Title:Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild ormoderate Alzheimer's disease: a randomised, controlled, double-blind,parallel-arm, phase 3 trial.

Authors: GauthierS, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, Moebius HJ,Bentham P, Kook KA, Wischik DJ, Schelter BO, Davis CS, Staff RT, Bracoud L,Shamsi K, Storey JM, Harrington CR, Wischik CM.

Journal: Lancet.2016 Nov 15.

Abstract

BACKGROUND:

Leuco-methylthioniniumbis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioniniummoiety, acts as a selective inhibitor of tau protein aggregation both in vitroand in transgenic mouse models. Methylthioninium chloride has previously shownpotential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM wassafe and effective in modifying disease progression in patients with mild tomoderate Alzheimer's disease.

METHODS:

We did a 15-month, randomised, controlleddouble-blind, parallel-group trial at 115 academic centres and privateresearch clinics in 16 countries in Europe, North America, Asia, and Russiawith patients younger than 90 years with mild to moderate Alzheimer's disease.Patients concomitantly using other medicines for Alzheimer's disease werepermitted to be included because we considered it infeasible not to allow theirinclusion; however, patients using medicines carrying warnings ofmethaemoglobinaemia were excluded because the oxidised form of methylthioniniumin high doses has been shown to induce this condition. We randomly assignedparticipants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, orcontrol (4 mg LMTM twice a day to maintain blinding with respect to urine orfaecal discolouration) administered as oral tablets. We did the randomisationwith an interactive web response system using 600 blocks of length ten, andstratified patients by severity of disease, global region, whether they wereconcomitantly using Alzheimer's disease-labelled medications, and site PET capability.Participants, their study partners (generally carers), and all assessors weremasked to treatment assignment throughout the study. The coprimary outcomeswere progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale(ADAS-Cog) and the Alzheimer'sDisease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessedat week 65 in the modified intention-to-treat population. This trial isregistered with Clinicaltrials.gov (NCT01689246) and the European UnionClinical Trials Registry (2012-002866-11).

FINDINGS:

Between Jan 29,2013, and June 26, 2014, we recruited and randomly assigned 891 participants totreatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mgLMTM twice a day). The prespecified primary analyses did not show any treatmentbenefit at either of the doses tested for the coprimary outcomes (change inADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02,-1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43,-2·06 to 1·20, p=0·9323; change inADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to1·26, p=0·8659; 125 mg LMTM twice a day-0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were themost common adverse events with both high doses of LMTM, and the most commoncauses for discontinuation. Non-clinically significant dose-dependentreductions in haemoglobin concentrations were the most common laboratoryabnormality. Amyloid-related imaging abnormalities were noted in less than 1%(8/885) of participants.

INTERPRETATION:

The primary analysis for this study was negative, andthe results do not suggest benefit of LMTM as an add-on treatment for patientswith mild to moderate Alzheimer's disease.Findings from a recently completed 18-month trial of patients with mildAlzheimer's disease will be reported soon.

FUNDING:

TauRx Therapeutics.

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