Leukine (Sargramostim) for Parkinson's Disease

NCT01882010 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 0487-12-FB2R01NS034239
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Parkinson's Disease

Keywords

Parkinson's disease; motor function; immune activation; T cells; CD4; GMCSF; leukine; sargramostim; magnetoencephalography

Outcome Measures

Primary Outcomes (1)

• Number of adverse events

  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.

  52 weeks

Secondary Outcomes (6)

• Change in UPDRS part III score

  -8, -4, 0, +2, +4, +6, +8, +12 weeks

• Change in blood analyses results

  -8, -4, 0, +2, +4, +6, +8, +12 weeks

• Abnormal findings in physical examination

  -8, -4, 0, +2, +4, +6, +8, +12 weeks

• Change in FACS results

  -8, -4, 0, +2, +4, +6, +8, +12 weeks

• Change in function of Treg cells

  -8, -4, 0, +2, +4, +6, +8, +12 weeks

Other Outcomes (1)

• Change in Motion Analysis

  -4, +8, +12 weeks

Study Arms (3)

Controls

SHAM COMPARATOR

Caregivers, spouse, friends, relatives of PD patients, have blood draws, MEG.

Diagnostic Test: Sham Comparator: Controls

PD Patients placebo

PLACEBO COMPARATOR

PD patients that receive placebo, have blood draw, physical exam and UPDRS part III assessment, MEG, Motion analysis.

Drug: placebo

PD Patients sargramostim

EXPERIMENTAL

PD patients that receive Leukine, have blood draw, physical exam and UPDRS part III assessment, MEG, Motion analysis.

Drug: sargramostim

Interventions

sargramostim DRUG

lyophilized 250 micrograms/vial 6 micrograms/kg daily subcutaneous injection 56 days

Also known as: Leukine

PD Patients sargramostim

placebo DRUG

saline solution daily subcutaneous injection 56 days

Also known as: saline solution

PD Patients placebo

Sham Comparator: Controls DIAGNOSTIC_TEST

Caregivers, spouse, friends, relatives of PD patients, have blood draws, MEG.

Controls

Eligibility Criteria

• Age: 35 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Nebraska: lead
• Sanofi: collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Nebraska Neuroscience Alliance: collaborator

Study Sites (2)

Neurology Consultants of Nebraska PC

Omaha, Nebraska, 68131, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Related Publications (11)

• 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.

  PMID: 23054369 BACKGROUND

• 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. doi: 10.1056/NEJMoa041109.

  PMID: 15917384 BACKGROUND

• 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.

  PMID: 20118279 BACKGROUND

• 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.

  PMID: 21377529 BACKGROUND

• 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.

  PMID: 19245369 BACKGROUND

• McGeer PL, McGeer EG. Glial reactions in Parkinson's disease. Mov Disord. 2008 Mar 15;23(4):474-83. doi: 10.1002/mds.21751.

  PMID: 18044695 BACKGROUND

• 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.

  PMID: 18167537 BACKGROUND

• 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. doi: 10.1073/pnas.0400569101. Epub 2004 Jun 14.

  PMID: 15197276 BACKGROUND

• 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.

  PMID: 18502693 BACKGROUND

• Kuhn AA, Kempf F, Brucke 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.

  PMID: 18550758 BACKGROUND

• 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.

  PMID: 24210793 BACKGROUND

MeSH Terms

Conditions

Parkinson Disease

Interventions

sargramostim; Saline Solution

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Howard E Gendelman, MD

  University of Nebraska

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2013
• First Posted: June 20, 2013
• Study Start: September 1, 2013
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: October 6, 2023

Record last verified: 2023-10

Locations

US (2)