Clinical Drug Experience Knowledgebase

Criteria

Inclusion Criteria:

Men and women (non-childbearing potential) with a diagnosis of Alzheimer's disease according to McKhann (2011) criteria
Age 50-85 years (50-80 in Czech Republic)
MRI or CT assessment within six months before baseline, corroborating the clinical diagnosis of AD and excluding other potential causes of dementia, especially cerebrovascular lesions (see exclusion criteria, number 3)
CSF AD specific biomarker profile; positive, defined as CSF Aβ42 < 550 ng l-1 or an Aβ 40/42 ratio < 0.89
Mild to moderate stage of Alzheimer's disease according to MMSE ≥ 18 and ≤ 26
Absence of major depressive disease according to GDS of < 5
Modified Hachinski Ischemic Scale ≤ 4
Formal education for eight or more years
Previous decline in cognition for more than six months as documented in patient medical records
A caregiver available and living in the same household or interacting with the patient a sufficient time each week (in Czech Republic: providing personal care for the patient during at least 10 hours per week ) and available if necessary to assure administration of drug
Patients living at home or nursing home setting without continuous nursing care
General health status acceptable for a participation in a 6-month clinical trial
Ability to swallow capsules
Stable pharmacological treatment of any other chronic condition for at least one month prior to screening
Stable treatment with one of the acetylcholinesterase inhibitors donepezil (Aricept ®), galantamine (Razadyne®), or rivastigmine (Exelon) or the partial NMDA receptor antagonist with memantine (Namenda®) at least 3-months before baseline Visit or Combination of both treatments mentioned above
No regular intake of prohibited medications as noted in Section 11.8 of the protocol
Signed informed consent by the patient, examined and verified to be mentally capable by an independent physician, prior to the initiation of any study specific procedure. Signed consent of the caregiver (see inclusion criteria 10).

Exclusion Criteria:

Failure to perform screening or baseline examinations
Hospitalization or change of chronic concomitant medication one month prior to screening or during screening period

Clinical, laboratory or neuro-imaging findings consistent with:

Other primary degenerative dementia, (dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Creutzfeldt-Jakob Disease, Down's syndrome, etc.)
Other neurodegenerative condition (Parkinson's disease, amyotrophic lateral sclerosis, etc.)
Cerebrovascular disease (major infarct, one strategic or multiple lacunar infarcts, extensive white matter lesions > one quarter of the total white matter)
Other central nervous system diseases (severe head trauma, tumors, subdural hematoma 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.)
A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder

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:

chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (ALT, AST, Gamma GT, alkaline phosphatase > 2.5 ULN)
Respiratory insufficiency
Renal insufficiency (serum creatinine > 2mg/dl) or creatinine clearance ≤ 30 mL/min according to Cockcroft-Gault formula). In case of creatinine clearance ≤ 30mL/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
Heart disease (myocardial infarction, unstable angina, heart failure, Cardiomyopathy within six months before screening)
Bradycardia (heart beat < 50/min.) or tachycardia (heart beat > 95/min.)
Hypertension (> 180/95 / Czech Republic >160/95) or hypotension (< 90/60) requiring treatment with more than three drugs
AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males > 450 and females > 470 msec.)
Uncontrolled diabetes defined by HbA1c > 8.5
Malignancies within the last five years except skin malignancies (other than melanoma) or indolent prostate cancer
Metastases
Disability that may prevent the patient from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.)
Women who are fertile and of childbearing potential

Chronic daily drug intake of ≥ 14 days or expected for ≥ 14 days:

benzodiazepines (except lorazepam ≤ 1mg for sleeping disorders only), neuroleptics or major sedatives
Antiepileptics
Centrally active anti-hypertensive drugs (clonidine, l-methyl DOPA, guanidine, guanfacine, etc.)
Opioid containing analgesics
Nootropic drugs with exception of Ginko Biloba
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 / in Czech Republic: 20 g alcohol per day for females (500 ml of beer or 250 ml of wine) and 30g alcohol per day for males (approximately 750 ml of beer or 375 ml of wine)) per day 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, which, in the opinion of the investigator, makes the patient unsuitable for inclusion
If patient is in any way dependent on the sponsor or the principal investigator or if the patient is accommodated in an establishment on judicial or administrative order