E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patient with Mild Cognitive Impairment |
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E.1.1.1 | Medical condition in easily understood language |
Patient with Mild Cognitive Impairment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009846 |
E.1.2 | Term | Cognitive impairment |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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).
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
3, 6, 12, 18, 24, 30 and 36 months |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |