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Biomarker Assessments of Leukine During Treatment of Parkinson's Disease

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ClinicalTrials.gov Identifier: NCT03790670
Recruitment Status : Recruiting
First Posted : January 2, 2019
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Howard Gendelman, MD, University of Nebraska

Brief Summary:
First, the investigators will determine the safety of a 24 month regimen of Leukine administered as a weight-based dose at 3 µg/kg/day for 5 days (week), followed by a 2-day holiday (weekend). This 24 month (n=10) pilot study will extend the prior 2 month observation tests towards the goal of assessing the safety of Leukine for treatment of Parkinson's disease (PD). Clinical signs and symptoms will be measured by personal well-being, physical, and neurological examinations (UPDRS Parts I, II, III, and IV assessments) and blood tests (CBC with differential, total T cell count, and a comprehensive metabolic sera panel). Second, we will assess regimen tolerability administered in a dose reduction, from 6 µg/kg/day without interruption, to 3 µg/kg/day with 2 day drug holidays. The investigators will examine over a time of 24 months, effects of treatment on defined adaptive immune deficits in PD as measured by analysis of peripheral blood mononuclear cells collected before, during, and after cessation of Leukine administration. Individual T cell parameters will be assessed and will include links between T cell function and subset analyses and clinical neurological signs and symptoms. In addition, the functional stability of the immune deficits will be assess in PD by examining T cell subsets in PD patients in this study against prior results. The investigators will also determine whether the immune deficits of PD are consistent during baseline data collection, and the potential Leukine-induced motor control and mobility improvements will be determined by UPDRS part I, II, III, and IV scores off treatment and on treatment.

Condition or disease Intervention/treatment Phase
Parkinson Disease Drug: sargramostim Phase 1

Detailed Description:

Primary Objectives: There are three study goals. First, the investigators will determine the safety of a 24 month regimen of Leukine administered as a weight-based dose at 3 µg/kg/day for 5 days (week), followed by a 2-day holiday (weekend). This 24 month (n=10) pilot study will extend the prior 2 month observation tests towards the goal of assessing the safety of Leukine for treatment of Parkinson's disease (PD). Clinical signs and symptoms will be measured by personal well-being, physical, and neurological examinations (UPDRS Parts I, II, III, and IV assessments) and blood tests (CBC with differential, total T cell count, and a comprehensive metabolic sera panel). Second, the investigators will assess regimen tolerability administered in a dose reduction, from 6 µg/kg/day without interruption, to 3 µg/kg/day with 2 day drug holidays. The lowered dose was chosen based on known tolerability and parallel-linked immune reconstitution seen in cancer-associated disease treatments. Due to fragility of the patient population and prior recorded adverse events the proposed dose reductions are justified.

Secondary Objectives:

Over a course of 24 months, the effects of treatment on defined adaptive immune deficits in PD as measured by analysis of peripheral blood mononuclear cells collected before, during, and after cessation of Leukine administration will be examined. Individual T cell parameters that include links between T cell function and subset analyses and clinical neurological signs and symptoms will be examined. These immune parameters will be serially examined as they may contribute to the immune deficits in PD. Thus, timed analyses of changes in T cell phenotypes and/or function will be completed. In addition, the investigators will assess the functional stability of the immune deficits in PD and will determine whether the immune deficits of PD are consistent during baseline data collection. The potential Leukine-induced motor control and mobility improvements will be determined by assessing UPDRS part I, II, III, and IV scores off treatment and on treatment. Specifically, over the course of this six-month treatment study, various biomarkers will be assessed including: T cell markers of immune activation, DNA methylation status, and B cell and bone marrow progenitor cell markers. We hope to uncover the time course of Treg induction, as well as link the pharmacokinetics of Leukine treatment (not previously recorded) to changes in specific biomarkers. Additionally, changes in the humoral response following extended Leukine treatment will be assessed by measuring the presence of antibodies against Leukine and alterations in B cell frequencies.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety, Tolerability and Biomarker Assessments of Leukine (Sargramostim) During Extended Timed Treatment for Parkinson's Disease: A Phase I Pilot Study
Actual Study Start Date : January 30, 2019
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Leukine Treatment
24 month regimen of Leukine administered as a weight-based dose at 3 µg/kg/day for 5 days (week), followed by a 2-day holiday (weekend)
Drug: sargramostim
Recombinant human GM-CSF produced by recombinant DNA technology using a yeast (S. cerevisiae) expression system
Other Name: Leukine




Primary Outcome Measures :
  1. Incidence of Treatment-Associated Adverse Events [ Time Frame: monthly during the course of treatment, up to 24 months, followed by 1 month drug cessation ]
    The safety of Leukine administration in PD will be examined by documenting abnormal results from CBC with differential, total T cell count, or comprehensive metabolic panel analyses; abnormal physical and or neurological exam findings; abnormal levels of antibodies to GM-CSF; clinically increasing Unified Parkinson's disease Rating Scale (UPDRS) part I, II, III, and IV scores as determined by the examining physician; and other adverse events. These safety assessments will be made every four weeks.


Secondary Outcome Measures :
  1. Determination of Immune Cell Phenotype [ Time Frame: 24 months of treatment, followed by 1 month drug cessation ]
    Measurements will include change in CD45RO+ or FAS+ frequencies in CD4+ T cells; change in CD31+ frequencies in CD4+ T cells, Teff or Treg subsets; change in ItgB7+ frequencies in CD4+ T cells or the Teff subset; change in ItgB4B7+ frequencies in CD4+ T cells or the Treg subset; change in CD27+ frequencies in CD4+ T cells, Teff or Treg subsets, change in CCR7+ frequencies in CD4+ T cells, Teff or Treg subsets; change in FoxP3+ frequencies in CD4+ T cells, Teff or Treg subsets; change in CD34, CD117, or CD135 levels; change in DNA methylation status. The measurements will be combined to determine overall changes in immune cell frequency and T cell subset phenotype both on and off treatment.

  2. Determination of Immune Cell Number [ Time Frame: 24 months of treatment, followed by 1 month drug cessation ]
    Measurements will include changes in levels of lymphocytes or CD4+ T cells, as well as T cell, B cell, and bone marrow progenitor subsets.

  3. Determination of Immune Cell Function [ Time Frame: 24 months of treatment, followed by 1 month drug cessation ]
    Measurements will include changes in T cell function via proliferation and suppression assays and/or changes in B cell function via antibody production assessments.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   35 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. Onset of bradykinesia and 1 or both of the following: rest tremor and/or rigidity

    2. Asymmetric onset of clinical signs

    3. Progressive motor symptoms

    4. Age at onset 35-85 years

    5. Duration of PD symptoms of at least 3 years

    6. Female subjects must be either:

    1. Not pregnant, not breastfeeding, and not planning on becoming pregnant during the study;
    2. 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
    3. 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.

      7. Must be stage 4 or less according to the Hoehn and Yahr scale

      Exclusion Criteria:

  • 1. 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

    2. Neuroleptic treatment at time of onset of parkinsonism

    3. Active treatment with a neuroleptic at time of study entry

    4. History of repeated strokes with stepwise progression of parkinsonism

    5. History of repeated head injury

    6. History of definite encephalitis

    7. More than one blood relative diagnosed with PD

    8. Prominent gait imbalance early in the course (< 5 years)

    9. Mini-mental state examination score <26

    10. Hematological malignancy or coagulopathy

    11. 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

    12. Serious medical illness or co-morbidity that may interfere with participation in the study

    13. Brain surgery for parkinsonism (DBS, cell implantation, gene therapy)

    14. History of an autoimmune disorder or systemic inflammatory disorder deemed significant by physician

    15. Immunostimulatory or immunosuppressive treatment (including amphet-amines or systemic corticosteroids) within 90 days

    16. Exclusively unilateral parkinsonism for longer than 3 years

    17. Known hypersensitivity to GM-CSF, yeast-derived products

    18. Current lithium treatment

    19. Individuals with current diagnoses of alcohol or substance abuse/dependence

    20. Anyone who is not appropriate for participation in this research protocol as deemed by the principal or co-investigator

    21. Anyone who has previously been treated with GM-CSF as an immunomodulatory therapy

    22. Anyone with poor venous access


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03790670


Contacts
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Contact: Katherine Olson, PhD 4025592547 katherine.olson@unmc.edu
Contact: Melinda Wojtkiewicz, B.S 402-559-0856 melinda.wojtkiewicz@unmc.edu

Locations
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United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Howard Gendelman       hegendel@unmc.edu   
Contact: Katherine Olson    4025592547    katherine.olson@unmc.edu   
Sponsors and Collaborators
University of Nebraska
Investigators
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Principal Investigator: Howard Gendelman, MD UNMC
Publications:
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Responsible Party: Howard Gendelman, MD, Principal Investigator, University of Nebraska
ClinicalTrials.gov Identifier: NCT03790670    
Other Study ID Numbers: 839-18-FB
First Posted: January 2, 2019    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Sargramostim
Immunologic Factors
Physiological Effects of Drugs