- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01429623
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)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Graz, Austria, 8036
- Medizinische Universitat Graz, Abteilung fur Neurologie
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Hall in Tirol, Austria, 6060
- Landeskrankenhaus Hall, Memory Klinik
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Wien, Austria, 1130
- Privatordination Rainer
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Berlin, Germany, 13088
- Studienambulanz St. Joseph Krankenhaus Berlin, Emovis GmbH
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Magdeburg, Germany, 30120
- Otto-von-Guericke-Universitat, Universitatsklinik fur Neurologie und fur Stereotaktische
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Westerstede, Germany, 26655
- Studienzentrum Nordwest
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Beersheva, Israel, 84170
- Department of Geriatrics and Memory Clinic, Mental Health Center, Israel
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Haifa, Israel, 31096
- Cognitive Neurology Unit, Rambam Health Care Campus
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Haifa, Israel, 34362
- Cognitive Clinic, Department of Geriatrics, Carmel Medical Center
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Jerusalem, Israel, 91240
- Department of Physical Medicine and Rehabilitation, Hadassah University Hospital, PO Box 24035
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Ramat Gan, Israel, 52621
- Memory Clinic, Sheba Medical Center at Tel Hashomer
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Tel Aviv, Israel, 64239
- Center for Memory and Attention Disorders, Department of Neurology, Sourasky Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: ladostigil hemitartrate
10mg ladostigil base
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10mg ladostigil base administered once daily as hard gelatin capsule
Other Names:
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Placebo Comparator: Placebo Control
drug product excipients
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Placebo comparator
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo
Time Frame: 3,6,12,18,24,30 and 36 months
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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. Composite rating ranges from 0 no symptoms of dementia to 3 Severe symptoms of dementia. |
3,6,12,18,24,30 and 36 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population
Time Frame: 3,6,12,18,24,30 and 36 months
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Mean value change (from baseline) in Geriatric Depression Scale (GDS) across entire study period.
The GDS ranges from 0 to 30.
Scores of 0-9 are considered "normal", 10-19 "mildly depressed", and 20-30 "severely depressed".
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3,6,12,18,24,30 and 36 months
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Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population
Time Frame: 3,6,12,18,24,30 and 36 months
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Mean value change (from baseline) in Neuropsychiatric Test Battery (NTB) across entire study period.
The NTB included the following well known cognitive tests: Rey Auditory Verbal Learning Test (RAVLT), Controlled Word Association Test (COWAT), Category Fluency Test (CFT), WMS-R Digit Span, and Trail Making Part A and B. The mean value was comprised of the z score of each of these tests with all z scores in the direction of higher scores better functioning.
Range -3 to +3.
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3,6,12,18,24,30 and 36 months
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Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population
Time Frame: 3,6,12,18,24,30 and 36 months
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Mean value change (from baseline) in Disability Assessment in Dementia (DAD) across entire study period.
DAD evaluates the basic and instrumental activities in daily activities of elderly people with dementia.
Higher scores reflect better functioning.
DAD ranges from 0 to 100.
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3,6,12,18,24,30 and 36 months
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Tzvi Dwolatzky, MD, Director, Department of Geriatrics and Memory Clinic, Mental Health Center, Israel P.O. Box 4600, Beersheva 84170
Publications and helpful links
General Publications
- Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Backman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004 Sep;256(3):240-6. doi: 10.1111/j.1365-2796.2004.01380.x.
- DeCarli C, Frisoni GB, Clark CM, Harvey D, Grundman M, Petersen RC, Thal LJ, Jin S, Jack CR Jr, Scheltens P; Alzheimer's Disease Cooperative Study Group. Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia. Arch Neurol. 2007 Jan;64(1):108-15. doi: 10.1001/archneur.64.1.108. Erratum In: Arch Neurol. 2007 Mar;64(3):459.
- Schneider LS, Geffen Y, Rabinowitz J, Thomas RG, Schmidt R, Ropele S, Weinstock M; Ladostigil Study Group. Low-dose ladostigil for mild cognitive impairment: A phase 2 placebo-controlled clinical trial. Neurology. 2019 Oct 8;93(15):e1474-e1484. doi: 10.1212/WNL.0000000000008239. Epub 2019 Sep 6.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- CO17730
- 2011-004187-30 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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