. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016 Dec 10;388(10062):2873-2884. Epub 2016 Nov 16 PubMed.

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  1. Primary results from the Phase 3 study of LMTX were not significant, but a significant treatment effect was reported in a subgroup of approximately 15 percent of ACTIVE patients who were not taking concomitant ACHEI therapy. Unfortunately, the analysis did not actually make a comparison within the subgroup as was implied, but instead compared the active group patients who were not on ACHEI to the total placebo group, including both those on and those not on ACHEI therapy. This is a totally inappropriate comparison, since progression rates often differ between those on and not on ACHEI therapy. If the appropriate comparison of ACHEI non-users on active treatment to ACHEI non-users on placebo had been significant, it would have been shown. There are no positive results that have been presented yet, even for the subgroup.

    Most criticism of these results is based on three opinions: 1. It's a post hoc subgroup analysis and only primary analyses should be considered. 2. Changing the primary analysis for the second Phase 3 study is "moving the goal posts." 3. Studies done outside of first-world countries may be suspect. Post hoc analyses can be appropriate, but they have to meet a higher standard than pre-specified analyses. Changing the primary analysis for an unblinded study may also be appropriate under the right circumstances. Studies may be done appropriately outside of first-world countries. But comparing all control subjects to a subgroup of active subjects is like comparing apples to oysters.

    I have no business relationships with TauRx or any tau-based programs.

    View all comments by Suzanne Hendrix
  2. The lack of using the proper placebo control group for this post-hoc analysis was the most glaring omission in the initial presentation and only brought to light when the questioning period started. Dr. Gauthier alluded the sister study had similar results, and I would hope they take a lesson here to present the data in a more acceptable way. If there truly is an effect, there needs to be a good hypothesis as to why. Again, this was not addressed in the presentation nor in any of the press releases so far. One could suppose this population may not have been truly demented or became more stabilized with the study procedures and oversight as surmised above.

    Overall, while interesting, I think caution is warranted before making claims of "effective treatment" without the statistics to back it up. Even if the signal is there, a confirmatory monotherapy study will assuredly be required before the FDA is going to accept it.

    View all comments by Thomas Zoda
  3. Dr. Aisen correctly notes that the alpha was spent on the analysis of the co-primary outcome measures, meaning that any subsequent analyses carry the risk of an inflated type I error. The fact that this sub-group analysis was pre-specified suggests that it was not the result of a massive hunting expedition for a nominally significant result, but it’s not clear just how many post-hoc comparisons were carried out.

    What was not discussed at the presentation was why there were patients diagnosed with mild to moderate AD who were not being treated despite there being approved therapies. Where did these subjects come from? Why were they not being treated? Were they more or less impaired than the ones being treated with acetylcholinesterase inhibitors/memantine?

    One minor correction regarding type I error: If one carries out 20 comparisons using a p-value of 0.05, the probability of at least one comparison having a p-value less than 0.05 is approximately 64 percent.

    View all comments by Michael Gold
  4. It is great that the Alzforum journalists set the record straight. There have been a lot of hyped and misleading news releases on this topic. The methylene blue drug trial has failed. Few people in the research area are surprised by this.

    At the end of the day, the scientists have the last word. The small effect of the monotherapy can only be classified as a pilot study. The stats are shaky, and we all have seen this before. One should not forget that there is a company behind all this that is trying to keep investments going.

    View all comments by Christian Holscher

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  1. In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period.