Efficacy and Safety of Filgrastim in Alzheimer's Disease

Study Overview
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Brief Summary
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Filgrastim (G-CSF) is widely used for treatment of patients who have a deficiency of white blood cells. It is also routinely used to stimulate and mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF, the side-effects profile has been reported to be mild and reversible. Currently, G-CSF is under investigation in clinical trials in Germany and the US that aim to enhance recovery from strokes and heart attacks. In animal studies, G-CSF has been observed to improve cognitive performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a mouse model of Alzheimer's Disease (AD). Since this drug is being used safely in many people throughout the world, the investigators hypothesize that it will also be safe to give to patients with Alzheimer's disease and that it may improve some aspects of memory and thinking. The present pilot study has two goals or objectives: 1) to investigate the effects of a five day schedule of Filgrastim administration on cognitive function and 2) to assess its tolerability and safety in a small group (12 patients) with mild to moderate stage AD. Patients who are eligible for the study will be randomly assigned to one of two groups (n=6 per group). One group will receive a five-day course of Filgrastim injections and the other group of subjects will receive vehicle injections (solution without drug). At the end of the first phase of the study (week 8), the groups will cross over to receive either vehicle or Filgrastim as appropriate. In this way all subjects will have received the active medication by the end of the study. After the study is finished the investigators should know whether or not Filgrastim improves some aspects of thinking and memory. And the investigators should know whether or not it is safe to give this medication to patients with Alzheimer's disease. To ensure that the drug is safe, a Safety Monitoring Committee will oversee the entire study. They will review all laboratory data, including complete blood counts, serum chemistry, EKGs and adverse events.

Detailed Description
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The study was originally designed to have two arms (GCSF first followed by placebo= Arm 1; placebo followed by GCSF=Arm2). Total length of study for each subject was 14 weeks, with crossover on week 7. Linear regression models could not be used because of the small number of subjects; n = 5 in the first Arm who received G-CSF before crossover to the placebo phase and n = 3 in Arm 2 (who received placebo first before crossover to the G-CSF treatment phase). The general rule for the sample size required for regression analysis is n = 15 per covariate. Therefore, comparison of the final cognitive scores on visit 5 (week 14) were compared to scores at baseline (visit 1) for all subjects (n = 8) using the Wilcoxon signed rank test. Plasma cytokine changes were plotted to compare effects following G-CSF to that following placebo, regardless of the order of treatment. Wilcoxon sum rank test was used to test differences between G-CSF treatment and placebo treatment at specific intervals after treatment. Statistical Package for the Social Sciences (SPSS Version 19) was used for all data analysis.

Official Title
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Efficacy and Safety of Filgrastim as a Pro-Cognitive Agent in Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: G-CSF; filgrastim
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: People with probable AD (by NINDS/ADRDA criteria) who are likely to be testable at the conclusion of the study period, and who do not have concurrent medical conditions or medications that might influence cognitive testing or that would increase the risk of treatment The participants will have a Min Mental State Examination score of between 10 and 24 stable medical condition and stable medications for 3 months prior to screening study partner (spouse or caregiver) to accompany patient to all scheduled visits; able to complete baseline assessments physically acceptable for this study as confirmed by medical history, physical exam, neurological exam and clinical tests Exclusion Criteria: clinically significant cardiac arrhythmia history of clinically significant stroke use of another investigational drug within 2 months of screening current evidence or history in the past 2 years of epilepsy, focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder alcohol or substance abuse; residence in a skilled nursing facility (but patients in assisted living facility are acceptable)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: G-CSF (filgrastim) first phase<br>Subjects assigned to this arm receive G-CSF for 5 days during the first phase of the study. At week 7 these subjects cross over to receive placebo injections for five days | Drug: G-CSF; filgrastim<br>* The drug is administered s.c. at a dose of 10 microg/kg daily for 5 days<br>* Other names: Neupogen; granulocyte colony stimulating factor (GCSF);|
| Placebo Comparator: Placebo first phase<br>Subjects assigned to this arm receive placebo injections daily for 5 days; after wk 7 they crossover to receive 5 daily injections of injections of G-CSF. | Drug: Placebo<br>* vehicle (D5W or 5% dextrose solution) is administered subcutaneously daily for 5 days<br>* Other names: Vehicle (5% dextrose water or D5W);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Measures Incluing ADAScog, Selected CANTABS Tests (Paired Associate Learning (PAL)and PAL ) | Scores from each of the cognitive assessments: mean ADAScog: a decrease in total score units = improvement, min=0 max=31 mean PAL (memory): an increase in score = improvement, min= 0 max=12 mean PAL (total trial adj): a decrease in score = improvement, | Baseline and 2wk and 4 wk after Rx; | 
| Cognitive Measures Incluing ADAScog, Selected CANTABS Tests (Paired Associate Learning (PAL)and PAL ) | Scores from each of the cognitive assessments: mean ADAScog: a decrease in total score units = improvement, min=0 max= mean PAL (memory): an increase in score = improvement, mean PAL (total trial adj): a decrease in score = improvement, | Baseline and final visit (14 wks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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G-CSF, granulocyte colony stimulating factor, Filgrastim