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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01409915

Enrollment

Registered

2011-08-04

Start date

2011-03-31

Completion date

2019-12-09

Last updated

2021-06-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer's Disease

Keywords

Alzheimer's disease, neuropsychological assessment, Granulocyte-Macrophage Colony-Stimulating Factor, Leukine

Brief summary

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

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.

Interventions

DRUGSagramostim

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

DRUGSaline -- placebo comparator

subcutaneous injection

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

55 Years to 85 Years

Healthy volunteers

Inclusion criteria

1. age 55 to 85 years; 2. should have a mild-to-moderate AD diagnosis (MMSE 10-26 inclusive); 3. 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. 4. if on anti-dementia treatment should be on stable treatment for at least 2 months (i.e. cholinesterase inhibitor and/or Memantine or Axona); 5. stable on all other medications for at least 30 days prior to screen; 6. should be fluent in English; 7. should be physically able to participate by medical history, clinical exam and tests; 8. should have a study partner to accompany them to scheduled visits.

Exclusion criteria

1. clinically relevant arrhythmias; 2. a resting pulse less than 50; 3. active cancer other than non-melanoma skin cancers; 4. use of another investigatory drug within 2 months of screening; 5. significant stroke or head trauma by history or MRI; 6. contraindication for having a MRI; 7. diagnostic and Statistical Manual of Mental Disorders-IV criteria for a current major psychiatric disorder; 8. sensitivity to yeast or yeast products; 9. impaired kidney function as measured by a Glomerular Filtration Rate less than 60 milliliters/min; 10. preexisting fluid retention, pulmonary infiltrates, or congestive heart failure; 11. history of moderate-to-severe lung disease; 12. history of moderate-to-severe liver disease; 13. pregnant women, or any women who feel they are likely to become pregnant during the study; 14. prisoners.

Design outcomes

Primary

Measure	Time frame	Description
Adverse Events (AEs) by Body System	20 weeks (From Consent to Follow-up 2)	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

Secondary

Measure	Time frame	Description
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)	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.
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)	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

Other

Measure	Time frame	Description
Alzheimer's Disease Cooperative Study -Activities of Daily Living Inventory (ADCS-ADL) From Baseline to End of Treatment (3 Weeks), Follow-Up 1 (45 Days Post Treatment) and Follow-Up 2 (90 Days Post Treatment)	Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment)	The ADCS-ADL is a caregiver/study partner rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. The ADCS-ADL assesses functional capacity across a wide spectrum of severity
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) From Baseline to End of Treatment (3 Weeks), Follow-Up 1 (45 Days Post Treatment) and Follow-Up 2 (90 Days Post Treatment)	Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment)	The CDR is a study partner/caregiver and participant based interview to assess changes in domains such as memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated as 0 (no dementia), 0.5 (uncertain dementia), 1 (mild dementia), 2 (moderate dementia), or 3 (severe dementia). The Sum of Boxes score (CDR-SB) score was tallied for each administration using the rules from the Washington University Knight ADRD scoring algorithm. Scores range from 0-18. The higher the score, the worse the impairment.
Trail Making Test - Part A (TMT-A) From Baseline to End of Treatment (3 Weeks), Follow-Up 1 (45 Days Post Treatment) and Follow-Up 2 (90 Days Post Treatment)	Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment)	The Trail Making Test- part A (TMT-A) is a assessment of psychomotor speed and is a timed test in which participants must connect a series of numbers randomly placed on a page. Time range is between 0 and 150 seconds, with higher score representing worse performance.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Sagramostim (Leukine) 250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	20
Control Group Saline placebo comparator: subcutaneous injection	20
Total	40

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	2
Overall Study	Protocol Violation	1	0
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Total	Sagramostim (Leukine)	Control Group
Age, Continuous	68.63 Years STANDARD_DEVIATION 6.59	67.10 Years STANDARD_DEVIATION 6.57	70.15 Years STANDARD_DEVIATION 6.42
Education Level (Mean years)	15.75 Years STANDARD_DEVIATION 2.78	15.70 Years STANDARD_DEVIATION 2.92	15.80 Years STANDARD_DEVIATION 2.71
Race/Ethnicity, Customized Race / Ethnicity Asian / Pacific Islander	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race / Ethnicity Black / African American	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Race / Ethnicity Hispanic / Latino	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race / Ethnicity Other	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race / Ethnicity White / Caucasian	39 Participants	20 Participants	19 Participants
Region of Enrollment United States	40 Participants	20 Participants	20 Participants
Sex: Female, Male Female	23 Participants	12 Participants	11 Participants
Sex: Female, Male Male	17 Participants	8 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 21	0 / 23
other Total, other adverse events	19 / 21	20 / 23
serious Total, serious adverse events	1 / 21	1 / 23

Outcome results

Primary

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

Time frame: 20 weeks (From Consent to Follow-up 2)

Population: Safety analysis set (SAS), all participants enrolled and randomized and who received at least one injection of sargramostim or placebo

Arm	Measure	Group	Value (NUMBER)
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Cardiovascular AE	5 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	ENT	2 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Musculoskeletal	8 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Constitutional	6 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Neurological	9 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Gastrointestinal	8 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Psychological	0 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Dental	1 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Respiratory	4 Adverse Events
Sagramostim (Leukine)	Adverse Events (AEs) by Body System	Dermatological	16 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Respiratory	4 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Dermatological	5 Adverse Events
Control Group	Adverse Events (AEs) by Body System	ENT	0 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Cardiovascular AE	2 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Constitutional	5 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Dental	0 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Gastrointestinal	5 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Musculoskeletal	11 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Neurological	2 Adverse Events
Control Group	Adverse Events (AEs) by Body System	Psychological	2 Adverse Events

Secondary

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

Time frame: Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment)