A 3 Year Study to Evaluate the Safety and Efficacy of Low Dose Ladostigil in Patients With Mild Cognitive Impairment
Condition: Mild Cognitive Impairment; Dementia
MeSH terms: Dementia; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether treatment with the investigational drug
      ladostigil will delay the onset of Alzheimer's disease(AD) in patients with Mild Cognitive
      Impairment (MCI). MCI is now recognized as a precursor to AD and clinical tools are available
      to assess cognitive performance at this earlier stage. Ladostigil is currently under
      investigation for the treatment of AD. In this study, the investigators will be examining
      ladostigil at a lower dose level. At this dose level, ladostigil has been shown to reduce
      signs of early memory loss in animals. Thus, in this study the investigators are attempting
      to determine if earlier invention with a lower dose of ladostigil will significantly reduce
      initial memory loss and delay the subsequent progression to more serious cognitive
      dysfunction.
    

Detailed description: 
      Ladostigil shows neuroprotective activity, reducing oxidative stress, activating microglia,
      and inhibiting pro-inflammatory cytokines in pre-clinical models. Study assessed its safety
      and potential efficacy in a 3-year, randomised, double-blind, placebo-controlled, phase 2
      clinical trial in patients with mild cognitive impairment (MCI). Patients from 16 centers in
      Austria, Germany and Israel with MCI (Albert et al 2011), Clinical Dementia Rating (CDR) =
      0.5, Mini-Mental State Examination (MMSE) > 24, Wechsler Memory Scale - Revised Verbal Paired
      Associates ≤ 18, and medial temporal lobe atrophy were stratified by APOE4 genotype and
      randomly assigned (1:1 allocation) using blocks of 4, to receive either ladostigil, 10 mg per
      day, or placebo as identically-appearing capsules. The primary endpoint was onset of
      Alzheimer's disease (AD). Secondary endpoints were the NTB, DAD, and GDS. Exploratory
      outcomes were MRI-derived whole brain, hippocampus, and entorhinal cortex volumes; the
      NeuroTrax Mindstreams computerized cognitive battery; and the CDR. Between February 17, 2012
      and August 1, 2013, we randomly allocated 210 patients to placebo (107 patients) or
      ladostigil (103 patients); 4 patients in each group lacked post baseline assessments. After
      36 months 20.4% (21 of 103 patients) of the placebo group and 14.1% (14 of 99 patients) of
      the ladostigil group progressed to AD (log-rank test p=.16). There were no significant
      effects on NTB, DAD, or GDS outcomes. There was less decline in whole brain volume in the
      ladostigil group as compared to placebo (p<.02), but not hippocampus and entorhinal cortex
      volumes, and CDR and a trend for less decline on the RAVLT total delayed score component of
      the NTB (p=.09). Fourteen patients taking placebo and 21 taking ladostigil discontinued
      treatment because of adverse events. Serious adverse events were reported by 26 (25.2%)
      patients in the ladostigil group and 28 (26.2%) patients in the placebo group. Ladostigil
      appeared safe, well-tolerated, and may have potential for improving memory and delaying
      progression to dementia.
    

Intervention name(s): ladostigil hemitartrate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 10mg ladostigil base administered once daily as hard gelatin capsule; Placebo comparator
Other intervention name(s): ladostigil; Ladostigil capsules
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Mild Cognitive Impairment; Early Stage Dementia; Conversion to Alzheimer's disease; Memory Impairment