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

Background: LMTM acts as a selective tau aggregation inhibitor (TAI) in vitro and in transgenic mouse models. It is a stabilised reduced form of the methylthioninium (MT) moiety previously found to have potential efficacy in Alzheimer’s disease (AD). Methods: This 15-month randomised controlled parallel arm trial in mild or moderate AD tested doses of 75 mg and 125 mg given twice daily (b.i.d.) compared with a control dose of 4 mg b.i.d. to maintain blinding with respect to urine/faecal discolouration (NCT01689246, EudraCT 2012-002866-11). 891 patients were randomised to either active dose or control in a 3:3:4 ratio, and stratified by severity, global region and AD-labelled co-medication status. Progression on the ADAS-cog and ADCS-ADL scales were co-primary outcomes, with reduction in brain lateral ventricular volume (LVV) as a key secondary outcome. Findings: The prespecified primary analyses failed to demonstrate treatment benefit at either of the doses tested, but showed significant benefits for LMTM monotherapy relative to both controls and LMTM add-on therapy (ADAS-cog, p<0.0001; ADCS-ADL, p=0.0174). Prespecified analyses confirmed monotherapy treatment benefits for 150 mg/day (ADAS-cog -6.3 units, CI -8.9 – -3.6, p<0.0001; ADCS-ADL 6.5 units, CI 2.9 – 10.1, p=0.0013; LVV -2.7 cm3, CI -4.0 – -1.4, p=0.0002) and 250 mg/day (ADAS-cog -5.8 units, CI -8.5 – -3.1, p<0.0001; ADCS-ADL 6.9 units, CI 3.3 – 10.6, p=0.0007; LVV -2.4 cm3, CI -3.6 – -1.1, p=0.0012). The decline in patients taking LMTM as add-on therapy was indistinguishable from control. Gastrointestinal and urinary effects were the most common adverse events and causes for discontinuation, with non-clinically-significant dose-dependent reduction in haemoglobin the most common laboratory abnormality. Amyloid related imaging abnormalities were seen in fewer than 1% (8/885). Interpretation: The results suggest that LMTM as monotherapy may be an efficacious and safe treatment for mild to moderate AD, but there is an unexplained attenuation of the effect when used as add-on to available approved treatments. Funding: The study was financed by TauRx Therapeutics Ltd.