Comparative Study to Test Safety and Efficacy of Neurotrophic and Cholinergic Treatment of Alzheimer's Disease
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Intervention: Cerebrolysin + donepezil; Cerebrolysin + placebo; Donepezil + placebo
Intervention description: Cerebrolysin (10 ml) was given as IV infusion on five days per week for four consecutive weeks (week 1-4) with repetition of this treatment course (week 13-16) after a two-months treatment free interval, accounting for a total of 40 infusions.
Donepezil was given PO once daily during the whole study duration (28 weeks). After four weeks the daily dosage was increased from 5 mg to 10 mg.; Cerebrolysin (10 ml) was given as IV infusion on five days per week for four consecutive weeks (week 1-4) with repetition of this treatment course (week 13-16) after a two-months treatment free interval, accounting for a total of 40 infusions.
Placebo for donepezil was given PO once daily during the whole study duration (28 weeks).; Placebo for Cerebrolysin was given as IV infusion on five days per week for four consecutive weeks (week 1-4) with repetition of this treatment course (week 13-16) after a two-months treatment free interval, accounting for a total of 40 infusions.
Donepezil was given PO once daily during the whole study duration (28 weeks). After four weeks the daily dosage was increased from 5 mg to 10 mg.
Intervention MeSH terms: Cerebrolysin; Donepezil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 217.0
Sex: All
Minimum age: 51 Years
Healthy volunteers: No
Keywords: Clinical Trial, Phase II; Randomized Controlled Trial; Multicenter Study; Cerebrolysin; Donepezil

Summary:

      The study was performed to compare the safety and efficacy of Cerebrolysin (10 mililiters
      [ml]), Aricept (10 miligrams [mg]), and a combination of both treatments on cognitive
      performance and global function in patients with probable Alzheimer's Disease (AD). It should
      also be assessed if the treatments have a positive effect on activities of daily living and
      neuropsychiatric symptoms.

      Oral treatment with Aricept or Placebo was given once daily throughout the study. Intravenous
      treatment with Cerebrolysin or Placebo was given once daily for 5 days per week during week 1
      to 4 and during week 13 to 16 of the study. During the study patients had six visits at the
      hospital for evaluation.
    

Eligibility criteria:

        Inclusion criteria

          -  Diagnosis of probable AD (Diagnostic and Statistical Manual of Mental Disorders, 4th
             revision [DSM-IV], National Institute of Neurological and Communicative Disorders and
             Stroke and the Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA])

          -  Mini-Mental-State-Examination (MMSE) of 12-25, inclusive

          -  Modified Hachinski score ≤4

          -  Computed tomography (CT) or magnetic resonance imaging (MRI) scan within 12 months
             prior to screening without evidence of infection, infarction, or other focal lesions
             and without clinical symptoms suggestive of intervening neurological disease. Patients
             who have had a single, clinically silent lacunar infarct are eligible provided the
             lacunar infarct is not felt to be responsible for the patient's symptoms, is <1
             centimeter (cm) maximal diameter in any dimension, is not present in hippocampus of
             either hemisphere, head of the left caudate, or the dorsomedial region of the left
             thalamus. Subjects with scans showing atrophy, ventricular enlargement or mild to
             moderate white matter changes (involving up to approximately 25% of hemispheric white
             matter) are eligible if the study is otherwise normal.

          -  Hamilton Depression Scale score of ≤15

          -  Adequate visual and auditory acuity to allow neuropsychological testing

          -  Ability to attempt all sections of the Alzheimer's Disease Assessment Scale Cognitive
             Subpart (extended version)(ADAS-cog+)

          -  Good general health without additional diseases expected to interfere with the study

          -  Normal B12, folic acid, venereal disease research laboratory (VDRL), and
             thyroid-stimulating hormone (TSH) or without any clinically significant laboratory
             abnormalities that would be expected to interfere with the study

          -  Electrocardiogram (ECG) and chest x-ray (if clinically necessary per Investigator)
             without clinically significant laboratory abnormalities that would be expected to
             interfere with the study

          -  Patient is not institutionalized

          -  Patient is not pregnant, lactating, or of childbearing potential

          -  Sufficient language skills to complete all testing without assistance of a language
             interpreter

          -  Responsible caregiver being present during administration of study drug, monitor the
             patient's compliance with study procedures and adverse events, and accompany the
             patient to all clinic visits

          -  Written informed consent obtained from the patient and caregiver prior to entry into
             the study

        Exclusion criteria

          -  Any clinically significant laboratory abnormalities on the battery of screening tests

          -  Patients who in the past have not tolerated treatment with 10 mg Aricept or treatment
             with a corresponding dose of another cholinesterase inhibitor

          -  Severe psychotic features, depression, agitation or behavioral problems within the
             last three months that could lead to difficulty complying with the protocol

          -  Any significant systemic illness or unstable medical condition that could lead to
             difficulty complying with the protocol

          -  Patients who in the Investigator's opinion would not comply with study procedures

          -  Any significant neurological disease other than Alzheimer's Disease, within the past
             five years, or with residual effects

          -  Delusional symptoms are often characteristic of Alzheimer's Disease, but patients with
             symptoms so pronounced that they warrant an alternative diagnosis are excluded

          -  History of alcohol or substance abuse or dependence within the past two years (DSM-IV)

          -  History of schizophrenia (DSM-IV)

          -  Patients with a history of systemic cancer within the past two years are excluded

          -  History of myocardial infarction in the past year or unstable or severe cardiovascular
             disease, including uncontrolled hypertension

          -  Uncontrolled insulin-requiring diabetes or non-insulin dependent diabetes mellitus
             (Haemoglobin A1c [HBA1c] > 10.0)

          -  Use of:

               -  systemic corticosteroids for more than one week within three months prior to
                  Baseline (BL)

               -  Anti-Parkinsonian agents within two months prior to baseline (BL)

               -  Approved or investigational Cholinesterase Inhibitors within 30 days or five
                  half-lives, whichever is longer, prior to BL

               -  Memantine or other N-methyl-D-aspartic acid (NMDA) antagonists within 30 days or
                  five half-lives, whichever is longer, prior to BL

               -  Treatment with high potency neuroleptics or narcotic analgesics within four weeks
                  prior to BL

               -  Cimetidine within four weeks prior to BL

               -  Sedatives more frequently than two times per week for sleep within four weeks
                  prior to BL