Trial to Evaluate Safety and Efficacy of GM-CSF /Sargramostim in Down Syndrome

Study Overview
=================
Brief Summary
-----------------
This trial protocol is designed to evaluate primarily whether the use of sargramostim (recombinant human GM-CSF), administered five days per week for four consecutive weeks (20 treatment days), will be well tolerated by and safe for use in young adult participants with Down syndrome.

Detailed Description
-----------------
This trial protocol is designed to evaluate primarily whether the use of sargramostim (recombinant human GM-CSF), administered five days per week (250 μg/m2/day subcutaneously) for four consecutive weeks (20 treatment days), will be well tolerated by and safe for use in young adult participants (age 18-35) with Down Syndrome; Secondarily whether sargramostim will have an impact on cognition, and exploratory whether sargramostim has an impact upon activities of daily and quality of life, and impact upon several biomarkers associated with DS, as evaluated by multimodal neuroimaging techniques and blood analyses.

Official Title
-----------------
Phase II Trial to Evaluate Safety and Efficacy of GM-CSF /Sargramostim in Down Syndrome

Conditions
-----------------
Down Syndrome

Intervention / Treatment
-----------------
* Drug: Sargramostim for Injection
* Drug: Saline Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females with Down syndrome between 18-35 years of age. A cytogenetic diagnosis of full trisomy 21 or complete unbalanced translocation of chromosome 21. 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 willing / able to provide written informed consent or assent. If assent is provided, consent must be provided by a legally authorized representative (LAR), who may or may not be the dedicated study partner / caregiver. Documentation of LAR status will follow local laws and regulations. Be physically able to participate by medical history, clinical exam, and other testing, with adequate visual acuity and auditory discrimination. Must reside within a proximity of the study site that will not preclude their regularly scheduled participation in the trial. Be willing to avoid pregnancy or fathering children for the duration of the study. Must have received recent testing for hypothyroidism during the past 6 months, and if positive for hypothyroidism, they must be stable on medications for treating hypothyroidism for at least 30 days prior to enrollment, and they must remain on their hypothyroidism treatments for the duration of the trial. Be stable on all other medications for at least 30 days prior to initial screening visit. Exclusion Criteria: 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. Vaccination with live attenuated virus within six weeks of inclusion in the study or planned during the study. 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). Active cancer / malignant neoplasm within five years of screening other than nonmelanoma skin cancers (e.g., basal cell or squamous cell). Previous diagnosis of leukemia, despite remission state or length of time, is exclusionary. Poor venous access not allowing repeated blood tests. 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). Concomitant treatment with other immunosuppressants (e.g., corticosteroids, methotrexate). History of deep vein thrombosis, pulmonary embolism, familial predisposition for deep vein thrombosis, or pulmonary embolism. History of asplenia, hyposplenia, or splenectomy (for any indication). Untreated or unstable medical condition that could interfere with the study assessments in the opinion of the study physician, or that may require immune-stimulating, immunesuppressive, or immune-modulating treatment(s) during the conduct of the study (e.g., therapeutic vaccines, cytokines, anti-cytokine monoclonal antibodies, etc.) History of seizures (except infant febrile seizures). Evidence of: 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 assessed by the study physician; prolonged QTc interval greater than 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 greater than 150 micromoles/L, or Glomerular Filtration Rate (GFR) less than 55 ml/min. Known hepatic dysfunction (apart from Gilbert's syndrome) or serum ALT greater than or equal to 3 times the upper limit of normal (ULN). Contraindication or inability to complete magnetic resonance imaging (e.g., cardiac pacemaker/defibrillator, ferromagnetic metal implants). Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), excepting 81 mg daily aspirin therapy. Note: For the purposes of this protocol, chronic use is defined as the weekly usage of an NSAID drug for three or more times per week and for two or more weeks within any four-week period. Chronic use of an anti-cholinergic drug. Note: For the purposes of this protocol, chronic use is defined as the weekly usage of an anti-cholinergic drug for three or more times per week and for two or more weeks within any four-week period. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: IP vs Placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sargramostim<br>Sargramostim 250 μg/m2/day subcutaneously (5 days per week) | Drug: Sargramostim for Injection<br>* Recombinant human GM-CSF<br>* Other names: Granulocyte Macrophage Colony Stimulating Factor;|
| Placebo Comparator: Placebo Control - Saline<br>Placebo equivalent volume subcutaneously (5 days per week) | Drug: Saline Placebo<br>* Bacteriostatic Saline<br>* Other names: Bacteriostatic Saline;|

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 one injection of sargramostim or placebo. | Informed consent to Follow-up Visit (20 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Down syndrome Mental Status Exam (DSMSE) | The DSMSE provides a broad assessment of cognitive function specially designed for use within the population of individuals with Down syndrome. Similar to the MMSE, the range for scores in the DMSE is from 0 to 30, with lower scores indicating greater impairment. | Baseline to End of Treatment, Follow-up (20 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Down syndrome, Trisomy 21