Leukine (Sargramostim) for Parkinson's Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University of Nebraska
Sponsor:
Collaborators:
Sanofi
UNeMed
Nebraska Neuroscience Alliance
Information provided by (Responsible Party):
Howard Gendelman, MD, University of Nebraska Medical Center
ClinicalTrials.gov Identifier:
NCT01882010
First received: June 13, 2013
Last updated: June 8, 2014
Last verified: June 2014
  Purpose

The purpose of this study is to determine if Leukine (sargramostim) can be safely administered to Parkinson's disease patients for an extended period of time (56 days) and restore immune deficits seen in Parkinson's patients compared to controls. The development of magnetoencephalography (MEG) as a monitoring tool for PD will also be explored. At enrollment and repeating again at two 4-week intervals, whole blood from PD patients and controls will be obtained for analyses and the results will be used to calculate immune response profiles as a baseline for comparison after drug treatment. Physical examinations and motor assessments will also be performed on PD patients. After the 8-week baseline data collection, control participation will end and drug treatment of PD patients will begin. PD patients will be randomized, and half will receive drug and half will receive placebo. Leukine at a dosage of 6 µg/kg or saline as placebo will be administered by subcutaneous injection daily for 56 days (8 weeks). During drug treatment, PD patients will be monitored every two weeks by physical examinations, motor assessments, and blood analyses. As follow-up, four weeks after drug administration has stopped, subjects will again have physical examinations, motor assessments, and blood analyses. MEG will be performed on PD patients and controls at the start of drug treatment, and on PD patients at the end of the drug treatment period and 4 weeks after drug is stopped.


Condition Intervention Phase
Parkinson's Disease
Procedure: blood draw
Procedure: physical exam and UPDRS part III assessment
Procedure: MEG
Drug: sargramostim
Drug: placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Leukine (Sargramostim) for Parkinson's Disease

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Number of adverse events [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    An adverse event is defined as any undesirable physical, psychological, or behavioral effect experienced by a patient in conjunction with the use of the study drug.


Secondary Outcome Measures:
  • Change in UPDRS part III score [ Time Frame: 0, 4, 8, 10, 12, 14, 16, 20 weeks ] [ Designated as safety issue: Yes ]
    Score from part III motor examination of the Unified Parkinson's Disease Rating Scale Score Sheet.

  • Change in blood analyses results [ Time Frame: 0, 4, 8, 10, 12, 14, 16, 20 weeks ] [ Designated as safety issue: Yes ]
    Comprehensive metabolic panel, complete blood count with white blood cell differential (CBC/dif), and total T cell counts blood analyses

  • Abnormal findings in physical examination [ Time Frame: 0, 4, 8, 10, 12, 14, 16, 20 weeks ] [ Designated as safety issue: Yes ]
    Physical examination including temperature, blood pressure, pulse, and skin, lung, liver, heart, and abdomen assessments.

  • Change in FACS results [ Time Frame: 0, 4, 8, 10, 12, 14, 16, 20 weeks ] [ Designated as safety issue: No ]
    T cell markers analyzed by fluorescence-activated cell sorting.

  • Change in function of Treg cells [ Time Frame: 0, 4, 8, 10, 12, 14, 16, 20 weeks ] [ Designated as safety issue: No ]
    Regulatory T cells isolated from peripheral blood are tested for their ability to suppress proliferation of activated T cells.

  • Change in magnetoencephalography results [ Time Frame: 8, 16, 20 weeks ] [ Designated as safety issue: No ]
    Magnetoencephalography measurements during behavioral tasks


Estimated Enrollment: 32
Study Start Date: September 2013
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Sham Comparator: Controls
Caregivers, spouse, friends, relatives of PD patients, have blood draws, MEG.
Procedure: blood draw
week 0
Procedure: blood draw
week 4
Procedure: blood draw
week 8
Procedure: MEG
week 8
Placebo Comparator: PD Patients placebo
PD patients that receive placebo, have blood draw, physical exam and UPDRS part III assessment, MEG.
Procedure: blood draw
week 0
Procedure: physical exam and UPDRS part III assessment
week 0
Procedure: blood draw
week 4
Procedure: physical exam and UPDRS part III assessment
week 4
Procedure: blood draw
week 8
Procedure: physical exam and UPDRS part III assessment
week 8
Procedure: MEG
week 8
Drug: placebo
saline solution daily subcutaneous injection 56 days
Other Name: saline solution
Procedure: blood draw
week 10
Procedure: physical exam and UPDRS part III assessment
week 10
Procedure: blood draw
week 12
Procedure: physical exam and UPDRS part III assessment
week 12
Procedure: blood draw
week 14
Procedure: physical exam and UPDRS part III assessment
week 14
Procedure: blood draw
week 16
Procedure: physical exam and UPDRS part III assessment
week 16
Procedure: MEG
week 16
Procedure: blood draw
week 20
Procedure: physical exam and UPDRS part III assessment
week 20
Procedure: MEG
week 20
Experimental: PD Patients sargramostim
PD patients that receive Leukine, have blood draw, physical exam and UPDRS part III assessment, MEG.
Procedure: blood draw
week 0
Procedure: physical exam and UPDRS part III assessment
week 0
Procedure: blood draw
week 4
Procedure: physical exam and UPDRS part III assessment
week 4
Procedure: blood draw
week 8
Procedure: physical exam and UPDRS part III assessment
week 8
Procedure: MEG
week 8
Drug: sargramostim

lyophilized 250 micrograms/vial

6 micrograms/kg daily subcutaneous injection

56 days

Other Name: Leukine
Procedure: blood draw
week 10
Procedure: physical exam and UPDRS part III assessment
week 10
Procedure: blood draw
week 12
Procedure: physical exam and UPDRS part III assessment
week 12
Procedure: blood draw
week 14
Procedure: physical exam and UPDRS part III assessment
week 14
Procedure: blood draw
week 16
Procedure: physical exam and UPDRS part III assessment
week 16
Procedure: MEG
week 16
Procedure: blood draw
week 20
Procedure: physical exam and UPDRS part III assessment
week 20
Procedure: MEG
week 20

  Hide Detailed Description

Detailed Description:

Parkinson's disease (PD) is a progressive and disabling neurological disorder involving the nigrostriatum and for which no cure is known. Evidence suggests that inflammation contributes, significantly, to the cause and/or progression of the disease. Studies in postmortem human brain, animal models, and human peripheral blood support the idea that the frequency and function of particular circulating T cell subsets are abnormal and worsen as disease progresses. This abnormality is linked specifically to increases in numbers of T effector neurodestructive cells (Teff) and to dysfunction of regulatory T cells (Treg) that control Teff. This imbalance tips the homeostatic balance to a pro-inflammatory profile with limited control. Nonetheless, whether such T cell deficits are a cause of PD or a reaction to it remains unknown. If these deficits are causal or exacerbative, then correcting the deficit could have significant positive effects on disease progression and could ameliorate nigrostriatal degeneration or its sequelae. Granulocyte macrophage colony stimulating factor (GM-CSF) is a potential immunomodulatory therapeutic for PD to increase Treg numbers or function and reduce or transform proinflammatory Teff responses, leading to neuroprotection of the nigrostriatum and improved clinical outcomes for disease. Recombinant human GM-CSF (sargramostim) is available as Leukine®. The purpose of this study is to determine if Leukine (sargramostim) can be safely administered to Parkinson's disease patients for an extended period of time (56 days).

In a previous study conducted at the University of Nebraska Medical Center (UNMC) using samples of whole blood, PD patients showed differences from caregiver controls according to results from complete blood count (CBC) with white blood cell (WBC) differential, fluorescence-activated cell sorting (FACS) analysis for T cell markers, and Treg functional assays. These immune aberrations correlated with motor dysfunction as determined by Parkinson's disease rating scale (UPDRS) part III assessments. In this pilot study, the effect of Leukine treatment on immune deficits in PD patients will be monitored. Immune cell analyses of whole blood, motor assessments, and physical examinations and blood analyses for safety, will be conducted before, during, and after Leukine or placebo treatment of PD patients, and using healthy controls during baseline data collection before drug treatment. Initially, 16 PD patients and 16 controls will be recruited. Subjects will be drawn from the previous study. Enrollment will be supplemented as needed with patients from Neurology Consultants of Nebraska-PC, UNMC Neurological Sciences, or recruitment through the American Parkinson's Disease Association. Enrollment will be staggered, and additional subjects will be recruited as needed to replace any withdrawing participants, with the goal of 32 subjects, 16 PD patients and 16 controls, completing the study.

At enrollment and repeating again at two 4-week intervals, whole blood from PD patients and controls will be obtained percutaneously using standard sterile techniques. CBC with WBC differential, FACS analysis for T cell markers, and Treg functional assays will be performed and used to calculate immune response profiles as a baseline for comparison after drug treatment. Blood chemistries will be analyzed including liver enzymes, electrolytes, blood urea nitrogen, creatinine, total protein, albumin and bilirubin levels, and anti-GM-CSF antibodies will be assessed in PD patients. PD patients will be evaluated by physical and clinical examinations, including UPDRS part III assessments for evaluation of motor function.

PD patients will then be randomized into two groups, placebo (n=8) and Leukine (n=8), and participation of the controls will end. Patients entered into the study will not have any noted co-morbid conditions including infection, inflammatory or cancerous diseases and will not be taking immunostimulatory or immunosuppressive medicines. Patients will continue to take medicines prescribed for the general treatment of PD, including, but not limited to, dopamine or dopamine agonists. There will be no history of prior surgeries linked to PD treatment. Patients will receive training for self-injection, and the treatment group will self-administer Leukine (6 µg/kg) by subcutaneous injection daily for eight weeks. The placebo group will self-administer saline as placebo. Every two weeks after the start of treatment and again 4 weeks after cessation of administration, all PD patients, receiving drug or placebo, will be evaluated by physical and clinical examinations, including UPDRS part III assessments. Every 2 weeks during Leukine treatment and again 4 weeks after cessation of drug, whole blood from PD patients will be obtained percutaneously using standard sterile techniques. At weeks 2, 4 and 8, results from CBC with WBC differential, FACS analysis for T cell markers, and Treg functional assays will be used to calculate immune response profiles and compared with baseline values. CBC with WBC differential, total T cell count, and blood chemistries will be analyzed every 2 weeks for evidence of potential toxicities, as well as 4 weeks after termination of Leukine treatment. Levels of anti-GM-CSF antibodies will be assessed for PD patients at enrollment and at 4 weeks intervals during drug treatment and 4 weeks after termination.

An additional component of the study includes the development of magnetoencephalography (MEG) as a monitoring tool for PD. MEG provides a non-invasive method to study brain activity. Currently, there are not adequate assessment tools for monitoring disease progression or treatment protocols in PD. In preliminary experiments on PD patients and their caregivers, MEG data have indicated strong beta synchronization during rest in PD and milder beta desynchronization during movement preparation compared to age- and sex-matched controls. In this study, the amplitude of this pathological beta synchronization/desynchronization will be monitored to evaluate improvements in cortical brain function of PD patients treated with Leukine. MEG will be performed on PD patients and controls at the start of drug treatment, and on PD patients at the end of the drug treatment period and 4 weeks after drug is stopped.

  Eligibility

Ages Eligible for Study:   35 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

PD Patients

  • Onset of bradykinesia and 1 or both of the following: rest tremor and/or rigidity
  • Asymmetric onset of clinical signs
  • Progressive motor symptoms
  • Age at onset 35-85 years
  • Duration of PD symptoms of at least 3 but not more than 10 years
  • Female subjects must be either:

Not pregnant, not breastfeeding, and not planning on becoming pregnant during the study; Not of childbearing potential, defined as one who has been postmenopausal for at least 1 year and with follicle stimulating hormone (FSH) levels in the laboratory defined postmenopausal range, or has been surgically sterilized, or has had a hysterectomy at least 3 months prior to the start of this trial; or If of childbearing potential, must agree to use an effective method of avoiding pregnancy to the end of the trial and must have a negative serum beta-human chorionic gonadotropin (β-HCG) test. Effective methods of avoiding pregnancy are contraceptive methods used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or female condoms with spermicide, or cervical cap), abstinence, or a sterile sexual partner

  • Have the ability to comply with basic instructions and have the ability to sit still comfortably inside the MEG
  • Caregiver, spouse, friend, or relative must agree to participate in the research study

Control subjects:

  • Age 35-85 years
  • Caregiver, spouse, relative, or friend of eligible PD patient
  • Female subjects must be either:

Not pregnant, not breastfeeding, and not planning on becoming pregnant during the study; Not of childbearing potential, defined as one who has been postmenopausal for at least 1 year and with follicle stimulating hormone (FSH) levels in the laboratory defined postmenopausal range, or has been surgically sterilized, or has had a hysterectomy at least 3 months prior to the start of this trial; or If of childbearing potential, must agree to use an effective method of avoiding pregnancy to the end of the trial and must have a negative serum beta-human chorionic gonadotropin (β-HCG) test. Effective methods of avoiding pregnancy are contraceptive methods used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or female condoms with spermicide, or cervical cap), abstinence, or a sterile sexual partner

  • Have the ability to comply with basic instructions and have the ability to sit still comfortably inside the MEG

Exclusion Criteria:

PD Patients

  • Atypical features indicative of a Parkinson-Plus disorder (Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Corticobasal Degeneration (CBD)) including cerebellar signs, supranuclear gaze palsy, apraxia and other cortical signs, or prominent autonomic failure
  • Neuroleptic treatment at time of onset of parkinsonism
  • Active treatment with a neuroleptic at time of study entry
  • History of repeated strokes with stepwise progression of parkinsonism
  • History of repeated head injury
  • History of definite encephalitis
  • More than one blood relative diagnosed with PD
  • Prominent gait imbalance early in the course (< 5 years)
  • Mini-mental state examination score <26
  • Hematological malignancy or coagulopathy
  • Abnormal blood analyses: hematocrit <30; WBC>11.5; clinically significant laboratory data (e.g. alanine aminotransferase [ALT] or aspartate aminotransferase [AST] 3x the upper limit of normal [ULN]), or any abnormal laboratory value that could interfere with the assessment of safety in the judgment of the investigator; significant abnormalities on the clinical examination, vital signs, and clinical chemistry or hematology results (excluding findings of Parkinson's disease), that may interfere with the study or present a safety risk for the subject as judged by the clinical investigator charged in the care of study participants
  • Serious medical illness or co-morbidity that may interfere with participation in the study
  • Brain surgery for parkinsonism (DBS, cell implantation, gene therapy)
  • History of an autoimmune disorder or systemic inflammatory disorder
  • Immunostimulatory or immunosuppressive treatment (including amphetamines or systemic corticosteroids) within 90 days
  • Exclusively unilateral parkinsonism for longer than 3 years
  • Known hypersensitivity to GM-CSF, yeast-derived products or benzyl alcohol
  • Current lithium treatment
  • Individuals who have ferrous metal implanted in their body other than fillings
  • Individuals with current diagnoses of alcohol or substance abuse/dependence
  • Anyone who is not appropriate for participation in this research protocol as deemed by the principal or co-investigator

Control subjects:

  • Positive response to more than 3 items on the PD Screening Questionnaire
  • More than one blood relative diagnosed with by PD
  • Mini-mental state examination score <26
  • Hematological malignancy or coagulopathy
  • Abnormal blood analyses: hematocrit <30; WBC>11.5; clinically significant laboratory data (e.g. alanine aminotransferase [ALT] or aspartate aminotransferase [AST] 3x the upper limit of normal [ULN]), or any abnormal laboratory value that could interfere with the assessment of safety in the judgment of the investigator; significant abnormalities on the clinical examination, vital signs, and clinical chemistry or hematology results that may interfere with the study or present a safety risk for the subject as judged by the investigator
  • Serious medical illness or comorbidity that may interfere with participation in the study
  • History of an autoimmune disorder or systemic inflammatory disorder
  • Immunostimulatory or immunosuppressive treatment (including amphetamines or systemic corticosteroids) within 90 days
  • Individuals who have ferrous metal implanted in their body other than fillings
  • Individuals with current diagnoses of alcohol or substance abuse/dependence
  • Anyone who is not appropriate for participation in this research protocol as deemed by the principal or co-investigator

PD Screening Questionnaire

  • Do you have trouble arising from a chair?
  • Is your handwriting smaller than it once was?
  • Do people tell you that your voice is softer than it once was?
  • Is your balance poor?
  • Do your feet ever seem to get stuck to the floor?
  • Do people tell you that your face seems less expressive than it once did?
  • Do your arms and legs shake?
  • Do you have trouble buttoning buttons?
  • Do you shuffle your feet and/or take tiny steps when you walk?
  • Has anyone ever told you that you have Parkinson's disease?
  • Have you ever taken levodopa or Sinemet?
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01882010

Contacts
Contact: Carolyn Peterson, RN, BSN 402-552-2239 cpeterson@nebraskamed.com
Contact: LuAnn Larson, RN, BSN 402-559-8555 llarson@unmc.edu

Locations
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Carolyn Peterson, RN, BSN    402-552-2239    cpeterson@nebraskamed.com   
Principal Investigator: Howard E Gendelman, MD         
Sub-Investigator: John Bertoni, MD         
Sub-Investigator: Philip J Bierman, MD         
Sub-Investigator: Jane L Meza, PhD         
Sub-Investigator: R L Mosley, PhD         
Sub-Investigator: Tony Wilson, PhD         
Sub-Investigator: Diego Torres-Russotto, MD         
Sub-Investigator: Amy Hellman, MD         
Neurology Consultants of Nebraska PC Recruiting
Omaha, Nebraska, United States, 68131
Contact: Pamela M Santamaria, MD    402-552-2650    pamsantamaria@nebraskaneurology.com   
Contact: Carolyn Peterson, RN, BSN    402-552-2239    cpeterson@nebraskamed.com   
Principal Investigator: Pamela M Santamaria, MD         
Sponsors and Collaborators
Howard Gendelman, MD
Sanofi
UNeMed
Nebraska Neuroscience Alliance
Investigators
Principal Investigator: Howard E Gendelman, MD University of Nebraska
  More Information

Publications:

Responsible Party: Howard Gendelman, MD, Margaret R. Larson Professor of Internal Medicine and Infectious Diseases;Chairman, Department of Pharmacology and Experimental Neuroscience;Director of the Center for Neurodegenerative Diseases, University of Nebraska Medical Center
ClinicalTrials.gov Identifier: NCT01882010     History of Changes
Other Study ID Numbers: 487-12-FB, 2R01NS034239
Study First Received: June 13, 2013
Last Updated: June 8, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Nebraska:
Parkinson's disease
motor function
immune activation
T cells
CD4
GMCSF
leukine
sargramostim
magnetoencephalography

Additional relevant MeSH terms:
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases

ClinicalTrials.gov processed this record on August 28, 2014