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Biomarker Assessments of Leukine During Treatment of Parkinson's Disease

Primary Purpose

Parkinson Disease

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
sargramostim
Sponsored by
University of Nebraska
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Parkinson Disease

Eligibility Criteria

35 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Nebraska Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Leukine Treatment

Arm Description

36 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)

Outcomes

Primary Outcome Measures

Incidence of Treatment-Associated Adverse Events
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

Determination of Immune Cell Phenotype
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.
Determination of Immune Cell Number
Measurements will include changes in levels of lymphocytes or CD4+ T cells, as well as T cell, B cell, and bone marrow progenitor subsets.
Determination of Immune Cell Function
Measurements will include changes in T cell function via proliferation and suppression assays and/or changes in B cell function via antibody production assessments.

Full Information

First Posted
December 18, 2018
Last Updated
September 28, 2023
Sponsor
University of Nebraska
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1. Study Identification

Unique Protocol Identification Number
NCT03790670
Brief Title
Biomarker Assessments of Leukine During Treatment of Parkinson's Disease
Official Title
Safety, Tolerability and Biomarker Assessments of Leukine (Sargramostim) During Extended Timed Treatment for Parkinson's Disease: A Phase I Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 30, 2019 (Actual)
Primary Completion Date
October 30, 2023 (Anticipated)
Study Completion Date
December 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Nebraska

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
First, the investigators will determine the safety of a 36 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 36 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 36 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.
Detailed Description
Primary Objectives: There are three study goals. First, the investigators will determine the safety of a 36 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 36 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 36 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Parkinson Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Leukine Treatment
Arm Type
Experimental
Arm Description
36 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)
Intervention Type
Drug
Intervention Name(s)
sargramostim
Other Intervention Name(s)
Leukine
Intervention Description
Recombinant human GM-CSF produced by recombinant DNA technology using a yeast (S. cerevisiae) expression system
Primary Outcome Measure Information:
Title
Incidence of Treatment-Associated Adverse Events
Description
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.
Time Frame
monthly during the course of treatment, up to 36 months, followed by 1 month drug cessation
Secondary Outcome Measure Information:
Title
Determination of Immune Cell Phenotype
Description
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.
Time Frame
36 months of treatment, followed by 1 month drug cessation
Title
Determination of Immune Cell Number
Description
Measurements will include changes in levels of lymphocytes or CD4+ T cells, as well as T cell, B cell, and bone marrow progenitor subsets.
Time Frame
36 months of treatment, followed by 1 month drug cessation
Title
Determination of Immune Cell Function
Description
Measurements will include changes in T cell function via proliferation and suppression assays and/or changes in B cell function via antibody production assessments.
Time Frame
36 months of treatment, followed by 1 month drug cessation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility 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: 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. 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Howard Gendelman, MD
Organizational Affiliation
University of Nebraska
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28649610
Citation
Gendelman HE, Zhang Y, Santamaria P, Olson KE, Schutt CR, Bhatti D, Shetty BLD, Lu Y, Estes KA, Standaert DG, Heinrichs-Graham E, Larson L, Meza JL, Follett M, Forsberg E, Siuzdak G, Wilson TW, Peterson C, Mosley RL. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson's disease trial. NPJ Parkinsons Dis. 2017 Mar 23;3:10. doi: 10.1038/s41531-017-0013-5. eCollection 2017.
Results Reference
background
PubMed Identifier
23054369
Citation
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.
Results Reference
background
PubMed Identifier
24210793
Citation
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.
Results Reference
background
PubMed Identifier
34000620
Citation
Olson KE, Namminga KL, Lu Y, Schwab AD, Thurston MJ, Abdelmoaty MM, Kumar V, Wojtkiewicz M, Obaro H, Santamaria P, Mosley RL, Gendelman HE. Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease. EBioMedicine. 2021 May;67:103380. doi: 10.1016/j.ebiom.2021.103380. Epub 2021 May 14.
Results Reference
derived

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Biomarker Assessments of Leukine During Treatment of Parkinson's Disease

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