| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with probable Alzheimer's Disease (AD) diagnosis according to NINCDS-ADRDA and DSM–IV criteria, who suffer from mild to moderate dementia with a Mini Mental State Examination (MMSE) of 15-26 |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10001897 |
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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 |
Assessment of tolerability, safety and MTD of different dose ranges of ladostigil in AD patients
Pharmacokinetic assessment of ladostigil and its metabolites.
Pharmacodynamic assessment of Ladostigil (in a study subpopulation ): (a) Inhibition of plasma and erythrocyte cholinesterase (ChE) (b) Inhibition of MAO-B in platelets (c) DHPG levels in plasma |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subjects of 60 years of age and older.
2. Gender distribution: men and women.
3. Diagnosis of probable Alzheimer’s disease according to DSM-IV (290.00 or 290.10) and NINCDS-ADRDA criteria.
4. Degree of dementia: MMSE score of ≥15 and ≤26 at Screening
5. Ambulatory or ambulatory-aided outpatients (i.e., walker or cane).
6. Corrected vision and corrected hearing sufficient for compliance with testing procedures.
7. Subjects must have a caregiver with whom they have daily contact (e.g., an average of 10 or more hours per week), and can observe possible adverse events, can assist the patient in study medication administration and can accompany the patient to all visits.
8. Subjects must be able to read, write and speak the local language.
9. Subjects and caregiver must be willing and able to give written informed consent prior to entering the study.
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| E.4 | Principal exclusion criteria |
1. Subjects taking acetylcholine esterase inhibitors within 8 weeks prior to screening.
2. Subjects taking memantine within 4 weeks prior to screening.
3. Subjects taking MAO inhibitors within 3 months prior to screening.
4. Neurological disorders affecting cognition other than Alzheimer’s Disease.
5. Neurological disorders, other than Alzheimer’s Disease that may be accounted for the dementia as verified by brain imaging (CT or MRI) obtained within 12 months prior to screening.
6. History of Schizophrenia or bipolar affective disorder.
7. Dementia complicated by delirium (DSM 290.30 or 290.11).
8. Any behavioral impairment within the last month prior to screening which in the discretion of the investigator could effect the subject’s ability to comply with study protocol (such as severe agitation).
9. Drug or alcohol abuse or dependence during the previous 5 years by DSM-IV criteria.
10. Abnormal laboratory values which are considered by the investigator to be of clinical significance.
11. Non-treated vitamin B12 deficiency.
12. Uncontrolled hypothyroidism.
13. Any acute or chronic clinically significant conditions affecting absorption, distribution, or metabolism of the study medication.
14. Significant or unstable medical or surgical condition which would preclude safe and complete study participation.
15. Uncontrolled hypertension (sitting systolic BP≥160 mmHg and/or diastolic ≥90 mmHg) regardless of whether or not the patient is taking antihypertensive medications.
16. Two or more abnormal blood pressure readings according to exclusion criterion number 15 during home blood pressure recording at screening period.
17. Uncontrolled Insulin or Non Insulin Dependant Diabetes Mellitus.
18. A current diagnosis of bradycardia (Heart rate<50 BPM), sick sinus syndrome or specific conduction deficits (sino-atrial block, second or third degree atrio-ventricular block, LBBB).
19. Donation of blood or blood products during 30 days prior to screening or plans to donate blood while participating in the study or planned donation within 30 days after completion of the study.
20. Patients and/or caregivers who are unwilling or unable to fulfill the requirements of the study.
21. Known hypersensitivity to cholinesterase inhibitors or MAO or MAO-B inhibitors.
22. Use of any experimental medication within 3 months prior to screening or as concomitant medications.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Outcome Measures:
• Safety of and tolerability of ladostigil will be monitored and evaluated by:
o Safety:
Adverse events
Vital signs
ECG
Clinical laboratory parameters
o Tolerability:
Number of subjects who terminated the study early.
Number of subjects who terminated the study early due to AE.
• Pharmacokinetic evaluation of ladostigil and its metabolites in plasma.
• Pharmacodynamic evaluation of ChE inhibition in serum and erythrocytes and evaluation of MAO-B inhibition in platelets.
Additional Assessments: Psychometric evaluation:
• ADAS-cog
• NPI
• CSDD
• CGIC
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Sequential Cohort Designed, Escalating Dose Study |
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| 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 | Information not present in EudraCT |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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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| If unexpected safety concerns will rise during the trial, the sponsor keeps the right to discontinue 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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