| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild to moderate dementia of Alzheimer type (DAT) |
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| E.1.1.1 | Medical condition in easily understood language |
| Mild to moderate dementia of Alzheimer type (DAT) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012292 |
| E.1.2 | Term | Dementia of the Alzheimer's type NOS |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objective of this trial is the global risk-benefit assessment of Cerebrolysin as compared to donepezil in patients with mild to moderate dementia of Alzheimer type (DAT). In addition, a traditional approach will be taken based on an evaluation of the
separate risk and benefit domains in comparison with donepezil |
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| E.2.2 | Secondary objectives of the trial |
Safety as compared to donepezil will be analyzed stand-alone by determining, whether the Cerebrolysin group shows non-inferiority with regard to the combined primary safety endpoints.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis and Main Criteria for Inclusion
1. Male and female patients ≥50 years of age
2. Diagnosis of probable mild to moderate Alzheimer’s disease according to DSM-IV-TR and NINCDS-ADRDA criteria (see section 18.2.1)
3. Screening MMSE score between 15 and 24, both inclusive
4. Modified Hachinski Ischemic score of ≤4
5. Hamilton Depression Scale score ≤10
6. Brain computerized tomography (CT) or brain magnetic resonance imaging (MRI) scans within 12 months prior to screening without evidence of infection, infarction, or other focal lesions and without clinical symptoms suggestive of intervening neurological disease. If no brain CT or brain MRI is available, a brain MRI shall be performed to exclude other causes of dementia-like syndromes. 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 less than 1 cm maximal diameter in any dimension, is not present in hippocampus of either hemisphere, head of the left caudate, or the thalamus. Patients with scans showing atrophy, ventricular enlargement or mild to moderate white matter changes (involving up to approximately 25% of hemispheric white matter) are eligible in the study if otherwise normal
7. Adequate visual and auditory acuity to allow neuropsychological testing
8. Sufficient language skills to complete all testing without assistance of a language interpreter
9. Ability to perform all sections of the ADAS-cog
10. Good general health without additional diseases expected to interfere with the study
11. Normal B12, folic acid, VDRL, and TSH or without any clinically significant laboratory abnormalities that would be expected to interfere with the study
12. ECG and chest x-ray if available without clinically significant laboratory abnormalities that would be expected to interfere with the study.
13. Patient is not of childbearing potential (i.e., women must be two years postmenopausal or surgically sterile)
14. Responsible caregiver (individual who continuously attends to the needs of the person or dependent adult), who agrees to be present during administration of study drug, monitor the patient’s compliance with study procedures and adverse events, accompanies the patient to all clinical visits and is willing and able to perform questionnaires as required by the study protocol
15. Written informed consent obtained from the patient and caregiver (and legally authorized representative or guardian if different from caregiver) prior to entry into the study (Screening Visit) |
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| E.4 | Principal exclusion criteria |
Exclusion criteria
1. Any abnormalities associated with significant central nervous disease other than Alzheimer’s Disease (e.g. Parkinson’s Disease, epilepsy, multi-infarct
dementia, Huntington’s Disease, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, history of head injury with loss of consciousness for a longer period than one day within the past five years, or with residual effects) or focal lesions, which may be responsible for the cognitive status of the patient such as infectious disease, space-occupying lesions, normal pressure hydrocephalus
2. Severe psychotic features, confusion, agitation or behavioral problems within the last three months that could lead to difficulties complying with the protocol
3. Delusional symptoms are often characteristic of Alzheimer’s disease, but patients with symptoms so pronounced that they warrant an alternative
psychiatric diagnosis are excluded
4. History of alcohol or substance abuse or dependence within the past two years (DSM-IV-TR criteria, see also sections 18.3.1 and 18.3.2)
5. History of schizophrenia, schizoaffective disorder, bipolar affective disorder (DSM-IV-TR criteria)
6. History of newly identified major depressive disorder within eight weeks before Screening Visit (DSM-IV-TR) (see also exclusion criteria 11 and inclusion
criteria 5)
7. Any significant systemic illness (or unstable medical condition that could lead to difficulties complying with the protocol). Patients with a history of systemic cancer within the past two years are excluded
8. History of myocardial infarction in the past year or unstable or severe cardiovascular disease, including uncontrolled hypertension
9. Any clinically significant laboratory abnormalities on the battery of screening tests (hematology, blood chemistry, urinalysis, ECG, chest x-ray (if available))
10. Uncontrolled insulin-requiring diabetes or non-insulin dependent diabetes mellitus (HbA 1c >10.0)
11. Use of any concomitant medication that could affect functioning of the CNS or interfere with efficacy assessment including:
- Cerebrolysin and/or donepezil, and/or other cholinesterase inhibitors, memantine or other NMDA antagonists and/or other investigational
medications within four weeks prior to Baseline
- Anticonvulsant or stimulating agents within the past four weeks
- Use of systemic corticosteroids for more than one week within three months prior to Baseline
- Anti-Parkinsonian agents (e.g., Sinemet®, amantadine, bromocriptine, pergolide and selegiline) within two months prior to Baseline
- Treatment with high potency antipsychotics or narcotic analgesics within four weeks prior to Baseline
- Cimetidine within four weeks prior to Baseline
- Sedatives more frequently than two times per week for anxiety or restlessness within four weeks prior to Baseline
- No sedatives are allowed within 12 hours before performing clinical evaluation scales
- Hypnotics more frequently than 3 times per week within four weeks prior to Baseline
- Antidepressants prescribed for period shorter than four weeks prior to screening, and/or unstable dosages within four weeks before the Screening Visit
- Monoaminooxidase inhibitors within four weeks prior to Baseline Visit
- Nootropics, and products on basis of Ginkgo Biloba, within four weeks prior to Baseline
12. Patients who in the Investigator’s opinion would not comply with study procedures
13. Patients with fragile or thin veins who may not be able to receive many i.v. infusions
14. Patients who in the past have not tolerated treatment with 10 mg donepezil or treatment with a corresponding dose of another cholinesterase inhibitor
15. Patients with history of any epileptic seizure
16. Patients with known or suspected hypersensitivity to Cerebrolysin, donepezil hydrochloride, piperidine derivates or any of the IMPs’excipients. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Global risk-benefit as compared to donepezil will be analyzed by determining whether the Cerebrolysin group shows a statistically significant non-inferiority with regard to the combined primary safety and efficacy endpoints (weighted multivariate ensemble).The endpoints will be combined by a global multivariate non-parametric procedure, weighting the safety and efficacy part 50:50 (regarding equally balancing risk and benefit see also O’Neill, FDA [O’Neill R 2008]). The individual weights are given as follows:
Risk (relative sum of weight factors: 6)
- (1) Proportion of patients with at least one AE during the main part of the study (Week 24), weight factor: 1
- (2) Proportion of patients with at least one SAE during the main part of the study (Week 24), weight factor: 2
- (3) Proportion of patients with premature discontinuation due to adverse event during the main part of the study (Week 24), weight factor: 3
Benefit (relative sum of weight factors: 6)
- (4) ADAS-cog changes Week 24, weight factor: 3
- (5) CIBIC+ Week 24, weight factor: 3
Thus, a total of 6 weighting points is given to the safety ensemble, and a total of 6 weighting points is also given to the efficacy ensemble, resulting in an overall 50:50 weighting of risk and benefit. This way, a combined and equally balanced global test for risk and benefit is obtained.
The weighting of the safety endpoints within the multivariate safety ensemble is the same as described above for the global risk-benefit assessment (AE: weight factor 1, SAE: weight factor 2, premature discontinuation due to AE: weight factor 3).
The multiple level alpha of the study (multiple level of significance) is defined as alpha = 0.025 (one-sided).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Efficacy:
o ADAS-cog responders at Visit 5
o ADAS-cog+ responders at Visit 5
o CIBIC+ responders at Visit 5
o Change from Baseline in ADAS-cog+ at Visit 5
o Change from Baseline in ADCS-ADL at Visit 5
o Change from Baseline in NPI at Visit 5
o Change from Baseline in QoL-AD at Visit 5
o Change from Baseline in the LARS at Visit 5
o Change from Baseline in the LARS-I at Visit 5
Safety:
o Adverse events
o Vital signs
o Laboratory tests (hematology, blood chemistry, urinalysis)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Austria |
| Canada |
| Chile |
| Germany |
| Mexico |
| Poland |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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