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The Efficacy of a Combination Regimen in Patients With Mild to Moderate Probable Alzheimer's Disease (AD-Combi)

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ClinicalTrials.gov Identifier: NCT01921972
Recruitment Status : Completed
First Posted : August 14, 2013
Last Update Posted : August 14, 2013
Sponsor:
Collaborator:
German Federal Ministry of Education and Research
Information provided by (Responsible Party):
Isabella Heuser, Charite University, Berlin, Germany

Brief Summary:
This is a national multicenter, double-blind, randomized, parallel-group trial of 12 months in duration. Following a 4 week wash-out period, subjects will be randomized to one of 2 treatment groups: (1) galantamine CR 24 mg/day with dose-titration over twelve weeks[maintenance phase from week 9], (2) a combination of galantamine CR 24 mg/day plus memantine 10 mg b.i.d. with a dose titration of sixteen weeks (12 weeks for galantamine [maintenance phase from week 9], additional 4 weeks for memantine).

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: Galantamine CR Drug: Memantine Drug: Placebo Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 232 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Competence Network - Dementia (BMBF) "Pharmacological and Psychosocial Treatment" (Modul E.2) Part II: The Efficacy of a Combination Regimen in Patients With Mild to Moderate Probable Alzheimer's Disease
Study Start Date : November 2004
Actual Primary Completion Date : November 2008
Actual Study Completion Date : May 2009


Arm Intervention/treatment
Active Comparator: Galantamine and Placebo
Subjects in this group will receive 4 weeks of 8 mg/day galantamine CR, followed by 4 weeks of 16 mg/day and from week 9 up to the end of the trial of 24 mg/day.
Drug: Galantamine CR
24 mg/day with dose-titration over twelve weeks

Drug: Placebo
Placebo will be similar in appearance to Memantine

Experimental: Galantamine and Memantine
Galantamine titration will be performed as described above. Memantine titration will be performed over 4 weeks in steps of 5 mg/day up to 20mg/day (10 mg b.i.d.). 50 % of this group will receive galantamine first, 50 % of the group will receive memantine first to allow for differential qualitative evaluation of tolerability of a combination therapy.
Drug: Galantamine CR
24 mg/day with dose-titration over twelve weeks

Drug: Memantine
memantine 10 mg b.i.d. with a dose titration of sixteen weeks




Primary Outcome Measures :
  1. ADAScog/11 [ Time Frame: change from Baseline to 12 months of treatment ]
    Alzheimer's Disease Assessment Scale (ADAS-cog/11) The ADAS consists of two parts - a cognitive subscale and a behavioral subscale. The behavioural subscale will not be used in this trial. The cognitive subscale, the ADAS-cog/11, consisting of Word Recall and Word Recognition memory tests, Object and Finger Naming, Commands, Constructional Praxis, Ideational Praxis, Orientation, Remembering Test Instructions, Spoken Language Ability, Comprehension of Spoken Language and Word Finding Difficulty will be the primary variable in this trial. In this trial the German version of the ADAS-cog/11 will be employed (Ihl & Weyer, 1993).


Secondary Outcome Measures :
  1. ADCS-ADL [ Time Frame: change from Baseline to 12 months of treatment ]
    The ability to perform activities of daily living will be assessed using the AD version of the Alzheimer's Disease Cooperative Study ADL inventory (Galasko et al., 1997, 2004). This instrument comprises questions about 23 basic and instrumental ADLs. For each ADL, the scores range from 0 (non-performance of the activity or the need for extensive help) to the highest score (representing independent performance of the activity). The total score ranges from 0 (no function) to 78 (maximal function).

  2. Clinical Dementia Rating [ Time Frame: change from Baseline to 12 months of treatment ]
    The CDR Scale is a clinician-rated dementia staging system that tracks the progression of cognitive and functional deterioration. Scores are on a scale of 0 - 5, with 0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia, 4 = profound dementia, and 5 = terminal dementia. Cognitive and functional abilities that are assessed are memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care. Memory is considered the primary driver for scoring with the other categories secondary.

  3. Neuropsychiatric Inventory NPI [ Time Frame: change from Baseline to 12 months of treatment ]
    The Neuropsychiatric Inventory (Cummings et al., 1994) is used to assess 10 areas of non-cognitive symptoms which are common in dementia, including delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time. Interrater reliability and test-retest reliability are acceptable.

  4. Resource Utilization of Dementia Scale (RUD) [ Time Frame: change from Baseline to 12 months of treatment ]
    For each patient, use of medical and social services will be determined using the Resource Utilization of Dementia Scale (Wimo et al., 1998). This instrument is used to rate the primary caregiver (time spent on caring, occupational status, use of medical and social services, use of medications) and the patient (living arrangement, nursing home and hospital admissions, use of medical and social services) to estimate healthcare cost

  5. Burden Interview (BI) [ Time Frame: change from Baseline to 12 months of treatment ]

    The Burden Interview (Zarit & Zarit, 1983, 1990) has been designed to assess the stress experienced by family caregivers of elderly and disabled persons. It can be completed by caregivers themselves or as part of an interview. Caregivers are asked to respond to a series of 22 items about the impact of the patient's disabilities on their life. For each item caregivers are to indicate how often they have felt that way: never, rarely, sometimes, quite frequently, or nearly always.

    The Burden Interview is scored by summing the responses of the individual items. The total score ranges from 0 to 88. Higher scores indicate greater caregiver distress.


  6. Adverse Event Reports [ Time Frame: 12 months of treatment ]
  7. Rate of brain atrophy [ Time Frame: change from baseline to 12 months of treatment ]
    Serial volumetric MRI will generate data-sets used for whole brain rate of atrophy determinations, hippocampal rate of atrophy measurements as well as MR-spectroscopic parameters



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willingness to participate, as indicated by written informed consent of the patient. The competence of the participating patient has to be assessed by a physician who is not involved in this trial.
  2. Male or postmenopausal female outpatients.
  3. Age of > 50 years at time of randomization.
  4. Diagnosis of probable Alzheimer's Disease (according to NINCDS-ADRDA criteria).
  5. Clinical and psychometric rating cut-off score (valid at randomisation): MMSE range of 15 to 26 points.
  6. MRI brain scan not older than 12 months (before randomization) compatible with the diagnosis of Alzheimer's Disease. (The MRI brain scan must be repeated if older than 12 months or if clinically indicated).
  7. Patient being ambulatory having adequate vision and hearing abilities to allow neuropsychological testing.
  8. Patient with a knowledgeable, cooperative, reliable caregiver/informant who is willing to follow the study procedure as indicated by written informed consent.

Exclusion Criteria:

  1. Dementia of any other type than AD:

    1. vascular dementia

      • HIS Score (modified acc. to Rosen) > 5 or
      • evidence for VD acc. to NINCDS-AIREN criteria.
    2. depressive pseudodementia defined acc. to DSM-IV criteria for major depression.
    3. other non-AD dementia.
  2. Significant neurological disease other than AD, such as cerebral tumor, Huntington's disease, Parkinson's disease, normal pressure hydrocephalus, subdural hematoma, mental retardation, history of brain surgery or serious head trauma with residual deficits.
  3. Diagnosis of psychosis (requiring hospitalization or antipsychotic therapy for more than two weeks) within the past 10 years not associated with AD or a diagnosis of alcoholism or drug dependence within the past 10 years.
  4. History of epileptic seizures or patient receiving antiepileptic drugs.
  5. Abnormal laboratory test results considered clinically relevant for dementia: e.g., electrolyte changes, folate deficiency, vitamin B12 deficiency, pathological thyroid function (T3 and TSH levels), positive syphilis serology.
  6. Patient who, in the opinion of the investigator, is suffering from an acute or poorly controlled illness, such as:

    1. Presently uncontrolled hypertension (> 180 mmHg systolic or > 100 mmHg diastolic).
    2. Myocardial infarction within the last six months.
    3. Patient with uncompensated congestive heart failure (NYHA Class III or IV)
    4. Severe renal, hepatic or gastrointestinal disease, which could alter absorption, metabolism or excretion of the trial drug.
    5. Serum creatinine > 130 μmol/l or 1.5 mg/dl, transaminases (ALAT, ASAT) or GGT > twice the upper limit of normal range.
    6. Uncontrolled diabetes on entry into the double-blind phase of the research project (fasting blood glucose > 10.0 mmol/l or 180 mg/dl in repeated tests) or patient requiring insulin treatment.
  7. Patient taking any inadmissible medication, such as:

    • Any investigational drug.
    • Anticonvulsants (incl. barbiturates).
    • Anti-Parkinson agents.
    • Dopaminergic agents.
    • Amantadine.
    • Antimuscarinic agents (i. e., anticholinergics).
    • Selegiline, MAOI.
  8. Any condition that precludes cooperation with the tests or other investigations during the study (e.g., seeing or hearing loss, relevant confusion or agitation, musculoskeletal disorders, contraindication for magnetic resonance imaging, i.e., presence of pacemaker, metallic implants in high risk areas, presence of metallic material in high risk areas, history of claustrophobia. Hip implants are not contraindicated).
  9. Patient has participated in an investigational clinical trial during the last 2 months.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01921972


Sponsors and Collaborators
Charite University, Berlin, Germany
German Federal Ministry of Education and Research
Investigators
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Study Director: Isabella Heuser, Prof. Dr. Free University of Berlin
Principal Investigator: Wolfgang Maier, Prof. Dr. University of Bonn
Principal Investigator: Wolfgang Gaebel, Prof. Dr. Heinrich-Heine University, Duesseldorf
Principal Investigator: Johannes Kornhuber, Prof. Dr. University of Erlangen-Nürnberg
Principal Investigator: Konrad Maurer, Prof. Dr. University of Frankfurt
Principal Investigator: C H Lücking, Prof. Dr. University of Freiburg
Principal Investigator: Eckhart Rüther, Prof. Dr. University of Göttingen
Principal Investigator: Mathias Berger, Prof. Dr. University of Freiburg
Principal Investigator: Dieter Naber, Prof. Dr. University of Hamburg
Principal Investigator: Christoph Mundt, Prof. Dr. Heidelberg University
Principal Investigator: Lutz Frölich, Prof. Dr. Heidelberg University
Study Director: Lutz Frölich, Prof. Dr. Central Institute of Mental Health
Principal Investigator: Fritz A Henn, Prof. Dr. Central Institute of Mental Health
Principal Investigator: Matthias C Angermeyer, Prof. Dr. LMU München
Principal Investigator: Hans Förstl, Prof. Dr. Technische Universität München
Principal Investigator: Peter Falkai, Prof. Dr. Universitäts-Nervenklinik Homburg

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Isabella Heuser, Prof. Dr., Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT01921972     History of Changes
Other Study ID Numbers: Modul E.2 II
First Posted: August 14, 2013    Key Record Dates
Last Update Posted: August 14, 2013
Last Verified: August 2013

Keywords provided by Isabella Heuser, Charite University, Berlin, Germany:
AD, Dementia

Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Memantine
Galantamine
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Cholinesterase Inhibitors
Enzyme Inhibitors
Cholinergic Agents
Parasympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Nootropic Agents