Clinical trial NCT00911807: Comparative Study to Test Safety and Efficacy of Neurotrophic and Cholinergic Treatment of Alzheimer's Disease
Official title: A Randomized, Double-Blind, Clinical Trial to Compare the Safety and Efficacy of Cerebrolysin and Aricept (Donepezil) and a Combination Therapy in Patients With Probable Alzheimer's Disease (AD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Keywords: Clinical Trial, Phase II
Randomized Controlled Trial
Multicenter Study
Cerebrolysin
Donepezil
Lead sponsor: Ever Neuro Pharma GmbH
Sponsor class: INDUSTRY
Collaborators: name: acromion GmbH
First posted: 2009-06-02
Enrollment: 217
Sex: ALL
Minimum age (years): 51
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: Endogenous neurotrophic factors, also called neurotrophins, are signaling molecules in various cellular pathways and allow proper neuronal function, survival and regeneration. Sufficient supply is therefore regarded as a pre-requisite for neuronal maintenance but sudden or chronic pathological changes result in an imbalance of this regulatory system.

Cerebrolysin is a peptide preparation acting in a similar way like endogenous neurotrophic factors. Due to its pleiotropic effects - neuroprotection, neuronal survival, neuroplasticity and neurogenesis -, Cerebrolysin is regarded as potential therapeutic tool in complex diseases like stroke or dementia. In contrast to naturally occurring neurotrophic factors, neuropeptides of Cerebrolysin enter the brain parenchyma by crossing the blood-brain barrier after peripheral (intravenous \[IV\]) administration.

Another treatment approach for Alzheimer's disease targets the cholinergic system to increase cortical acetylcholine. One of these drugs is the anticholinesterase donepezil (Aricept). However, anticholinesterases seem to provide only symptomatic benefit for a limited period and not to influence the progression of the disease. In view of the different mechanisms of action and clinical profile of Cerebrolysin and Aricept, a combination therapy of both may provide synergistic treatment effects. The combination of a treatment targeting the neurotrophic axis (Cerebrolysin) with a treatment to improve cholinergic neurotransmission (Aricept) can arguably be expected to provide additional benefits to AD patients.

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

Primary outcomes:
measure: Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive Subpart (Extended Version) (ADAS-COG+) at Week 28
timeFrame: baseline and week 28
measure: Clinical Interview-based Impression of Change (CIBIC+) Score
timeFrame: week 28
Secondary outcomes:
measure: Change From Baseline for ADAS-COG+
timeFrame: week 4, 12, 16
measure: ADAS-COG+ Responders
timeFrame: week 4, 12, 16, 28
measure: Change From Baseline for Original ADAS-COG
timeFrame: week 4, 12, 16, 28
measure: CIBIC+ Score
timeFrame: week 4, 12, 16
measure: CIBIC+ Responders
timeFrame: week 4, 12, 16, 28
measure: Clinical Interview-based Impression of Severity (CIBIS+) Score
timeFrame: week 28
measure: Change From Baseline for Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)
timeFrame: week 16, 28
measure: Change From Baseline in Total Score for Neuropsychiatric Inventory (NPI)
timeFrame: week 16, 28
measure: Combined Responders, i.e. Response in ADAS-COG+ and CIBIC+
timeFrame: week 4, 12, 16, 28
measure: Adverse Experiences, Vital Signs, Physical and Neurological Examinations, Laboratory Tests (Hematology, Clinical Chemistry , Urinalysis, Electrocardiogram [ECG])
timeFrame: Baseline, week 4, 12, 16, 28
Other outcomes:
Locations:
city: Granada
country: Spain
facility: Centro Geriátrico Fuente Salinas
city: La Coruna
country: Spain
facility: EuroEspes Biomedical Research Centre
city: Málaga
country: Spain
facility: Clínica de Memoria
Study officials:
affiliation: EuroEspes Biomedical Research Center
name: Ánton X Àlvarez, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: EBEWE Pharma
name: Herbert Moessler, PhD
role: STUDY_DIRECTOR
References:
citation: Alvarez XA, Cacabelos R, Sampedro C, Couceiro V, Aleixandre M, Vargas M, Linares C, Granizo E, Garcia-Fantini M, Baurecht W, Doppler E, Moessler H. Combination treatment in Alzheimer's disease: results of a randomized, controlled trial with cerebrolysin and donepezil. Curr Alzheimer Res. 2011 Aug;8(5):583-91. doi: 10.2174/156720511796391863.