monotherapy for the first phase 3 of LMTX might even be worth looking at.
We know that the second phase 3 was also positive. I am greatly looking forward to the meta-analysis of all the studies.
The phase 3 trial yesterday included several Eastern European nations which are thought to have uncertain quality control in their clinical trial process. This was mentioned in the coverage as one possible reason why the monotherapy subgroup might have shown the strong result reported yesterday. However, the second phase 3 trial that is to be disclosed more fully later this year did not include Eastern European nations. The result for the second phase 3 trial has already been disclosed as positive in the monotherapy subgroup. The second phase 3 trial will be in mild AD whereas the first was in mild-moderate AD. In the phase 2 trial the mild AD patients showed less of a benefit at some of the early time points.
In the second trial the mild patients will be treated for longer 78 weeks (versus 65 in the first trial). There were 19% (150) versus 15% (135) patients on monotherapy in the first and second phase 3 trials respectively. Each of these trials might have roughly equal power to detect changes in mental status.
As I mentioned above, if taurx has changed the primary endpoint as the monotherapy subgroup on the second trial, then the headline statement for the trial will be Success.
Of course the first phase 3 trial is already 35 weeks past the time of the datalock. If those patients have continued to be treated, then there will already be a huge dataset that has accumulated on them. Of additional note, is that this first phase 3 trial also included APOE genotyping (while the second one did not). I am sure many on the forum will be interested to see how this sub subgroup fared in the different treatment arms.
I am now fairly encouraged that the answer either yeah or nay is now within sight. With 2000 patients in the 3 phase 3 trials, it should not be unexpected that a truly definitive answer will be presented at ICAD 2017 in London. The effect size that taurx is claiming will be too large to ignore in even a smallish follow on study. We should know soon.
Re: Methylene Blue Phase 3 failed?
This has now started to become very confusing.
taurx is confirming that the primary analysis for the second phase 3 will be for the monotherapy group.
They have already stated that the monotherapy group in the second trial had a positive result.
Therefore, the second phase 3 has hit its primary endpoint.
If the primary endpoint is all that matters, then can the second trial be called a success?
Not necessarily.
It appears that there could have been quite a bit of confounding.
The patients in the monotherapy LMTX group were probably slow progressors that is likely why they
chose not to be treated with standard of care. They were compared with those on placebo who were on
standard of care probably because they were fast progressors.
How do you write a catchy headline that the primary endpoint was reached, though it was not valid?
Fortunately, all this should be cleared up when the results of the open label extension are known next year.
The three phase 3 trials would have a range of rates of progression that have been documented in the trial for
over a year for each patient. Selecting only those who were not progressing or might not have even had
Alzheimer's would not apply during the open label.
http://www.alzforum.org/news/conference ... ork-period
taurx is confirming that the primary analysis for the second phase 3 will be for the monotherapy group.
They have already stated that the monotherapy group in the second trial had a positive result.
Therefore, the second phase 3 has hit its primary endpoint.
If the primary endpoint is all that matters, then can the second trial be called a success?
Not necessarily.
It appears that there could have been quite a bit of confounding.
The patients in the monotherapy LMTX group were probably slow progressors that is likely why they
chose not to be treated with standard of care. They were compared with those on placebo who were on
standard of care probably because they were fast progressors.
How do you write a catchy headline that the primary endpoint was reached, though it was not valid?
Fortunately, all this should be cleared up when the results of the open label extension are known next year.
The three phase 3 trials would have a range of rates of progression that have been documented in the trial for
over a year for each patient. Selecting only those who were not progressing or might not have even had
Alzheimer's would not apply during the open label.
http://www.alzforum.org/news/conference ... ork-period
Re: Methylene Blue Phase 3 failed?
The second LMTX phase 3 result (this one in bvFTD) is now expected soon.
Fasten your seat belts everyone!
http://taurx.com/taurx-phase-3-trial-tr ... mentia.pdf
Fasten your seat belts everyone!
http://taurx.com/taurx-phase-3-trial-tr ... mentia.pdf
Re: Methylene Blue Phase 3 failed?
Error alert!
In the above article: Table 2, the entry at the intersection of the row labeled Lateral ventricular volume, and the column labeled taking LMTM as monotherapy is -0.13 (-0.42 to -0.16), p = 0.6158. This is clearly wrong. -0.13 is not at the mid-point of the 95% confidence interval. If the "-0.16" were converted to "0.16", then it would be logically consistent. Why didn't they ask J11 to help out? I am here to help! Just send me a pre-print and I'll make sure everything is on the straight and narrow.
The LMTM results are even more puzzling than when I originally signed on. Apparently, the 4 mg monotherapy "placebo" arm had a large treatment effect versus the 4 mg on AD standard of care "placebo" arm. That is quite odd. In fact the treatment effect of the monotherapy placebo nearly matches the treatment effects seen in the 75 mg and 125 mg monotherapy arms.
What does this imply? One would think that the most parsimonious explanation is that these apparent large treatment effects in the 4 mg monotherapy group highlight how highly distorting this particular study design can be. For example, there was a large percentage of those on monotherapy who left the study, these patients were self-selected and they were aware and chose not to take other AD medications.
Instead of pursuing this more plausible line of thought the above article chose the unexpected explanation that the 4 mg "placebo" monotherapy arm showed such a large relative benefit over the other 4 mg arm because 4 mg of LMTM was much more powerful an anti-dementia treatment than anyone had anticipated. Connecting the dots in this way starts to resemble the paths that demented mice take to find the water platform or painting the bullseye around the dart after it has been thrown.
Apparently, the 4 mg arm had such a powerful apparent effect that there will be no measurable difference when comparing monotherapy treatment (75 mg and 125 mg) and monotherapy placebo (4 mg). The only comparison that is left is to compare the monotherapy treatment arms with the placebo arm especially those on standard of care. This is to say we are pretty much left comparing apples with watermelons.
In the above article: Table 2, the entry at the intersection of the row labeled Lateral ventricular volume, and the column labeled taking LMTM as monotherapy is -0.13 (-0.42 to -0.16), p = 0.6158. This is clearly wrong. -0.13 is not at the mid-point of the 95% confidence interval. If the "-0.16" were converted to "0.16", then it would be logically consistent. Why didn't they ask J11 to help out? I am here to help! Just send me a pre-print and I'll make sure everything is on the straight and narrow.
The LMTM results are even more puzzling than when I originally signed on. Apparently, the 4 mg monotherapy "placebo" arm had a large treatment effect versus the 4 mg on AD standard of care "placebo" arm. That is quite odd. In fact the treatment effect of the monotherapy placebo nearly matches the treatment effects seen in the 75 mg and 125 mg monotherapy arms.
What does this imply? One would think that the most parsimonious explanation is that these apparent large treatment effects in the 4 mg monotherapy group highlight how highly distorting this particular study design can be. For example, there was a large percentage of those on monotherapy who left the study, these patients were self-selected and they were aware and chose not to take other AD medications.
Instead of pursuing this more plausible line of thought the above article chose the unexpected explanation that the 4 mg "placebo" monotherapy arm showed such a large relative benefit over the other 4 mg arm because 4 mg of LMTM was much more powerful an anti-dementia treatment than anyone had anticipated. Connecting the dots in this way starts to resemble the paths that demented mice take to find the water platform or painting the bullseye around the dart after it has been thrown.
Apparently, the 4 mg arm had such a powerful apparent effect that there will be no measurable difference when comparing monotherapy treatment (75 mg and 125 mg) and monotherapy placebo (4 mg). The only comparison that is left is to compare the monotherapy treatment arms with the placebo arm especially those on standard of care. This is to say we are pretty much left comparing apples with watermelons.