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Alzheimer DiseasePhase 2CombiNCT00911807

Comparative Study to Test Safety and Efficacy of Neurotrophic and Cholinergic Treatment of Alzheimer's Disease

A Phase 2 study testing Cerebrolysin + donepezil in people with Alzheimer Disease, run by Ever Neuro Pharma GmbH at 3 sites in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 51 years and older
Conditions the study is for
Alzheimer Disease
What is being tested?
Cerebrolysin + donepezil
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
217 participants
Where
3 sitesSpain
Study dates
Oct 2004to Apr 2008
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 51 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

3 sites in 1 country.

Spain3 sites

  • EuroEspes Biomedical Research Centre

    A Coruña, 15166

  • Centro Geriátrico Fuente Salinas

    Granada, 18340

  • Clínica de Memoria

    Málaga, 29005

Other trials in Spain

About this study

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)

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.

Read the 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.

Being tested
Cerebrolysin + donepezil, Cerebrolysin + placebo, Donepezil + placebo
Keywords
Clinical Trial, Phase II, Randomized Controlled Trial, Multicenter Study, Cerebrolysin, Donepezil
Medical subject headings
Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Cerebrolysin + donepezilDrug

    Also called Brand name for donepezil: Aricept, Brand name for Cerebrolysin: Cerebrolysin

    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 + placeboDrug

    Also called Brand name for Cerebrolysin: Cerebrolysin

    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).

  • Donepezil + placeboDrug

    Also called Brand name for donepezil: Aricept

    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.

Study groups in NCT00911807
Study groupRoleWhat they receive
Cerebrolysin + donepezilExperimentalNot described
Receives: Drug: Cerebrolysin + donepezil
Cerebrolysin + placeboExperimentalNot described
Receives: Drug: Cerebrolysin + placebo
Donepezil + placeboActive comparatorNot described
Receives: Drug: Donepezil + placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: baseline and week 28

  2. Clinical Interview-based Impression of Change (CIBIC+) Score

    Measured: week 28

Secondary outcomes (10)

  1. Change From Baseline for ADAS-COG+

    Measured: week 4, 12, 16

  2. ADAS-COG+ Responders

    Measured: week 4, 12, 16, 28

  3. Change From Baseline for Original ADAS-COG

    Measured: week 4, 12, 16, 28

  4. CIBIC+ Score

    Measured: week 4, 12, 16

  5. CIBIC+ Responders

    Measured: week 4, 12, 16, 28

  6. Clinical Interview-based Impression of Severity (CIBIS+) Score

    Measured: week 28

  7. Change From Baseline for Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)

    Measured: week 16, 28

  8. Change From Baseline in Total Score for Neuropsychiatric Inventory (NPI)

    Measured: week 16, 28

  9. Combined Responders, i.e. Response in ADAS-COG+ and CIBIC+

    Measured: week 4, 12, 16, 28

  10. Adverse Experiences, Vital Signs, Physical and Neurological Examinations, Laboratory Tests (Hematology, Clinical Chemistry , Urinalysis, Electrocardiogram [ECG])

    Measured: Baseline, week 4, 12, 16, 28

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jun 2009 (estimated)
  2. Study startOct 2004
  3. Primary completionApr 2008
  4. Study completionApr 2008

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
217 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00911807
Sponsor's protocol ID
EBE-031010
Acronym
Combi
Status last verified
Jun 2009
First submitted
7 Apr 2009
Last updated
10 Jun 2009
Data monitoring committee
No

Publications

  • 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.

    PubMed 21679156

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cerebrolysin + donepezil in people with Alzheimer Disease, run by Ever Neuro Pharma GmbH at 3 sites in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jun 2009. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Jun 2009). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive Subpart (Extended Version) (ADAS-COG+) at Week 28 (time frame: baseline and week 28). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00911807, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jun 2009.

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