Leukine (Sargramostim) for Parkinson's Disease
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 1

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.
    

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.
    

Intervention name(s): sargramostim; placebo; Sham Comparator: Controls
Intervention type(s): Drug; Drug; Diagnostic Test
Intervention description(s): lyophilized 250 micrograms/vial
6 micrograms/kg daily subcutaneous injection
56 days; saline solution daily subcutaneous injection 56 days; Caregivers, spouse, friends, relatives of PD patients, have blood draws, MEG.
Other intervention name(s): Leukine; saline solution
Intervention MeSH terms: Sargramostim
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Parkinson's disease; motor function; immune activation; T cells; CD4; GMCSF; leukine; sargramostim; magnetoencephalography