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

This trial protocol is designed to evaluate primarily whether the long-term use of sargramostim (recombinant human GM-CSF), administered seven 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).

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 4-24 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 60 days (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.
• Have had a dental exam within 6 months of date of screening.

Exclusion criteria

• Individuals with a first degree relative diagnosed with AD before 55 years of age.
• BMI ≥35.
• Is unable to read/write at an appropriate level to reliably participate in clinical trial psychometric assessments.
• Is a prisoner.
• 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 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.
• History of chronic or recurrent bacterial infections, at the discretion of the PI or delegated Sub-I.
• 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:

• 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.
• Is unable to cooperate because of a language problem or because of a developmental disability.
• 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.