Study of the Safety & Efficacy of Leukine® in the Treatment of Alzheimer's Disease

Study Overview
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Brief Summary
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A medicine that is FDA-approved for bone marrow stimulation (called Leukine) will be tested for its ability to be tolerated by Alzheimer's disease patients and potentially to improve their memory.

Detailed Description
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Preliminary preclinical results demonstrated that GM-CSF (Granulocyte macrophage colony-stimulating factor, e.g. Leukine®/Sargramostim) rapidly reduced cerebral amyloid deposition and completely reversed memory deficits in transgenic mouse models of Alzheimer's Disease (AD). To assess the efficacy of GM-CSF in humans, the investigators performed a retrospective analysis of a cognition study of human patients undergoing hematopoietic cell transplantation for cancer and who garner cognitive impairments from the chemotherapy or irradiation. In the patients that received a colony-stimulating factor (CSF) to stimulate the bone marrow and recover immune system function, the investigators found that those who received GM-CSF (Leukine®/Sargramostim) plus G-CSF (Filigrastim) significantly improved in cognitive function as compared to those who received G-CSF alone. These findings combined with over two decades of accrued safety data using recombinant human GM-CSF, Leukine®/Sargramostim, in elderly leukopenic patients, suggested that Leukine® should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD.

Official Title
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Pilot Phase 2 Trial of the Safety & Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor (Leukine®) in the Treatment of Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Sagramostim
* Drug: Saline -- placebo comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 55 to 85 years; should have a mild-to-moderate AD diagnosis (MMSE 10-26 inclusive); should have evidence of elevated cortical amyloid by PET using florbetapir F18 (Amyvid) [i.e. a positive scan], assessed qualitatively according to the Amyvid product label. if on anti-dementia treatment should be on stable treatment for at least 2 months (i.e. cholinesterase inhibitor and/or Memantine or Axona); stable on all other medications for at least 30 days prior to screen; should be fluent in English; should be physically able to participate by medical history, clinical exam and tests; should have a study partner to accompany them to scheduled visits. Exclusion Criteria: clinically relevant arrhythmias; a resting pulse less than 50; active cancer other than non-melanoma skin cancers; use of another investigatory drug within 2 months of screening; significant stroke or head trauma by history or MRI; contraindication for having a MRI; diagnostic and Statistical Manual of Mental Disorders-IV criteria for a current major psychiatric disorder; sensitivity to yeast or yeast products; impaired kidney function as measured by a Glomerular Filtration Rate less than 60 milliliters/min; preexisting fluid retention, pulmonary infiltrates, or congestive heart failure; history of moderate-to-severe lung disease; history of moderate-to-severe liver disease; pregnant women, or any women who feel they are likely to become pregnant during the study; prisoners.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sagramostim (Leukine)<br>5 subjects 250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks. Data and Safety Monitoring Board will then review data and recommend whether to continue at the same current recommended dose for additional subjects or to reduce the dose by half if excessive leukocytosis occurs | Drug: Sagramostim<br>* 5 subjects 250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks. Data and Safety Monitoring Board will then review data and recommend whether to continue at the same current recommended dose for additional subjects or to reduce the dose by half if excessive leukocytosis occurs<br>* Other names: Granulocyte-Macrophage Colony-Stimulating Factor;|
| Placebo Comparator: Control Group<br>Saline -- placebo comparator. Given as a subcutaneous injection. | Drug: Saline -- placebo comparator<br>* subcutaneous injection<br>* Other names: Sterile solution of sodium chloride in water;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) by Body System | Count of AE's from Consent to Follow-up 2 within a safety analysis set consisting of all participants who were enrolled and randomized and who received at least one injection of sargramostim or placebo | 20 weeks (From Consent to Follow-up 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MMSE (Mini Mental State Examination) From Baseline to End of Treatment (3 Weeks), Follow-Up 1 (45 Days Post Treatment) and Follow-Up 2 (90 Days Post Treatment) | Mini-Mental State Examination (MMSE) is a brief psychometric instrument developed to assess cognitive function in elderly populations. It is a standard assessment used by all NIH Alzheimer's Disease Centers (ADCCs and ADRCs) to identify and monitor individuals with AD. The range for scores in the MMSE is from 0 to 30, with lower scores indicating greater impairment. | From Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment) | 
| Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) From Baseline to End of Treatment (3 Weeks), Follow-Up 1 (45 Days Post Treatment) and Follow-Up 2 (90 Days Post Treatment) | Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-Cog13). The ADAS-Cog13 is the most popular cognitive testing instrument used in clinical trials of nootropics (drugs or agents that improve cognitive function). It consists of 13 tasks measuring the disturbances of memory, language, praxis, attention and other cognitive abilities, which are often referred to as the core symptoms of AD. Score ranges from 0-85, with a higher score representing more severe impairment | Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, neuropsychological assessment, Granulocyte-Macrophage Colony-Stimulating Factor, Leukine