Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989.
Single-evening cabergoline is an efficacious and well-tolerated short-term therapy for sensorimotor symptoms of restless legs syndrome and associated sleep disturbances.
We investigated the effects of zuclopenthixol on aggressive behaviour in patients with intellectual disabilities by randomly withdrawing it after a 6-week period of open treatment. Of the 49 patients responding to the treatment, 39 took part in a randomised withdrawal trial. The placebo subgroup (n=20) showed more aggressive behaviour as indicated by outcomes observed by external raters on the Modified Overt Aggression Scale than did the continuing subgroup (n=19). The results indicate that discontinuation of zuclopenthixolin this population leads to an increase in aggressive behaviour.
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