Vascular Dementia
Conditions
Brief summary
This clinical trial was performed to assess the clinical efficacy and safety of two 4 week treatment courses of daily intravenous administration of Cerebrolysin (20mL \[milliliter\] IV \[intravenous\] per day). The study was performed as prospective, randomised, double-blind, placebo-controlled, parallel group, multicentre study with 2 study groups. Group 1: 20 mL Cerebrolysin and 100 mg (milligram) acetylsalicylic acid Group 2: Placebo (0.9% NaCl \[sodium chloride\]) and 100 mg acetylsalicylic acid The study drug was given once daily by intravenous infusion (20ml in 250ml saline solution) for 4 weeks on five consecutive days per week. This treatment regimen was repeated after a two-month treatment-free interval. Acetylsalicylic acid was given orally, once daily throughout the study duration of 24 weeks. Altogether five clinical evaluation visits at Baseline (day 0) and at week 4, 12, 16, and 24 were necessary.
Interventions
DRUGCerebrolysin
Sponsors
acromion GmbH
Geny Research Corp.
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
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Men or post-menopausal women between 50 and 85 years * Clinical diagnosis of vascular dementia according to NINDS-AIREN criteria * CT or MRI results compatible with clinical diagnosis * MMSE score between 10 and 24, both inclusive * Modified Hachinski Ischemic Score \>4 * Hamilton Depression Scale score of less than or equal to 15 * Adequate visual and auditory acuity to allow neuropsychological testing * Informed consent given by the patient and/or the next-of-kin
Exclusion criteria
* Gastric ulcer associated with intolerance of acetylsalicylic acid treatment * Severe psychotic features, schizophrenia, depression, agitation or behavioral problems within the last three months that could lead to difficulty complying with the protocol * Any severe systemic illness or unstable medical condition that could lead to difficulty complying with the protocol or significantly limits life span. * Patients who in the investigator's opinion, would not comply with study procedures * Any significant neurological disease other than vascular dementia, such as Parkinson's disease, epilepsy, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, or multiple sclerosis * History of alcohol or substance abuse or dependence within the past two years * Patients with a history of systemic cancer within the past two years * Severe congestive heart failure or malignant, uncontrollable hypertension * Participation in a clinical trial with an investigational drug in the past four weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in ADAS-cog+ (Alzheimer's Disease Assesment Scale - Cognitive Subpart) at Week 24 | baseline and week 24 | The ADAS-COG+ is a psychometric instrument used to evaluate memory, attention, reasoning, language, orientation and praxis. The score ranges from 0 to 85 with 85 being the worst score. A negative change indicates cognitive improvement. |
| CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | week 24 | This rating scale is based on the health care provider's general clinical impressions with the informant input (i.e. family members). It evaluates global function and is scored from 1 (marked improvement) to 7 (marked worsening). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline for Original ADAS-COG | week 4, 12, 16, 24 | The Original Alzheimer's Disease Assessment Scale - Cognitive (ADAS-COG) is comprised of items 1-11 of the modified ADAS-COG+. |
| CIBIC+ Score | week 4, 12, 16 | The Clinician Interview-based Impression of Change (CIBIC+) score is assigned by an experienced physician familiar with the manifestations of dementia after interviewing the patient and the caregiver. |
| CIBIC+ Response | week 4, 12, 16, 24 | A patient with a CIBIC+ score of 1 to 3 at a particular visit is considered to have a CIBIC+ response at that visit. Patients with a score of 0, indicating that the assessment was not performed, are considered to be non-responders. |
| CIBIS+ (Clinicians Interview-Based Impression of Severity) | week 24 | The Clinician Interview-based Impression of Disease Severity (CIBIS+) score is assigned by an experienced physician, familiar with the manifestations of dementia, after interviewing the patient and the caregiver. |
| Change From Baseline in ADAS-COG+ (Alzheimer's Disease Assessment Scale Cognitive Subpart) | week 4, 12, 16 | The modified Alzheimer's Disease Assessment Scale - Cognitive (ADAS-COG+) is a psychometric instrument used by a neuropsychologist that evaluates memory, attention, reasoning, language, orientation and praxis. |
| Change From Baseline in ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale) | week 4, 12, 16, 24 | The ADCS-ADL is a measure of functional disability. The ADCS-ADL assessment of activities of daily living is based on an interview with the caregiver. |
| Change From Baseline in Trail-making Test | week 4, 12, 16, 24 | The Trail-making test is a frequently used instrument for the assessment of executive function. |
| Change From Baseline in Clock-drawing Test | week 4, 12, 16, 24 | The Clock-drawing test is a frequently used screening instrument for dementia drug studies. It evaluates executive function of demented patients. |
| Combined Response, i.e. Response in ADAS-COG+ and CIBIC+ | week 4, 12, 16, 24 | — |
| Change From Baseline in MMSE (Mini-Mental State Examination) Score | week 4, 12, 16, 24 | The Mini-Mental State Examination (MMSE) is a frequently used screening instrument for clinical trials conducted in patients with Alzheimer's Disease. It evaluates orientation, registration, attention and calculation, recall and language. |
| ADAS-COG+ Response | week 4, 12, 16, 24 | A patient with an improvement from baseline of ≥ 4 points in the ADAS-COG+ score at a particular visit is considered to have an ADAS-COG+ response at that visit. |
Countries
Russia
Participant flow
Recruitment details
Date of recruitment period: 24-Oct-2006 - 02-Feb-2007 Type of location: Hospitals, Medical Universities, Medical Military Academy, Research Institutes
Pre-assignment details
Patients were excluded from the trial before assignment to a group when not all inclusion criteria were met or when exclusion criteria were applicable.
Participants by arm
| Arm | Count |
|---|---|
| Cerebrolysin | 121 |
| 0.9% Saline Solution | 121 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Reason | 0 | 1 |
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 7 |
Baseline characteristics
| Characteristic | Total | Cerebrolysin | 0.9% Saline Solution |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 165 Participants | 83 Participants | 82 Participants |
| Age, Categorical Between 18 and 65 years | 77 Participants | 38 Participants | 39 Participants |
| Age, Continuous | 67.3 years STANDARD_DEVIATION 8 | 67.1 years STANDARD_DEVIATION 8 | 67.6 years STANDARD_DEVIATION 8 |
| Region of Enrollment Russian Federation | 242 participants | 121 participants | 121 participants |
| Sex: Female, Male Female | 154 Participants | 82 Participants | 72 Participants |
| Sex: Female, Male Male | 88 Participants | 39 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 117 | 0 / 115 |
| serious Total, serious adverse events | 3 / — | 0 / — |
Outcome results
Primary
Change From Baseline in ADAS-cog+ (Alzheimer's Disease Assesment Scale - Cognitive Subpart) at Week 24
The ADAS-COG+ is a psychometric instrument used to evaluate memory, attention, reasoning, language, orientation and praxis. The score ranges from 0 to 85 with 85 being the worst score. A negative change indicates cognitive improvement.
Time frame: baseline and week 24
Population: The primary and confirmatory analysis is based on the ITT analysis set. The LOCF method is applied to account for missing data. The ITT analysis set consists of all randomized patients, who received at least one dose of study medication and had a baseline and at least one post-baseline assessment for both primary efficacy measures.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cerebrolysin | Change From Baseline in ADAS-cog+ (Alzheimer's Disease Assesment Scale - Cognitive Subpart) at Week 24 | -10.60 points on a scale | Standard Deviation 7.77 |
| 0.9% Saline Solution | Change From Baseline in ADAS-cog+ (Alzheimer's Disease Assesment Scale - Cognitive Subpart) at Week 24 | -4.49 points on a scale | Standard Deviation 8.13 |
Comparison: The null-hypothesis stated no difference between the two treatment groups. A sample size of 103 evaluable patients per treatment group was estimated to allow for the detection of a significant group difference of 4.1 points in ADAS-cog+ weak 24 change score (standard deviation \[SD\] 9.0) in favor of Cerebrolysin with a power of 90% and a probability level of alpha-level 0.025 (one-sided).p-value: <0.000195% CI: [-8.22, -4.13]ANCOVA
Primary
CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24
This rating scale is based on the health care provider's general clinical impressions with the informant input (i.e. family members). It evaluates global function and is scored from 1 (marked improvement) to 7 (marked worsening).
Time frame: week 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cerebrolysin | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Minimal improvement | 38 Participants |
| Cerebrolysin | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Minimal worsening | 9 Participants |
| Cerebrolysin | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Moderate improvement | 43 Participants |
| Cerebrolysin | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Moderate worsening | 0 Participants |
| Cerebrolysin | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | No change | 20 Participants |
| Cerebrolysin | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Marked worsening | 0 Participants |
| Cerebrolysin | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Marked improvement | 7 Participants |
| 0.9% Saline Solution | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Marked worsening | 0 Participants |
| 0.9% Saline Solution | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Marked improvement | 2 Participants |
| 0.9% Saline Solution | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Moderate improvement | 14 Participants |
| 0.9% Saline Solution | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Minimal improvement | 27 Participants |
| 0.9% Saline Solution | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | No change | 52 Participants |
| 0.9% Saline Solution | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Minimal worsening | 16 Participants |
| 0.9% Saline Solution | CIBIC+ (Clinicians Interview-based Impression of Change) Score at Week 24 | Moderate worsening | 4 Participants |
Secondary
ADAS-COG+ Response
A patient with an improvement from baseline of ≥ 4 points in the ADAS-COG+ score at a particular visit is considered to have an ADAS-COG+ response at that visit.
Time frame: week 4, 12, 16, 24
Secondary
Change From Baseline for Original ADAS-COG
The Original Alzheimer's Disease Assessment Scale - Cognitive (ADAS-COG) is comprised of items 1-11 of the modified ADAS-COG+.
Time frame: week 4, 12, 16, 24
Secondary
Change From Baseline in ADAS-COG+ (Alzheimer's Disease Assessment Scale Cognitive Subpart)
The modified Alzheimer's Disease Assessment Scale - Cognitive (ADAS-COG+) is a psychometric instrument used by a neuropsychologist that evaluates memory, attention, reasoning, language, orientation and praxis.
Time frame: week 4, 12, 16
Secondary
Change From Baseline in ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale)
The ADCS-ADL is a measure of functional disability. The ADCS-ADL assessment of activities of daily living is based on an interview with the caregiver.
Time frame: week 4, 12, 16, 24
Secondary
Change From Baseline in Clock-drawing Test
The Clock-drawing test is a frequently used screening instrument for dementia drug studies. It evaluates executive function of demented patients.
Time frame: week 4, 12, 16, 24
Secondary
Change From Baseline in MMSE (Mini-Mental State Examination) Score
The Mini-Mental State Examination (MMSE) is a frequently used screening instrument for clinical trials conducted in patients with Alzheimer's Disease. It evaluates orientation, registration, attention and calculation, recall and language.
Time frame: week 4, 12, 16, 24
Secondary
Change From Baseline in Trail-making Test
The Trail-making test is a frequently used instrument for the assessment of executive function.
Time frame: week 4, 12, 16, 24
Secondary
CIBIC+ Response
A patient with a CIBIC+ score of 1 to 3 at a particular visit is considered to have a CIBIC+ response at that visit. Patients with a score of 0, indicating that the assessment was not performed, are considered to be non-responders.
Time frame: week 4, 12, 16, 24
Secondary
CIBIC+ Score
The Clinician Interview-based Impression of Change (CIBIC+) score is assigned by an experienced physician familiar with the manifestations of dementia after interviewing the patient and the caregiver.
Time frame: week 4, 12, 16
Secondary
CIBIS+ (Clinicians Interview-Based Impression of Severity)
The Clinician Interview-based Impression of Disease Severity (CIBIS+) score is assigned by an experienced physician, familiar with the manifestations of dementia, after interviewing the patient and the caregiver.
Time frame: week 24
Secondary
Combined Response, i.e. Response in ADAS-COG+ and CIBIC+
Time frame: week 4, 12, 16, 24