Phase II Trial to Evaluate Safety and Efficacy of GM-CSF/Sargramostim in Alzheimer's Disease (SESAD)

Phase II Trial to Evaluate Safety and Efficacy of GM-CSF/Sargramostim in Alzheimer's Disease (SESAD)

A medicine that is FDA-approved for bone marrow stimulation (called sargramostim) will be tested for its safety and efficacy in individuals with mild-to-moderate Alzheimer's disease over a six month treatment period.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Sargramostim; Drug: Saline - placebo comparator

Detailed Description

This trial protocol is designed to evaluate primarily whether the long-term use of sargramostim (recombinant human GM-CSF), administered five days per week for six consecutive months (24 weeks), will be tolerated by and safe for use in participants with mild-to-moderate AD, secondarily whether sargramostim can slow, halt, or reverse cognitive decline, and exploratory whether sargramostim can slow, halt, or reverse decline in activities of daily living, reverse or improve several biomarkers associated with AD, as evaluated by multimodal neuroimaging techniques and blood and cerebrospinal fluid analyses. This trial extends the safety results from recently completed Phase 2 double-blind, placebo-controlled clinical trial in mild-to-moderate AD participants (NCT01409915, COMIRB#12-1273), using sargramostim that was administered five days per week for three consecutive weeks and in which there were no incidence of drug-related serious adverse events (SAEs).

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Neurology Research Partners, CU Department of Neurology; Phone Number: 303-724-4644; Email: neurologyresearchpartners@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz Medical Campus
      • Contact: Neurology Research Partners; Phone Number: 303-724-4644; Email: neurologyresearchpartners@cuanschutz.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males or females between age 60 and 85 years, inclusive, at time of consent.
• Have a dedicated partner/caregiver informant who is in the company of the participant at least 12 hours a week, who can accompany them to scheduled visits, and who is able to provide accurate reporting upon the behavioral, cognitive and functional abilities of the participant.
• Be physically able to participate with adequate visual acuity and auditory discrimination.
• Be willing / able to provide written informed consent or assent.
• Must reside within a proximity of the study site that will not preclude their regularly-scheduled participation in the trial, as well as a catchment area for local lab blood draws (i.e. central contracted laboratory).

• Meet criteria for probable AD dementia according to the National Institute of Aging - Alzheimer's Association (NIA-AA) 2018 core research criteria, and have the following at screening:

  • A diagnosis of mild AD or moderate AD, or
  • A provisional research diagnosis consistent with probable mild AD or moderate AD, and
  • MoCA score of 10-22 inclusive.

• Have positive biomarker for brain amyloid pathology as shown by:

  • Positive plasma assay for Aβ(42)/ Aβ(40) ratio AND
  • Either postivie CSF assay for AD assessment or positive amyloid PET, per PI read.
• If receiving anti-dementia treatment (i.e. AChEI), be on stable treatment for at least 2 months (i.e., cholinesterase inhibitor and/or Memantine) before initial screening visit.
• Be stable on all other medications for at least 30 days prior to initial screening visit.

Exclusion Criteria:

• Individuals with a first degree relative diagnosed with AD before 55 years of age.
• BMI ≥35.
• Is unable to read/write at a 6th grade level.
• Is a prisoner.
• Modified Hachinski Ischemic Score >4.
• Other neurological or psychiatric condition (other than AD) that can impact cognition, as well as atypical presentations of AD and AD related dementias, including logopenic primary progressive aphasia (PPA), or posterior cortical atrophy (PCA); or, CT/MRI evidence of potentially significant intracranial abnormalities not related to AD (e.g., evidence of major stroke or lacune in an area critical to cognition, infections, cancer, hydrocephalus, multiple sclerosis, etc.); or abnormal CSF not consistent with AD.
• Presence of current, serious mood or anxiety disorder, and/or a psychotic disorder, and/or a substance-related disorder according to Diagnostic and Statistical Manual of Psychiatric Disorders, Edition IV, text revision (DSM-IV-TR) or DSM-V that, in the opinion of the Principal Investigator, might impact cognitive assessment, affect participants ability to complete the study, or confound interpretation of the study drug effect; or is considered suicidal or shows suicidal ideation as assessed by the study physician
• History of deep vein thrombosis, pulmonary embolism, familial predisposition for deep vein thrombosis, or pulmonary embolism.
• Active cancer / malignant neoplasm within 5 years of screening other than non-melanoma skin cancers (e.g. Basal cell or squamous cell). Previous diagnosis of Leukemia, despite remission state or length of time, is considered exclusionary.
• History of a latex or yeast allergy.
• Presence/history of drug hypersensitivity; or known hypersensitivity to sargramostim, yeast-derived products, any other component of the product, or benzyl alcohol (present in bacteriostatic water or saline for injection).
• History of asplenia, hyposplenia, or splenectomy
• History of, or treatment for, an autoimmune disease (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Myasthenia Gravis, etc.).
• Untreated or unstable medical condition that could interfere with the study assessments in the opinion of the study physician, or may require immune-stimulating, immune-suppressive, or immune-modulating treatment(s) during the conduct of the study.
• History of seizures (except infant febrile seizures).
• Pregnant or breastfeeding female, or female of childbearing potential and not protected by highly effective contraceptive method of birth control (i.e., oral or depot contraceptives or intrauterine device (IUD) or participant was surgically sterilized) and/or unwilling or unable to be tested for pregnancy; Male refusing to use condoms, if partner can get pregnant.
• MRI evidence of >4 micro-hemorrhages; participants who may be prone to spontaneous ARIA-H and/or may be more susceptible to adverse effects of the ARIA-H.
• Laboratory results that are, in the judgement of the investigator, indicative of an untreated medical or hematologic condition that could increase risk or interfere with study assessments

• Evidence of:

  • Clinically significant pre-existing fluid retention (clinical or radiological);
  • respiratory symptoms (e.g., dyspnea), moderate-to-severe lung disease (e.g. COPD, pulmonary infiltrates)
  • cardiovascular symptoms or electrocardiographic evidence of cardiac disease that warrant therapeutic intervention (e.g., congestive heart failure, supraventricular arrhythmia, heart block, uncontrolled atrial fibrillation, etc.)
  • a resting pulse less than 50, as reviewed by the study physician;
  • prolonged QTc interval >470 ms in females, 450 ms in males).
  • screening blood pressure measurement of greater than 160 systolic and/or 95 diastolic
• Known renal dysfunction or serum creatinine >150 μmol/L, or Glomerular Filtration Rate (GFR) less than 55 ml/min
• Known hepatic dysfunction (apart from Gilbert's syndrome) or serum ALT ≥3 times the upper limit of normal (ULN)
• Positive serology for hepatitis B surface antigen (HBs Ag), anti-hepatitis C virus (anti-HCV), anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab) or spirochetal infection (e.g. syphilis)
• Contraindication to lumbar dural puncture, including coagulopathy, concomitant anticoagulation therapy (except daily 81 mg aspirin), prior spinal surgery, significant deformity of the lumbar/sacral region, or any other factor that, in the opinion of the investigator, precludes safe LP procedure.
• Contraindication or inability to complete magnetic resonance imaging (e.g., cardiac pacemaker/defibrillator, ferromagnetic metal implants) or PET scan.
• Sensitivity to fluorodeoxyglucose F 18
• Having past or planned exposure to ionizing radiation that would, together with the radiation resulting from the administrations of the PET tracer(s) used in this study, exceed applicable institutional, local, or national recommendations for annual or lifetime exposure.
• Poor venous access.
• Chronic use of no-n-steroidal anti-inflammatory drugs (NSAIDs), excepting 81 mg daily aspirin therapy.
• Chronic use of an anti-cholinergic drug(s)
• Taking any prohibited medication or therapy
• Be the recipient of an investigational drug within 60 days of screening, or within 5 times the elimination half-life of that drug, whichever is the longest.
• Prior treatment with an investigational anti-amyloid or anti-tauopathy therapy, or AD vaccine, unless it can be documented that they were on placebo.
• Participation in the treatment phase of an investigational sargramostim clinical trial within 6-months of screening.

• Any interested participant who:

  1. Is in the judgement of the Principal Investigator likely to be non-compliant with study protocol, including, but not limited to, leaving the area of the study for any extended period; or separate from the designated caregiver/informant, without acceptable replacement, for any of the scheduled assessment visits during the study.
  2. Is unable to cooperate because of a language problem or because of a developmental disability.
  3. Oversees or implements any aspect of the study, or is employed by Partner Therapeutics or its affiliates or subsidiaries, or is an employee of the University of Colorado Alzheimer's and Cognition Center and is engaged in the conduct of the study, or first degree relative of such.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sargramostim; 250 mcg/m2/day subcutaneously 5 days/week for 24 weeks	Drug: Sargramostim; Sargramostim is a granulocyte macrophage colony stimulating factor that will be administered at a dose of 250 mcg/m2 per day subcutaneously, 5 days/week, for 24 weeks; Other Names: Leukine; Granulocyte Macrophage Colony Stimulating Factor
Placebo Comparator: Placebo Control - Saline; Placebo comparator (saline) subcutaneously 5days/week for 24 weeks	Drug: Saline - placebo comparator; Saline will be administered subcutaneously, 5 days/week, for 24 weeks; Other Names: Sterile solution of sodium chloride in water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety as measured by number of Adverse Events (AEs) by body system	The safety of sargramostim will be assessed through number of adverse events (AEs) by body system from consent to follow-up within a safety analysis set consisting of all individuals who were enrolled and and randomized and who received at least on injection of sargramostim or placebo.	Informed consent to Follow-up Visit (38 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mini-Mental State Examination	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.	Baseline to End of Treatment, Follow-up (30 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-Cog13)	The ADAS-Cog13 measures the severity of the most important symptoms of AD. and 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. The score ranges form 0-85, with higher score denoting worse performance	Baseline to End of Treatment, Follow-up (30 weeks)
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)	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). Range is 0-18. Higher scores denote worse functioning	Baseline to End of Treatment, Follow-up (30 weeks)
Trail Making Test - Part A (TMT-A)	Psychomotor speed will be assessed by the Trail Making Test-A, a timed test in which participants must connect a series of numbers randomly placed on a page. Time range is 0-150 seconds, with a higher time denoting worse performance	Baseline to End of Treatment, Follow-up (30 weeks)
Alzheimer's Disease Cooperative Study -Activities of Daily Living Inventory (ADCS-ADL)	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.	Baseline to End of Treatment, Follow-up (30 weeks)
Montreal Cognitive Assessment (MoCA)	The Montreal Cognitive Assessment (MoCA) is a brief, assessment developed for detection and tracking of cognitive impairment and is sensitive for detecting Alzheimer's disease. Measuring multiple domains, it is commonly used in both clinical and research settings, and is well validated, with a range of scores from 0-30.	Baseline to End of Treatment, Follow-up (30 weeks)
Neuropsychiatric Inventory (NPI)	Neuropsychiatric Inventory (NPI) is a study partner/caregiver interview to assess any changes in neuropsychiatric status in such domains as hallucinations, delusions, agitation, depression, anxiety, disinhibition, apathy and aberrant motor behaviors. It assesses presence of symptoms, and scores by severity X frequency (Range 0-12 in each symptom category), and caregiver distress (Range 0-5). The higher the scores, the the greater the presence of the impact of the symptom.	Baseline to End of Treatment, Follow-up (30 weeks)
Verbal Fluency	Verbal fluency (producing words that start with a specific letter of the alphabet, also known as letter fluency) is a timed test where a participant produces as many works as they can in 60 seconds. The more correct words that a participant produces, the higher the score.	Baseline to End of Treatment, Follow-up (30 weeks)
Exploratory: Fluorodeoxyglucose Positron Emission Tomography (FDG PET) assessment of brain metabolism	FDG-PET assessment of metabolic activity, overall, as well in different brain regions, particularly in the medial temporal lobe in potential correlation with changes in MTA	Baseline to End of Treatment (24 weeks)
Semantic Fluency	Semantic fluency (producing words that belong in a category, such as animals, also known as category fluency) is a timed test where a participant produces as many works as they can in 60 seconds within a category. The more correct words that a participant produces, the higher the score.	Baseline to End of Treatment, Follow-up (30 weeks)

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute on Aging (NIA); Alzheimer's Association; Partner Therapeutics, Inc.
• Investigators: Principal Investigator: Peter Pressman, MD, University of Colorado Alzheimer's and Cognition Center

Publications and helpful links

General Publications

• Potter H, Woodcock JH, Boyd TD, Coughlan CM, O'Shaughnessy JR, Borges MT, Thaker AA, Raj BA, Adamszuk K, Scott D, Adame V, Anton P, Chial HJ, Gray H, Daniels J, Stocker ME, Sillau SH. Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease. Alzheimers Dement (N Y). 2021 Mar 24;7(1):e12158. doi: 10.1002/trc2.12158. eCollection 2021.

Helpful Links

• CU Alzheimer's and Cognition Center Clinical Research Portal

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Estimated): July 31, 2025
• Study Completion (Estimated): July 31, 2025

Study Registration Dates

• First Submitted: May 14, 2021
• First Submitted That Met QC Criteria: May 21, 2021
• First Posted (Actual): May 26, 2021

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Alzheimer; GM-CSF; Leukine; Alzheimers Disease; sargramostim
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Sargramostim; Molgramostim
• Other Study ID Numbers: 19-2727; 1R01AG071151-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No