Alzheimer Disease
Conditions
Keywords
Clinical Trial, Phase II, Randomized Controlled Trial, Multicenter Study, Cerebrolysin, Donepezil
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.
Interventions
DRUGCerebrolysin + donepezil
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.
DRUGCerebrolysin + placebo
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).
DRUGDonepezil + placebo
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.
Sponsors
acromion GmbH
Ever Neuro Pharma GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
51 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive Subpart (Extended Version) (ADAS-COG+) at Week 28 | baseline and week 28 | The ADAS-cog+ is a validated, widely used, 14 item psychometric instrument for testing cognitive functions with increased sensitivity in detecting changes in milder patients compared to the original ADAS-cog. It has a maximum score of 85 with a higher score indicating impairment and was assessed by a qualified neuropsychologist. |
| Clinical Interview-based Impression of Change (CIBIC+) Score | week 28 | — |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline for Original ADAS-COG | week 4, 12, 16, 28 |
| CIBIC+ Score | week 4, 12, 16 |
| CIBIC+ Responders | week 4, 12, 16, 28 |
| Clinical Interview-based Impression of Severity (CIBIS+) Score | week 28 |
| Change From Baseline for ADAS-COG+ | week 4, 12, 16 |
| Change From Baseline in Total Score for Neuropsychiatric Inventory (NPI) | week 16, 28 |
| Combined Responders, i.e. Response in ADAS-COG+ and CIBIC+ | week 4, 12, 16, 28 |
| Adverse Experiences, Vital Signs, Physical and Neurological Examinations, Laboratory Tests (Hematology, Clinical Chemistry , Urinalysis, Electrocardiogram [ECG]) | Baseline, week 4, 12, 16, 28 |
| Change From Baseline for Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) | week 16, 28 |
| ADAS-COG+ Responders | week 4, 12, 16, 28 |
Countries
Spain
Participant flow
Recruitment details
Dates of recruitment period: 18-OCT-2004 - 29-OCT-2007 Type of location: hospital (La Coruna), institutions specialized on cognitive disorders (Granada, Malaga)
Pre-assignment details
Patients were excluded from the trial before assignment to groups when not all inclusion criteria were met or when exclusion criteria were applicable.
Participants by arm
| Arm | Count |
|---|---|
| Cerebrolysin + Donepezil | 72 |
| Cerebrolysin | 70 |
| Donepezil | 75 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 5 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Organizational reasons | 1 | 3 | 1 |
| Overall Study | Protocol Violation | 6 | 4 | 9 |
| Overall Study | Withdrawal by Subject | 8 | 10 | 7 |
Baseline characteristics
| Characteristic | Cerebrolysin | Donepezil | Cerebrolysin + Donepezil | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0.0 Participants |
| Age, Categorical >=65 years | 61 Participants | 69 Participants | 63 Participants | 193.0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 6 Participants | 9 Participants | 24.0 Participants |
| Age Continuous | 75.1 years STANDARD_DEVIATION 7.6 | 76.0 years STANDARD_DEVIATION 7.7 | 74.5 years STANDARD_DEVIATION 8.3 | 75.2 years STANDARD_DEVIATION 7.9 |
| Region of Enrollment Spain | 70 participants | 75 participants | 72 participants | 217.0 participants |
| Sex: Female, Male Female | 51 Participants | 58 Participants | 60 Participants | 169.0 Participants |
| Sex: Female, Male Male | 19 Participants | 17 Participants | 12 Participants | 48.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 45 / — | 40 / — | 46 / — |
| serious Total, serious adverse events | 1 / — | 1 / — | 2 / — |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive Subpart (Extended Version) (ADAS-COG+) at Week 28
The ADAS-cog+ is a validated, widely used, 14 item psychometric instrument for testing cognitive functions with increased sensitivity in detecting changes in milder patients compared to the original ADAS-cog. It has a maximum score of 85 with a higher score indicating impairment and was assessed by a qualified neuropsychologist.
Time frame: baseline and week 28
Population: Analysis was intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cerebrolysin + Donepezil | Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive Subpart (Extended Version) (ADAS-COG+) at Week 28 | -2.348 points on a scale | Standard Deviation 5.993 |
| Cerebrolysin | Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive Subpart (Extended Version) (ADAS-COG+) at Week 28 | -1.711 points on a scale | Standard Deviation 7.5 |
| Donepezil | Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive Subpart (Extended Version) (ADAS-COG+) at Week 28 | -1.246 points on a scale | Standard Deviation 6.147 |
Comparison: The null-hypothesis stated no differences between the three treatment groups regarding the mean change from baseline in ADAS-cog+ at week 28. A sample size of approximately 60 evaluable patients per treatment arm was estimated to allow for the detection of a significant group difference of two points in ADAS-cog+ week 28 change score (standard deviation \[SD\] 3.3) between the three groups with a power of \> 80% and a probability level of alpha = 0.05 (two-sided).p-value: 0.6348ANCOVA
Comparison: Multiple testing of individual null hypotheses that control for the overall significance level alpha = 0.05 were performed by using the 'closed testing procedure'p-value: 0.58395% CI: [-2.891, 1.63]t-test, 2 sided
Comparison: Multiple testing of individual null hypotheses that control for the overall significance level alpha = 0.05 were performed by using the 'closed testing procedure'.p-value: 0.343495% CI: [-3.324, 1.163]t-test, 2 sided
Comparison: Multiple testing of individual null hypotheses that control for the overall significance level alpha = 0.05 were performed by using the 'closed testing procedure'.p-value: 0.696295% CI: [-2.719, 1.819]t-test, 2 sided
Primary
Clinical Interview-based Impression of Change (CIBIC+) Score
Time frame: week 28
Secondary
ADAS-COG+ Responders
Time frame: week 4, 12, 16, 28
Secondary
Adverse Experiences, Vital Signs, Physical and Neurological Examinations, Laboratory Tests (Hematology, Clinical Chemistry , Urinalysis, Electrocardiogram [ECG])
Time frame: Baseline, week 4, 12, 16, 28
Secondary
Change From Baseline for ADAS-COG+
Time frame: week 4, 12, 16
Secondary
Change From Baseline for Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)
Time frame: week 16, 28
Secondary
Change From Baseline for Original ADAS-COG
Time frame: week 4, 12, 16, 28
Secondary
Change From Baseline in Total Score for Neuropsychiatric Inventory (NPI)
Time frame: week 16, 28
Secondary
CIBIC+ Responders
Time frame: week 4, 12, 16, 28
Secondary
CIBIC+ Score
Time frame: week 4, 12, 16
Secondary
Clinical Interview-based Impression of Severity (CIBIS+) Score
Time frame: week 28
Secondary
Combined Responders, i.e. Response in ADAS-COG+ and CIBIC+
Time frame: week 4, 12, 16, 28