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

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01409915
• Collaborator: The Dana Foundation (Other)
• Enrollment: 44
• Location: 1
• Arms: 2
• Duration (Months): 105.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Sagramostim; Drug: Saline -- placebo comparator	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Pilot Phase 2 Trial of the Safety & Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor (Leukine®) in the Treatment of Alzheimer's Disease
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Dec 9, 2019
• Actual Study Completion Date: Dec 9, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sagramostim (Leukine) 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; 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; Other Names: Leukine Granulocyte-Macrophage Colony-Stimulating Factor
Placebo Comparator: Control Group Saline -- placebo comparator. Given as a subcutaneous injection.	Drug: Saline -- placebo comparator; subcutaneous injection; Other Names: Sterile solution of sodium chloride in water

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Denver, Anschutz Medical Campus	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• The Dana Foundation

Investigators

• Principal Investigator: Huntington Potter, PhD, University of Colorado, Denver

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 23, 2020

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01409915
• Other Study ID Numbers: 12-1273
• First Posted: Aug 4, 2011
• Last Update Posted: Jun 2, 2021
• Last Verified: May 1, 2021

• Keywords provided by University of Colorado, Denver: Alzheimer's disease; neuropsychological assessment; Granulocyte-Macrophage Colony-Stimulating Factor; Leukine
• Additional relevant MeSH terms: Alzheimer Disease; Molgramostim; Sargramostim

Study Results

Participant Flow

Arm/Group Title	Sagramostim (Leukine)	Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection
Period Title: Overall Study
STARTED	21	23
COMPLETED	20	20
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Sagramostim (Leukine)	Control Group	Total
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection	Total of all reporting groups
Overall Participants	20	20	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.10 (6.57)	70.15 (6.42)	68.63 (6.59)
Sex: Female, Male (Count of Participants)
Female	12 60%	11 55%	23 57.5%
Male	8 40%	9 45%	17 42.5%
Race/Ethnicity, Customized (Count of Participants)
White / Caucasian	20 100%	19 95%	39 97.5%
Black / African American	0 0%	1 5%	1 2.5%
Asian / Pacific Islander	0 0%	0 0%	0 0%
Hispanic / Latino	0 0%	0 0%	0 0%
Other	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	20 100%	20 100%	40 100%
Education Level (Mean years) (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	15.70 (2.92)	15.80 (2.71)	15.75 (2.78)

Outcome Measures

1. Primary Outcome

Title	Adverse Events (AEs) by Body System
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sagramostim (Leukine)	Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection
Measure Participants	21	22
Cardiovascular AE	5	2
Constitutional	6	5
Dental	1	0
Dermatological	16	5
ENT	2	0
Gastrointestinal	8	5
Musculoskeletal	8	11
Neurological	9	2
Psychological	0	2
Respiratory	4	4

2. Secondary Outcome

Title	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)
Description	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.
Time Frame	From Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment)

Outcome Measure Data

Analysis Population Description

The analysis population is Per Protocol, with all participants enrolled and randomized in the clinical trial, and who complete the treatment without major breaches in the study protocol.

Arm/Group Title	Sagramostim (Leukine)	Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection
Measure Participants	20	20
Baseline	17.10 (4.57)	20.75 (4.97)
End of Treatment (3 weeks)	18.55 (4.99)	20.40 (5.28)
Follow-up 1 (45 days post treatment)	18.00 (5.52)	19.90 (5.19)
Follow-up 2 (90 days pot treatment)	17.10 (5.78)	19.40 (5.47)

3. Secondary Outcome

Title	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)
Description	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)

Outcome Measure Data

Analysis Population Description

The analysis population is Per Protocol, with all participants enrolled and randomized in the clinical trial, and who complete the treatment without major breaches in the study protocol.

Arm/Group Title	Sagramostim (Leukine)	Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection
Measure Participants	20	20
Baseline	43.20 (12.45)	36.20 (12.01)
End of Treatment (3 weeks)	43.54 (12.02)	36.68 (11.63)
Follow-up 1 (45 days post treatment)	47.67 (11.89)	36.33 (9.85)
Follow-up 2 (90 days post treatment)	45.87 (13.21)	36.85 (10.24)

4. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis population is Per Protocol, with all participants enrolled and randomized in the clinical trial, and who complete the treatment without major breaches in the study protocol.

Arm/Group Title	Sagramostim (Leukine)	Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection
Measure Participants	20	20
Baseline	56.50 (12.30)	62.75 (8.98)
End of Treatment (3 weeks)	57.00 (11.93)	61.85 (9.32)
Follow-up 1 (45 days post treatment)	53.35 (14.02)	59.85 (9.05)
Follow-up 2 (90 days post treatment)	53.30 (15.00)	60.30 (9.00)

5. Other Pre-specified Outcome

Title	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)
Description	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.
Time Frame	Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment)

Outcome Measure Data

Analysis Population Description

The analysis population is Per Protocol, with all participants enrolled and randomized in the clinical trial, and who complete the treatment without major breaches in the study protocol.

Arm/Group Title	Sagramostim (Leukine)	Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection
Measure Participants	20	20
Baseline	7.10 (3.32)	6.10 (2.67)
End of Treatment (3 weeks)	7.53 (3.37)	5.95 (2.37)
Follow-up 1 (45 days post treatment)	8.42 (4.22)	6.81 (3.12)
Follow-up 2 (90 days post treatment)	8.57 (4.14)	7.03 (3.27)

6. Other Pre-specified Outcome

Title	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)
Description	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.
Time Frame	Baseline to End of Treatment (3 weeks), Follow-Up 1 (45 days post treatment) and Follow-Up 2 (90 days post treatment)

Outcome Measure Data

Analysis Population Description

The analysis population is Per Protocol, with all participants enrolled and randomized in the clinical trial, and who complete the treatment without major breaches in the study protocol.

Arm/Group Title	Sagramostim (Leukine)	Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.	Saline placebo comparator: subcutaneous injection
Measure Participants	20	20
Baseline	101.50 (46.17)	84.85 (48.83)
End of Treatment (3 weeks)	92.60 (45.49)	79.40 (44.56)
Follow-up 1 (45 days post treatment)	107.85 (45.81)	84.00 (45.64)
Follow-up 2 (90 days post treatment)	110.35 (45.55)	85.45 (48.10)

Adverse Events

Time Frame	Adverse events were completed over a 20 week period, from Consent to Follow-up 2
Adverse Event Reporting Description	Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
Arm/Group Title	Sagramostim (Leukine)		Control Group
Arm/Group Description	250 mcg /m2/day Leukine subcutaneously for 5 days/week for three weeks.		Saline placebo comparator: subcutaneous injection
All Cause Mortality
	Sagramostim (Leukine)		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/23 (0%)
Serious Adverse Events
	Sagramostim (Leukine)		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		1/23 (4.3%)
Cardiac disorders
Myocardial Infarction	1/21 (4.8%)	1	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/21 (0%)	0	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Sagramostim (Leukine)		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/21 (90.5%)		20/23 (87%)
Gastrointestinal disorders
Nausea	3/21 (14.3%)		1/23 (4.3%)
Diarrhea	2/21 (9.5%)		3/23 (13%)
General disorders
Fatigue	2/21 (9.5%)		4/23 (17.4%)
Musculoskeletal and connective tissue disorders
Pain/Myalgia	4/21 (19%)		5/23 (21.7%)
Fall	1/21 (4.8%)		4/23 (17.4%)
Nervous system disorders
Headache, Benign NOS	8/21 (38.1%)		2/23 (8.7%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory infection	3/21 (14.3%)		3/23 (13%)
Skin and subcutaneous tissue disorders
Injection site reaction	9/21 (42.9%)		5/23 (21.7%)
Rash	3/21 (14.3%)		0/23 (0%)

Limitations/Caveats

The main weakness is the small sample size of the study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.