Leukine (Sargramostim) for Parkinson's Disease
Information source: University of Nebraska
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Parkinson's Disease
Intervention: blood draw (Procedure); physical exam and UPDRS part III assessment (Procedure); blood draw (Procedure); physical exam and UPDRS part III assessment (Procedure); blood draw (Procedure); physical exam and UPDRS part III assessment (Procedure); MEG (Procedure); sargramostim (Drug); placebo (Drug); blood draw (Procedure); physical exam and UPDRS part III assessment (Procedure); blood draw (Procedure); physical exam and UPDRS part III assessment (Procedure); blood draw (Procedure); physical exam and UPDRS part III assessment (Procedure); blood draw (Procedure); physical exam and UPDRS part III assessment (Procedure); MEG (Procedure); blood draw (Procedure); physical exam and UPDRS part III assessment (Behavioral); Motion Analysis (Procedure); Motion Analysis (Procedure); Motion Analysis (Procedure)
Phase: Phase 1
Status: Recruiting
Sponsored by: Howard Gendelman, MD Official(s) and/or principal investigator(s): Howard E Gendelman, MD, Principal Investigator, Affiliation: University of Nebraska
Overall contact: Carolyn Peterson, RN, BSN, Phone: 402-552-2239, Email: carolyn.peterson@unmc.edu
Summary
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. In addtion, at the second cohort of
8 PD subjects, we will evaluate the potential Leukine-induced motor control and mobility
improvements. Also, levels of the neurotransmitters glutamate, glutamine, serotonin,
acetylcholine, GABA, norepinephrine and epinephrine in serum/plasma will be analyzed to
correlate with changes in motor function and drug treatment.
Clinical Details
Official title: Leukine (Sargramostim) for Parkinson's Disease
Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Primary outcome: Number of adverse events
Secondary outcome: Change in UPDRS part III scoreChange in blood analyses results Abnormal findings in physical examination Change in FACS results Change in function of Treg cells Change in magnetoencephalography results
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. Optional video recordings
will be made at baseline, end of drug/placebo treatment and at follow-up.
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.
Among the first 8 patients enrolled in the study, we have observed unexpected and
statistically significant changes in the unified PD rating scale part III (UPDRS part III)
clinical evaluations for motor function in half of the patients tested. This test,
however, is viewed as subjective. To more objectively and analytically score motor
functions, biomechanical assessments of the subject's mobility, postural balance, upper
extremity motor control and resting state tremor will be performed on the remaining eight PD
patients receiving Leukine or placebo. These assessments will occur at baseline, between 7
and 8 weeks of drug treatment, and at 4-5 weeks after cessation of drug treatment. Motor
function tests are designed to provide an objective, computer generated score as measured by
patient performance on each test. To investigate a possible mechanism for changes in motor
function observed within two weeks of therapy, testing for plasma/serum neurotransmitters
will be performed to include glutamate, glutamine, serotonin, acetylcholine,
gamma-aminobutyric acid (GABA), norepinephrine and epinephrine. These measures will be
performed on the last cohort of PD patients of the study before initiation of treatment, 8
weeks after treatment is initiated and at 4 weeks after cessation of drug treatment. The
tests will be evaluated by enzyme-linked immunosorbent assay (ELISA) or by ultra-performance
liquid chromatography (UPLC). A decision on which assay will be done for which
neurotransmitter will be based on sensitivity and standard curve measures. Relationships
between neurotransmitter levels and motor function will be determined. These tests are in
addition to current ongoing and approved laboratory tests. Eligibility requirements are
unchanged from those currently imposed. Measures of motor function and serum/plasma
neurotransmitter concentrations will also be completed 4-5 weeks after cessation of
treatment. The notion of exploring neurotransmitters in this study is based on role in motor
function that include fatigue, bowel, sexual dysfunction and mood changes that are also
observed in PD as well as that GM-CSF has been shown to affect neurotransmitter levels (96).
This range of listed neurotransmitters was not investigated in the first part of this study
and will require limited additional blood and assay resources for the last part of the
investigation.
Eligibility
Minimum age: 35 Years.
Maximum age: 85 Years.
Gender(s): Both.
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 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
- Must be stage 4 or less according to the Hoehn and Yahr scale
- 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?
Locations and Contacts
Carolyn Peterson, RN, BSN, Phone: 402-552-2239, Email: carolyn.peterson@unmc.edu
Neurology Consultants of Nebraska PC, Omaha, Nebraska 68131, United States; Recruiting Pamela M Santamaria, MD, Phone: 402-552-2650, Email: pamsantamaria@nebraskaneurology.com Carolyn Peterson, RN, BSN, Phone: 402-552-2239, Email: carolyn.peterson@unmc.edu Pamela M Santamaria, MD, Principal Investigator
University of Nebraska Medical Center, Omaha, Nebraska 68198, United States; Recruiting Carolyn Peterson, RN, BSN, Phone: 402-552-2239, Email: carolyn.peterson@unmc.edu Howard E Gendelman, MD, Principal 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, Sub-Investigator
Additional Information
Related publications: Saunders JA, Estes KA, Kosloski LM, Allen HE, Dempsey KM, Torres-Russotto DR, Meza JL, Santamaria PM, Bertoni JM, Murman DL, Ali HH, Standaert DG, Mosley RL, Gendelman HE. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson's disease. J Neuroimmune Pharmacol. 2012 Dec;7(4):927-38. doi: 10.1007/s11481-012-9402-z. Epub 2012 Oct 11. Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ; Sargramostim in Crohn's Disease Study Group. Sargramostim for active Crohn's disease. N Engl J Med. 2005 May 26;352(21):2193-201. Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol. 2010 Mar 1;184(5):2261-71. doi: 10.4049/jimmunol.0901852. Epub 2010 Jan 29. Mangano EN, Peters S, Litteljohn D, So R, Bethune C, Bobyn J, Clarke M, Hayley S. Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease. Neurobiol Dis. 2011 Jul;43(1):99-112. doi: 10.1016/j.nbd.2011.02.011. Epub 2011 Mar 4. Kim NK, Choi BH, Huang X, Snyder BJ, Bukhari S, Kong TH, Park H, Park HC, Park SR, Ha Y. Granulocyte-macrophage colony-stimulating factor promotes survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced murine Parkinson's disease model. Eur J Neurosci. 2009 Mar;29(5):891-900. doi: 10.1111/j.1460-9568.2009.06653.x. Epub 2009 Feb 24. McGeer PL, McGeer EG. Glial reactions in Parkinson's disease. Mov Disord. 2008 Mar 15;23(4):474-83. Review. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One. 2008 Jan 2;3(1):e1376. doi: 10.1371/journal.pone.0001376. Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, Nemachek C, Green SR, Przedborski S, Gendelman HE. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9435-40. Epub 2004 Jun 14. Sheng JR, Li LC, Ganesh BB, Prabhakar BS, Meriggioli MN. Regulatory T cells induced by GM-CSF suppress ongoing experimental myasthenia gravis. Clin Immunol. 2008 Aug;128(2):172-80. doi: 10.1016/j.clim.2008.03.509. Epub 2008 May 27. Kühn AA, Kempf F, Brücke C, Gaynor Doyle L, Martinez-Torres I, Pogosyan A, Trottenberg T, Kupsch A, Schneider GH, Hariz MI, Vandenberghe W, Nuttin B, Brown P. High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance. J Neurosci. 2008 Jun 11;28(24):6165-73. doi: 10.1523/JNEUROSCI.0282-08.2008. Kosloski LM, Kosmacek EA, Olson KE, Mosley RL, Gendelman HE. GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J Neuroimmunol. 2013 Dec 15;265(1-2):1-10. doi: 10.1016/j.jneuroim.2013.10.009. Epub 2013 Oct 29.
Starting date: September 2013
Last updated: January 9, 2015
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