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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Avraham Pharmaceuticals Ltd
ClinicalTrials.gov Identifier:
NCT01429623
First received: September 3, 2011
Last updated: July 22, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Mild Cognitive Impairment
Dementia
Drug: ladostigil hemitartrate
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Avraham Pharmaceuticals Ltd:

Primary Outcome Measures:
  • Conversion from Mild Cognitive Impairment to Alzheimer's disease compared to placebo [ Time Frame: 3,6,12,18,24,30 and 36 months ] [ Designated as safety issue: No ]
    Total number of conversions from Mild Cognitive Impairment to Alzheimer's disease across entire 3 year study period. Conversion is determined, or defined, by a Clinical Dementia Rating (CDR) score of greater than or equal to one.


Secondary Outcome Measures:
  • Change in Geriatric Depression Scale for ladostigil versus placebo population [ Time Frame: 3,6,12,18,24,30 and 36 months ] [ Designated as safety issue: No ]
    Mean value change (from baseline) in Geriatric Depression Scale across entire study period.

  • Change in Neuropsychiatric Test Battery for ladostigil versus placebo population [ Time Frame: 3,6,12,18,24,30 and 36 months ] [ Designated as safety issue: No ]
    Mean value change (from baseline) in Neuropsychiatric Test Battery across entire study period.

  • Change in Disability Assessment in Dementia for ladostigil versus placebo population [ Time Frame: 3,6,12,18,24,30 and 36 months ] [ Designated as safety issue: No ]
    Mean value change (from baseline) in Disability Assessment in Dementia across entire study period.

  • Safety of 10mg ladostigil versus placebo treatment. [ Time Frame: 3,6,9,12,15,18,21, 24, 27, 30, 33 and 36 months ] [ Designated as safety issue: Yes ]
    Clinical laboratory safety data will be collected at 3,6 12,18,24,20 and 36 months. Vital signs will be measured and adverse events (including changes to concomitant medications) will be documented at all study visits (i.e. 3,6,9,12,15,18,21,24,27,30,33 and 36 months).

  • Time to development of probable or possible Alzheimer's disease [ Time Frame: 3, 6, 12, 18, 24, 30 and 36 months ] [ Designated as safety issue: No ]
    Mean time to development of probable or possible Alzheimer's disease (according to NINCDS-ADRDA criteria) for ladostigil versus placebo conversion populations. Development of, or converion to, Alzheimer's disease will determined by a Clinical Dementia Rating (CDR) score of greater than or equal to one. Time to conversion from MCI to AD will be analysed by means of Kaplan Meier's survival method.


Estimated Enrollment: 200
Study Start Date: January 2012
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ladostigil
10mg ladostigil base
Drug: ladostigil hemitartrate
10mg ladostigil base administered once daily as hard gelatin capsule
Placebo Comparator: Placebo Control
drug product excipients
Drug: Placebo
Placebo comparator

  Eligibility

Ages Eligible for Study:   55 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01429623

Locations
Austria
Medizinische Universitat Graz, Abteilung fur Neurologie
Graz, Austria, 8036
Landeskrankenhaus Hall, Memory Klinik
Hall in Tirol, Austria, 6060
Privatordination Rainer
Wien, Austria, 1130
Germany
Studienambulanz St. Joseph Krankenhaus Berlin, Emovis GmbH
Berlin, Germany, 13088
Otto-von-Guericke-Universitat, Universitatsklinik fur Neurologie und fur Stereotaktische
Magdeburg, Germany, 30120
Studienzentrum Nordwest
Westerstede, Germany, 26655
Israel
Department of Geriatrics and Memory Clinic, Mental Health Center, Israel
Beersheva, Israel, 84170
Cognitive Clinic, Department of Geriatrics, Carmel Medical Center
Haifa, Israel, 34362
Cognitive Neurology Unit, Rambam Health Care Campus
Haifa, Israel, 31096
Department of Physical Medicine and Rehabilitation, Hadassah University Hospital, PO Box 24035
Jerusalem, Israel, 91240
Memory Clinic, Sheba Medical Center at Tel Hashomer
Ramat Gan, Israel, 52621
Center for Memory and Attention Disorders, Department of Neurology, Sourasky Medical Center
Tel Aviv, Israel, 64239
Sponsors and Collaborators
Avraham Pharmaceuticals Ltd
Investigators
Principal Investigator: Tzvi Dwolatzky, MD Director, Department of Geriatrics and Memory Clinic, Mental Health Center, Israel P.O. Box 4600, Beersheva 84170
  More Information

Publications:
Responsible Party: Avraham Pharmaceuticals Ltd
ClinicalTrials.gov Identifier: NCT01429623     History of Changes
Other Study ID Numbers: CO17730, 2011-004187-30
Study First Received: September 3, 2011
Last Updated: July 22, 2013
Health Authority: Austria: Agency for Health and Food Safety
Germany: Federal Institute for Drugs and Medical Devices
Israel: Ministry of Health

Keywords provided by Avraham Pharmaceuticals Ltd:
Mild Cognitive Impairment
Early Stage Dementia
Conversion to Alzheimer's disease
Memory Impairment

Additional relevant MeSH terms:
Dementia
Cognition Disorders
Mild Cognitive Impairment
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders

ClinicalTrials.gov processed this record on October 01, 2014