Trial document





This trial has been registered retrospectively.
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  DRKS00000440

Trial Description

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Title

Randomized Controlled Trial of Simvastatin in Amnestic MCI Patients

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

A German multicenter clinical trial (SIMaMCI) investigates, if the risk of developing Alzheimer’s disease can be lowered by intake of Simvastatin, a drug used to lower plasma cholesterol level. The study is sponsored by the Federal Ministry of Education and Research.
Apart from lowering cholesterol levels, Simvastatin presumably inhibits the production of beta-amyloid, a protein which is related closely to the development of Alzheimer’s disease. Retrospective analyses showed, that patients who have taken Statins, developed less frequently dementia.
Clinical lead is Prof. Isabella Heuser, Head of the Department of Psychiatry and Psychotherapy at the Charité, Berlin.
Worldwide, this is the first placebo-controlled, double-blinded prevention trial. In total 640 subjects will be included. Treatment with Simvastatin, resp. placebo will be offered for up to 5 years. Additionally, neuropsychological tests, blood and liquor tests, genetic analyses and MRI will be carried out, to monitor the success of the treatment and to investigate further the possible mechanisms of Statins in the prevention of Alzheimer’s disease.
To participate the following criteria have to be met:
1. Impaired objective memory function; 2. No current or previous use for more than 3 months of an approved, experimental or over-the-counter antidementia drug; 3. No Medical indication for treatment with a statin or intake of a statin for more than 6 weeks; 4. No severe cardiovascular or other diseases. 5. Presence of a spouse of close relative; 6. age 55 - 85

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Brief Summary in Scientific Language

Probands with MCI are at high risk to develop Alzheimer´s dementia (AD). Simvastatin may lower the production of β-amyloid a hallmark of AD in the brain and may additionally reduce oxidative stress and inflammation as well as increase endothelial nitric oxide synthetase and improve endothelial function. Simvastatin crosses the blood brain barrier, effects phospholipid transfer protein activity and phospho-tau-181 levels. Simvastatin protects cortical neurons from excitotoxicity.
Primary hypothesis: Simvastatin significantly reduces the conversion rate to Alzheimer’s disease in patients with MCI as compared to MCI patients receiving placebo
Secondary hypotheses (to be evaluated by means of exploratory statistical methods): (1) The benefit from simvastatin treatment is larger in patients with a low level of β-amyloid (Aβ42 530ng/l; Aβ40 5612 ng/l) / increased level of Tau (t-Tau 350 ng/l; p-Tau 60 ng/l) in CSF as compared to patients above/below the respective cut-off values. (2)The benefit from simvastatin treatment is larger in APO-E4 allele carriers than in other APO-E allele individuals

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Organizational Data

  •   DRKS00000440
  •   2010/06/07
  •   2009/02/11
  •   yes
  •   Approved
  •   ZS EK 12 4725/08, Ethik-Kommission des Landes Berlin
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Secondary IDs

  •   2008-002226-11 
  •   NCT00842920  (ClinicalTrials.gov)
  •   4034563 
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Health Condition or Problem studied

  •   F06.7 -  Mild cognitive disorder
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Interventions/Observational Groups

  •   Simvastatin, 60 mg, once a day, oral
  •   placebo, once a day, oral
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Double or multiple blind
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  •   Placebo
  •   Prevention
  •   Parallel
  •   IV
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Primary Outcome

Length of conversion-free interval, staring at the time of randomization, with conversion being defined as an increase of the CDR score beyond 0.5

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Secondary Outcome

1. Change in ADAS-cog and FCSRT score; 2. Change in CDR sum of boxes; 3. Change in ADCS-ADL score; 4. Change in volumetric brain measures; 5. Change in CSF and blood measures of ß-amyloid peptides, total and phosphorylized TAU proteins and measures of cerebral cholesterol metabolites; 6. Impact on cost efficacy ratio (ICER); 7. Pharmacogenetic prediction parameters

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Actual
  •   2009/01/09
  •   640
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   55   Years
  •   85   Years
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Additional Inclusion Criteria

(1) Self and informant report of gradually increasing memory impairment for at least six months.
(2) Objective memory impairment
(3) Intact basic activities of daily living
(4) Preserved general cognitive function, not demented
(5) Absence of a detectable cause of memory disorder
(6) Age 55 to 85.
(7) Females without childbearing potential
(8) A total cholesterol ≥90 mg/dl
(9) LDL-cholesterol <130 mg/dl. LDL-cholesterol 130-160 mg/dl ≤ 3 risk factors including age or 160-190 mg/dl and 2 risk factors (only controlled hypertension and age)
(10) Informed consent (according AMG §40 (1) 3b)
(11) No participation in other clinical trials 2 months before and
after participation in this study

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Exclusion Criteria

(1) Hypersensitivity against Simvastatin, active liver disease or
lasting increase of serum transaminases for unclear reason
(2) Unstable medical, neurological or psychiatric disease
(3) Lack of a spouse or a close relative
(4) Use of a registered anti-dementia drug or a nootropic
(5) Chronic use of anti-inflammatory drugs
(6) History of stroke, coronary heart disease or myocardial infarction. Severe renal insuffiency.
(7) LDL-cholesterol 130-160 mg/dl and > 3 risk factors or 160-190 mg/dl and > 2 risk factors including age. LDL-cholesterol >190 mg/dl
(8) Comedication with Diltiazem, Verapamil, Amiodaron, Itraconazol, Ketokonazol, Erythromycin,Clarithromycin, Telithromycin, Ciclosporin, Gemfibrozil,Nefazodon, HIV-protease inhibitors, Benzodiazepines,
Tricyclic antipsychotics or other anticholinergic drugs;Comedication of other statins.
(9) Persons who are detained officially or legally to an official institute

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Addresses

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    • Charité Universitätsmedizin Berlin
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • Klinik für Psychiatrie und Psychotherapie, Charité - Universitätsmedizin Berlin CBF
    • Mr.  Dr. med.  Oliver   Peters 
    • Eschenallee 3
    • 14050  Berlin
    • Germany
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    • Klinik für Psychiatrie und Psychotherapie, Charité -Universitätsmedizin CBF
    • Ms.  Dr. rer. nat.  Brigitte  Haas 
    • Eschenallee 3
    • 14050   Berlin
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung - BMBF Dienstsitz Berlin
    • Hannoversche Straße 28-30
    • 10115   Berlin
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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