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    Summary
    EudraCT Number:2011-004187-30
    Sponsor's Protocol Code Number:CO17730
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-18
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2011-004187-30
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of Ladostigil to treat patients with Mild Cognitive Impairment.
    A.3.2Name or abbreviated title of the trial where available
    MCI - CO17730
    A.4.1Sponsor's protocol code numberCO17730
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAvraham Pharmaceuticals Ltd.
    B.1.3.4CountryIsrael
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAvraham Pharmaceuticals Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAvraham Pharmaceuticals Ltd.
    B.5.2Functional name of contact pointVice President of Clin Development
    B.5.3 Address:
    B.5.3.1Street Address42 Hayarkon Street
    B.5.3.2Town/ cityYavneh
    B.5.3.3Post code81227
    B.5.3.4CountryIsrael
    B.5.4Telephone number0097289324000
    B.5.5Fax number0097289324001
    B.5.6E-mailyg@avphar.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLadostigil hemitartrate
    D.3.2Product code Ladostigil hemitartrate
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLadostigil
    D.3.9.1CAS number 209394-46-7
    D.3.9.2Current sponsor codeLadostigil hemitartrate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patient with Mild Cognitive Impairment
    E.1.1.1Medical condition in easily understood language
    Patient with Mild Cognitive Impairment
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10009846
    E.1.2Term Cognitive impairment
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the trial is to assess whether 10 mg ladostigil q.d. can slow or stop the conversion from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) during a three year treatment period compared to placebo.
    The primary endpoint will be the percentage of subjects that progress from MCI to probable or possible AD according to NINCDS-ADRDA criteria. Conversion to AD will be determined using Clinical Dementia Rating (CDR).
    E.2.2Secondary objectives of the trial
    Secondary objective:
    The effect of 10 mg ladostigil q.d. on Geriatric Depression Scale (GDS), Neuropsychiatric Test Battery (NTB) and Disability Assessment in Dementia (DAD) compared to baseline will be determined as secondary outcomes.
    Time to conversion from MCI to AD will be analysed by means of Kaplan Meier’s survival method.
    Safety of 10 mg ladostigil will be evaluated.

    Explorative objective:
    The effect of 10 mg ladostigil q.d. versus placebo on changes (from baseline) in different cognitive domains using NeuroTrax Mindstreams computerized cognitive battery.
    The effect of 10 mg ladostigil q.d. versus placebo , at 12, 24 and 36 months, on changes in (from baseline) in hippocampal, entorhinal cortex and whole brain volume using MRI.
    The effect of 10 mg ladostigil q.d. versus placebo on immunological parameters and on MAO-B inhibition and circulating DHPG as indication of MAO-A inhibition will be evaluated.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women (non-childbearing potential) with a diagnosis of MCI according to consensus criteria as defined by Petersen and according to NIA recommendations.
    2. Abnormal memory function will be evaluated by Verbal Paired Associates from the Wechsler Memory Scale – Revised. Normal 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 ≤ 18 will be included.
    3. Clinical Dementia Rating (CDR) score of 0.5 (Memory box score 0.5 or 1, no box score greater than 1).
    4. Mini-Mental State Examination (MMSE) > 24.
    5. General cognition and functional performance sufficiently preserved such that a diagnosis of AD can be excluded by the site physician at the time of the screening visit.
    6. No significant cerebrovascular disease indicated by Modified Hachinski Ischaemic Score equal to or below 4.
    7. Age 55 - 85 years, because no significant correlation of cognition and Schelten's score has been observed above the age of 85.
    8. Geriatric Depression Scale (GDS) of less than or equal to 5.
    9. An available informer who has frequent contact with the subject (e.g. an average of 10 hours per week or more) who will agree 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.
    10. All patients will need to undergo an MRI scan after the screening visit, i.e. during the screening period, irrespective of MRIs having been performed prior to entry into the study. MRI findings have to be consistent with a diagnosis of MCI.
    11. Central rating of medial temporal lobe according to Schelten's scale [3]. The right and left medial temporal structures will be rated separately, and an overall estimate will be created using the average of the two ratings [5]. An average score > 1 is required to make patients eligible for the study.
    12. Adequate visual and auditory acuity must be given to allow neuropsychological testing.
    13. Good general health status acceptable for a participation in a 36-month clinical trial, with no additional diseases expected to interfere with the study.
    14. ECG without clinically significant abnormalities
    E.4Principal exclusion criteria
    1. Failure to perform screening or baseline examinations.
    2. Any significant neurologic disease other than suspected MCI.
    3. 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 less than 1.5 cm 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
    4. Clinical or laboratory findings consistent with:
    - Central nervous system diseases such as those resulting from severe head trauma, tumours, subdural haematoma 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.)
    5. History or evidence of schizophrenia or bipolar disorder (DSM IV criteria ). Active major depression.
    6. Clinically significant advanced or unstable diseases 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 with 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 > 170 mmHg or diastolic pressure > 100 mmHg).
    - Bradycardia (persistent heart beat < 50/min) or tachycardia (persistent heart beat > 100/min) at rest.
    - AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males > 450 msec, females > 470 msec)
    - 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 >2mg/dl or creatinine clearance ≤ 45 mL/min according to Cockgroft-Gault formula). In case of creatinine clearance ≤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.
    7. Any prior use of medications approved by local authorities for the treatment of AD (e.g. tacrine, donepezil, rivastigmine, galantamine, memantine or other newly approved medications).
    8. Disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.)
    9. Women who are fertile and of child bearing potential.
    10. Chronic daily intake of antidepressants as noted in section 9.5. of the clinical study protocol.
    11. Suspected or known drug or alcohol abuse, i.e. more than approximately 60 g alcohol (approximately 1 liter of beer or 0.5 liter of wine) per day indicated by elevated MCV significantly above normal value at screening.
    12. Suspected or known allergy to any components of the study treatments.
    13. Enrollment in another investigational study or intake of investigational drug within the previous three months.
    14. Any condition (e.g.epilepsy) which in the opinion of the investigator makes the patient unsuitable for inclusion.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the percentage of subjects that progress from MCI to probable or possible AD as determined by assessment of CDR during a three year treatment period. Upon verification of a clinical diagnosis of AD, Treatment of subjects will be discontinued, and the subject is removed from the trial thus becoming eligible to receive standard of care AD treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3, 6, 12, 18, 24, 30 and 36 months
    E.5.2Secondary end point(s)
    Secondary outcome measures will evaluate the effect of 10 mg ladostigil q.d. versus placebo on changes (from baseline) in NTB, GDS and DAD. The safety of 10 mg ladostigil will be evaluated.
    Exploratory outcome measures will evaluate the effect of 10 mg ladostigil q.d. versus placebo on changes (from baseline) in different cognitive domains using NeuroTrax Mindstreams computerized cognitive battery and the effect of ladostigil on disease modification will be evaluated using MRI for hippocampus and entorhinal cortex volume. The effect of 10 mg ladostigil q.d. versus placebo on immunological parameters and on MAO-B inhibition and circulating DHPG as indication of MAO-A inhibition will be evaluated. Interim analyses will be done optionally after 100 patients per each treatment arm have completed 52 and 104 weeks of treatment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    3, 6, 12, 18, 24, 30 and 36 months for NTB, DAD, GDS and Neurotrax.
    12, 24, 36 months for MRI.
    3, 6, 12, 24, 36 months for MAO-A and MAO-B.
    Immunology tests are only for Israel.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Germany
    Israel
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    "LVLS"
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard medical treatment for Mild Cognitive Impairmant or standard medical treatment for Alzheimer Disease in cases where the patient converted.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation N/A
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-12-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-07-26
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