19 March 2018
Treatment and interpretation of LMTM trial data by Wilcock and colleagues  is reminiscent of the Monty Python sketch in which the demise of an obviously dead parrot is disputed by a desperate shop owner who describes it as merely resting, stunned or pining for the fjords. This phase 3 trial of 18 months' treatment in patients with mild Alzheimer's disease (AD) followed a 15-month study in mild to moderate patients that showed no treatment benefits for LMTM . The latest trial was also apparently negative. Faced with the task of how to best sell their own dead parrot, the authors present a case for the efficacy of LMTM-but only in AD patients not additionally treated with a cholinesterase inhibitor or memantine. In their introduction, the authors say: "As the originally intended analysis was unlikely to achieve its intended purpose, we modified the primary analyses and treatment comparisons in the TRx-237-005 Statistical Analysis Plan prior to database lock and unblinding to investigate whether the monotherapy differences could be confirmed as observational cohort comparisons defined as primary outcomes with strong control of family-wise type 1 error in the second independent study". The intention of any clinical trial will always be to test whether or not pre-specified drug-placebo differences achieve statistical and clinical significance. Once objectivity and respect for the conventions of clinical trial design are lost, so too is the value that can be placed upon one of Medicine's most trusted and powerful research tools. The statement of intent in the introduction is followed by an inventive analysis approach involving counter-intuitive, non-randomised, unmatched and unblinded participant group comparisons, which are themselves much more likely to have generated any apparent benefits than the unsupported theory that LMTM works to slow AD, but acetylcholinesterase inhibitor treatment sabotages this by impairing the clearance of tau monomers.
Monty Python's dead parrot was, of course, a Norwegian Blue. A challenge for those who design trials involving compounds based on methylene blue is that administration of these agents discolours participants' urine and faeces, quickly unblinding treatment allocation. Of all the claims made in the current report, the most remarkable is that the dose of 4mg of LMTM twice daily, chosen to act as a urine-colouring placebo, turned out to be as effective as the active intervention dose of 100mg twice daily, selected on the basis of earlier dose-ranging studies. It is worth bearing in mind that this group previously justified post-hoc exclusion of data from participants allocated to the highest dose of methylthioninium on the basis of unconvincing and unsupported mechanisms to generate an apparently positive outcome , but claims of efficacy based on data from placebo participants represent a whole new level of audacity.
The authors acknowledge some of the limitations of their analysis, but the overall message of the paper is misleadingly positive about LMTM's potential as an AD therapy. For example, there is no mention in the abstract of the overall non-significance of the originally intended primary outcome data and these are not presented in the paper. Convincing failure of LMTM in two large and well-conducted AD trials should have been sufficient to finally close down investigation of this agent. Conduct of future AD trials involving participants who are not receiving cholinesterase inhibitors or memantine should be acknowledged as hugely problematic, even by those who don't share our scepticism about the use of these latest data. Will potential participants be persuaded to forgo evidence-based treatments by a flimsy promise of disease modification based on the data? Will only patients who can't tolerate licensed dementia drugs (and very few are likely to be intolerant of memantine) be eligible for such a trial, in which case recruitment will be slow and participants highly unrepresentative? Even, in the unlikely event of demonstration of a degree of disease-modification in such a trial, is there a realistic market for an agent that cannot be given alongside the current symptomatic treatments?
We hope that the authors will quickly publish the results of the original full per protocol analysis. The search for AD-modifying treatments must now move on to other and more promising agents, despite what look like increasingly ridiculous efforts to nail LMTM's feet to its perch.
Robert Howard, Professor of Old Age Psychiatry, Division of Psychiatry, University College London, 149 Tottenham Court Road, London W1T 7NF, UK. E-mail: firstname.lastname@example.org.
Alex Berry, Core Trainee in Psychiatry, Camden and Islington NHS Trust, 4 St Pancras Way, London NW1 0PE, UK.
 Wilcock GK, Gauthier S, Frisoni GF, Jia J, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Schelter BO, Wischik DJ, Davis CS, Staff RT, Vuksanovic V, Ahearn T, Bracoud L, Shamsi K, Marek K, Seibl J, Riedel G, Storey JMD, Harrington CR, Wischik CM (2018) Potential of low dose leuco-methylthioninium bis(hydromethanesulphonamate) (LMTM) monotherapy for treatment of mild Alzheimer's disease: Cohort analysis as modified primary outcome in a phase III clinical trial. J Alzheimers Dis 61, 435-457.
 Gauthier S, Feldman HH, Schneider LS, Wilcock GW, Frisoni GB, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Wischik DJ, Schelter BO, Davis CS, Staff RT, Bracoud L, Shamsi K, Storey JMD, Harrington CR, Wischik CM (2016) 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 388, 2873-2884.
 Wischik CM, Staff RT, Bentham P, Murray AD, Storey JMD, Kook KA, Harrington CR (2015) Tau aggregation inhibitor therapy: An exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis 44, 705-720.