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
Intervention: ladostigil hemitartrate; Placebo
Intervention description: 10mg ladostigil base administered once daily as hard gelatin capsule; Placebo comparator
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 210.0
Sex: All
Minimum age: 55 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Mild Cognitive Impairment; Early Stage Dementia; Conversion to Alzheimer's disease; Memory Impairment

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.
    

Eligibility criteria:

        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