A 3 Year Study to Evaluate the Safety and Efficacy of Low Dose Ladostigil in Patients With Mild Cognitive Impairment

A 36-month, Multi-centre, Randomized, Double Blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Low Dose Ladostigil in Patients With Mild Cognitive Impairment (MCI)

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.

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.

Inclusion Criteria:

• Men and women (non-childbearing potential) with a diagnosis of Mild Cognitive Impairment (MCI) according to consensus criteria as defined by Petersen
• Abnormal memory function will be evaluated by Verbal Paired Associates from the Wechsler Memory Scale - Revised. Norm values for healthy adults in two age cohorts are: a) 50-70 years 19.7 (SD=2.9) and b) 75-95 years 18.3 (SD=2.8). Patients that score < or = 23 will be included.
• Clinical Dementia Rating (CDR) score of 0.5 (Memory box score 0.5 or 1, no box score > 1)
• Mini Mental State Examination (MMSE) > 24 and < or = 30
• General cognition and functional performance is sufficiently preserved such that a diagnosis of AD can be excluded by the site physician at the time of the screening visit.
• No significant cerebrovascular disease indicated by Modified Hackinski Ischaemic Score equal to or below 4
• Age 55-85 years based upon correlation of cognition and Scheltens score observed in this age range
• Geriatric Depression Scale (GDS) of < or = 5
• An informer who has frequent contact with the subject (e.g. an average of 10 hours per week or more) is available and agrees to monitor administration of study drug, to observe the subject for adverse events and to accompany the subject to clinical visits during the trial, if the presence of the informer is required.
• All patients have to undergo an MRI scan after the screening visit, i.e. during the screening visit, irrespective of MRIs having been performed prior to entry into the study. MRI findings have to be consistent with a diagnosis of MCI.
• Central rating of medial temporal lobe according to Scheltens scale. The right and left medial temporal structures will be rated separately and an overall estimate will be deduced using the average of the two ratings. An average score > 1 is required to make patients eligible for the study.
• Adequate visual and auditory acuity must be demonstrated to allow for neuropsychological testing.
• Good general health status acceptable for participation in a 36-month clinical trial, with no additional diseases expected to interfere with the study
• ECG without clinically significant abnormalities according to exclusion criteria listed below
• Subject is not pregnant, lactating or of childbearing potential (i.e. women must be two years post menopausal or surgically sterile)
• Signed informed consent by patient and informer prior to any study specific procedure

Exclusion Criteria:

• Failure to perform screening or baseline examinations

• Any significant neurological disease other than suspected MCI

• MRI exclusion criteria which allow for mild concomitant vascular lesions are:

  • Thromboembolic infarction
  • Other focal lesions which may be responsible for the cognitive status of the patient such as infectious disease, space-occupying lesions, normal pressure hydrocephalus or any other abnormalities associated with significant central nervous disease
  • More than one lacunar infarct defined as a focal lesion of CSF signal intensity with a diameter of < 1.5cm in any dimension
  • Any lacunar infarct in a strategically important location such as the thalamus, hippocampus of either hemisphere, head of the left caudate
  • White matter lesions involving more than 25% of the hemispheric white matter
  • Implants such as pacemakers, insulin pumps, cochlear implants, nerve stimulators, implantable cardioverter defibrillators, and other medical implants that have not been certified for MRI
  • Ferromagnetic foreign bodies such as shell fragments need to be considered on an individual basis
  • Metallic implants that can cause artifacts and RF induced heating such as surgical prostheses or aneurysm clips need to be considered on an individual basis

• Clinical or laboratory findings consistent with:

  • Central nervous system diseases such as those resulting from severe head trauma, tumours, subdural haematomas or other space occupying processes, etc
  • Seizure disorder
  • Other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc)

• History or evidence of schizophrenia or bipolar disorder (DSM IV criteria); active major depression

• Clinically significant advanced or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the patient or put the patient at special risk, such as:

  • Malignant tumours within the last five years except skin malignancies (other than melanoma) or indolent prostate cancer
  • Metastases
  • History of myocardial infarction within one year prior to screening or unstable or severe cardiovascular disease including angina or congestive heart failure with symptoms at rest
  • Uncontrolled hypertension (systolic pressure > 170mmHg or diastolic pressure > 100mmHg)
  • Bradycardia (persistent heart beat < 50/min) or tachycardia ( persistent heart beat > 100/min)
  • AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males > 450msec, females > 470msec)
  • Clinically significant obstructive pulmonary disease or asthma
  • Clinically significant laboratory findings that indicate abnormalities in blood biochemistry, blood haematology or urinalysis
  • Uncontrolled diabetes mellitus defined by HbA1c > 8.5
  • Clinically significant liver disease, coagulopathy or vitamin K deficiency within the past two years prior to screening
  • Renal insufficiency (serum creatinine > mg/dl or creatinine clearance < or = to 45ml/min according to Cockgroft-Gault formula); in case of creatinine clearance < or = 45ml/min, an alternative verification of the renal function must be completed using cystatin C analysis. In case of normal level of cystatin C, the patient can be included in the study.

• Any prior use of medications approved by local authorities for the treatment of Alzheimer's disease (e.g. tacrine, donepezil, rivastigmine, galantamine, memantine or other newly approved medications)

• Disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc)

• Women who are fertile and of child bearing potential

• Chronic daily intake of antidepressants as noted in section 9.5 of the clinical study protocol

• Suspected or known drug or alcohol abuse, i.e. more than approximately 60g alcohol (approximately 1 lter of beer or 0.5 liter of wine) per day as indicated by elevated MCV significantly above normal value at screening

• Suspected or known allergy to any components of the study treatments

• Enrollment in another investigational study or intake of investigational drug within the previous three months

• Any condition (e.g. epilepsy) which in the opinion of the investigator makes the patient unsuitable for inclusion